contact dermatitis 5th ed - j. johansen, et al., (springer, 2011)

The popular dictionary of contact allergens and lists of patch test concentrations have been expanded and provide the tool for evidence-based investigation and infor-mation of patients w

Contact Dermatitis

Fifth Edition

Jeanne Duus Johansen • Peter J Frosch Jean-Pierre Lepoittevin

Editors

Contact Dermatitis

Fifth Edition

ISBN: 978-3-642-03826-6 e-ISBN: 978-3-642-03827-3

DOI: 10.1007/978-3-642-03827-3

Springer Heidelberg Dordrecht London New York

Library of Congress Control Number: 2010923774

© Springer-Verlag Berlin Heidelberg 2011

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Copenhagen University Hospital Gentofte

National Allergy Research Centre

Institut le Bel, Labo Dermatochimie

4, rue Blaise Pascal

67070 Strasbourg cedex France

jplepoit@unistra.fr

Peter J Frosch

Preface to the Fifth Edition

This is the fifth edition of the book since 1992 A lot of changes have been made over the years, but the biggest transformation came with the fourth edition in 2005: many new chapters, easy overview, and core messages providing all the clinical photos and dia-grams All these advantages have been retained for the fifth edition, where an extensive update of chapters has been made including new versions and authors for several topics Contact dermatitis is one of the major problems in occupational skin diseases This is reflected in the book, where new chapters on occupational contact dermatitis have been written: a general chapter, which gives an overview of the subject, provides clear definitions and gives valuable guidance for the investigation of patients sus-pected of occupational contact dermatitis; followed by specific chapters on three high-risk professions

The popular dictionary of contact allergens and lists of patch test concentrations have been expanded and provide the tool for evidence-based investigation and infor-mation of patients with contact dermatitis

Contact dermatitis is a frequent, disabling and expensive disease This brings both primary and secondary prevention in focus of research A solid basis has already been established for intervention on a personal, organizational and regulatory level The significant level of knowledge in these areas is summarised in three new chapters, which also cover therapy, a previous somewhat neglected subject in the book Other chapters on different aspects of prevention have gone through a significant updation and revision Basic understanding of pathophysiology within the fields of genes, skin barrier and chemistry has taken a leap forward and these new developments are reflected in new and former chapters of the book

With this edition, Torkil Menné has resigned from the editorial group Torkil Menné was one of the initiators of this textbook and has been part of the editorial board since then The editors would like to express their sincere thanks to Torkil Menné for his invaluable contributions to the book and to the field of contact derma-titis over many years

The fourth edition was a great success, and even though it seemed an impossible task to surpass it, we think we have done so with the fifth edition This has, of course, only been possible with the help of the many great contributors and the editors are very grateful to each and every one of them

Last but not the least, we would like to thank Springer-Verlag for their excellent support to this project

1 Historical Aspects 1Jean-Marie Lachapelle

Part I Basic Features

2 Genetics and Individual Predispositions in Contact Dermatitis 13Axel Schnuch and Berit Christina Carlsen

3 Mechanisms of Irritant and Allergic Contact Dermatitis 43Thomas Rustemeyer, Ingrid M.W van Hoogstraten,

B Mary E von Blomberg, Sue Gibbs, and Rik J Scheper

4 Molecular Aspects in Allergic and Irritant Contact Dermatitis 91Jean-Pierre Lepoittevin

5 Bio-Guided Fractionation and Identification of Allergens

in Complex Mixtures and Products 111

Elena Giménez-Arnau

6 Role of the Permeability Barrier in Contact Dermatitis 121

Ehrhardt Proksch and Jochen Brasch

7 Immediate Contact Reactions 137

David Basketter and Arto Lahti

8 Mechanisms of Phototoxic and Photoallergic Reactions 155

Renz Mang, Helger Stege, and Jean Krutmann

Part II Pathology

9 Histopathological and Immunohistopathological

Features of Irritant and Allergic Contact Dermatitis 167

Jean-Marie Lachapelle and Liliane Marot

Contents

10 Ultrastructure of Irritant and Allergic Contact Dermatitis 179

Carolyn M Willis

11 Epidemiology 193

Pieter-Jan Coenraads, Wolfgang Uter,

and Thomas Diepgen

Part III Dermatotoxicology

12 Skin Penetration 215

Hans Schaefer, Thomas E Redelmeier, and Jürgen Lademann

13 Predictive Tests for Irritants and Allergens and Their

Use in Quantitative Risk Assessment 229

David Basketter and Ian Kimber

14 Allergic Contact Dermatitis in Humans: Experimental

and Quantitative Aspects 241

Jeanne Duus Johansen, Peter J Frosch, and Torkil Menné

Part IV Clinical Features

15 Clinical Features 255

Niels K Veien

16 Clinical Aspects of Irritant Contact Dermatitis 305

Peter J Frosch and Swen Malte John

17 Systemic Contact Dermatitis 347

Niels K Veien and Torkil Menné

18 Phototoxic and Photoallergic Reactions 361

21 Protein Contact Dermatitis 407

An Goossens and Cristina Amaro

22 Noneczematous Contact Reactions 415

Anthony Goon and Chee-Leok Goh

23 Respiratory Symptoms from Fragrances and the Link with Dermatitis 429

Jesper Elberling

Part V Diagnostic Tests

24 Patch Testing 439

Magnus Lindberg and Mihaly Matura

25 Atopy Patch Testing with Aeroallergens and Food Proteins 465

Ulf Darsow and Johannes Ring

26 Patch Testing in Adverse Drug Reactions 475

Margarida Gonçalo and Derk P Bruynzeel

27 Allergens Exposure Assessment 493

Birgitta Gruvberger, Magnus Bruze, Sigfrid Fregert, and Carola Lidén

28 Skin Tests for Immediate Hypersensitivity 511

Part VI Allergic Contact Dermatitis Related to Specific Exposures

31 Allergens from the European Baseline Series 545

Klaus E Andersen, Ian R White, and An Goossens

32 Cosmetics and Skin Care Products 591

Jonathan M.L White, Anton C de Groot, and Ian R White

35 Metals 643

Carola Lidén, Magnus Bruze, Jacob Pontoppidan Thyssen,

and Torkil Menné

36 Metalworking Fluids 681

Johannes Geier and Holger Lessmann

37 Plastic Materials 695

Bert Björkner, Malin Frick-Engfeldt, Ann Pontén,

and Erik Zimerson

An Goossens and James S Taylor

42 Occupational Contact Dermatitis 831

Peter J Frosch and Katrin Kügler

43 Occupational Contact Dermatitis: Health Personnel 841

46 Plants and Plant Products 873

Christophe J Le Coz, Georges Ducombs, and Evy Paulsen

47 Pesticides 927

Carola Lidén

48 Contact Allergy in Children 937

Marie-Anne Morren and An Goossens

49 Therapy and Rehabilitation of Allergic

and Irritant Contact Dermatitis 963

Dimitar Antonov, Sibylle Schliemann, and Peter Elsner

50 Prevention of Hand Eczema: Gloves, Barrier Creams and Workers’ Education 985

Britta Wulfhorst, Meike Bock, Christoph Skudlik, Walter Wigger-Alberti, and Swen Malte John

51 Prevention of Allergic Contact Dermatitis: Safe Exposure Levels of Sensitizers 1017

Jacob Pontoppidan Thyssen and Torkil Menné

52 Legislation 1023

Ian R White and David Basketter

53 International Comparison of Legal Aspects of Workers’

Compensation for Occupational Contact Dermatitis 1029

Peter J Frosch, Werner Aberer, Paul J August, Tove Agner, Lieve Constandt, L Conde-Salazar, Swen M John,

Christophe Le Coz, Howard I Maibach, Haydn L Muston, Rosemary L Nixon, Hanspeter Rast, W.I van Tichelen, Jason Williams, Patricia Engasser, Felipe Heras, Magnus Lindberg, and Antti Laurema

54 Databases and Networks The Benefit of Research and Quality Assurance in Patch Testing 1053

Wolfgang Uter, Axel Schnuch, Ana Giménez-Arnau, David Orton, and Barry Statham

55 Contact Dermatitis Research Groups 1065

Derk P Bruynzeel

56 Patch Test Concentrations and Vehicles for Testing Contact Allergens 1071

Anton C De Groot and Peter J Frosch

57 Patch Testing with the Patients’ Own Products 1107

Peter J Frosch, Johannes Geier, Wolfgang Uter, and An Goossens

58 Dictionary of Contact Allergens: Chemical Structures, Sources, and References 1121

Christophe J Le Coz and Jean-Pierre Lepoittevin

Index 1249

J.D Johansen et al (eds.), Contact Dermatitis,

DOI: 10.1007/978-3-642-03827-3_1, © Springer-Verlag Berlin Heidelberg 2011

1.1 Introduction

Contact dermatitis, an inflammatory skin reaction to direct contact with noxious agents in the environment, was most probably recognized as an entity even in ancient times, since it must have accompanied man-kind throughout history Early recorded reports include Pliny the Younger who, in the first century a.d., noticed that some individuals experienced severe itching when cutting pine trees A review of the ancient literature could provide dozens of similar, mostly anecdotal, examples, and some are cited in modern textbooks, monographs, and papers

It is interesting to note that the presence of syncrasy was suspected in some cases of contact derma titis reported in the nineteenth century, many decades before the discovery of allergy by von Pirquet

idio-For instance, in 1829, Dakin, describing Rhus

derma-titis, observed that some people suffered from the ease, whereas others did not He therefore posed the question: “Can it be possible that some peculiar struc-ture of the cuticule or rete mucosum constitutes the idiosyncrasy?”

dis-The history of contact dermatitis in the twentieth century is indistinguishable from the history of patch testing, which is considered the main tool for unmask-ing the causative chemical culprits Nevertheless, start-ing in the early 1980s, additional tests (within the scope of patch testing) have been introduced, such as the open test, the semi-open test, the repeated open application test (ROAT) and its variants, referred to as

“use tests.” Moreover, prick testing, which has been underestimated for decades in dermato-allergology, has gained popularity, as an investigatory tool for immediate contact hypersensitivity

Historical Aspects

Jean-Marie Lachapelle

J.-M Lachapelle

Department of Dermatology, Catholic University of Louvain,

30, Clos Chapelle-aux-Champs, UCL 3033, 1200 Brussels,

1.2.1 The Pre-Jadassohn Period 2

1.2.2 Josef Jadassohn, the Father of Patch

Testing in Dermatology 2

1.2.3 Jean-Henri Fabre’s Experiments 3

1.2.4 A General Overview of Patch Testing

During the Period 1895–1965 4

1.2.5 Bruno Bloch’s Pioneering Work

in Basel and in Zurich 4

1.2.6 The Influence of Poul Bonnevie

in Scandinavian Countries 5

1.2.7 A Controversial Period: The Pros

and Cons of a Standard Series 6

1.2.8 Marion Sulzberger, the Initiator of Patch

Testing in North America and Alexander

Fisher, a World Leader in the Field

of Contact Dermatitis 6

1.2.9 The Founding of Groups 6

1.2.10 The Founding of the European Environmental

and Contact Dermatitis Research Group

(EECDRG) and the European Society

of Contact Dermatitis (ESCD) 7

1.2.11 Dermatochemistry and Contact Dermatitis 7

1.2.12 Recent Advances in the Management

of Patch Testing 7

1.2 Historical Aspects of Patch Testing

Historical aspects of patch testing are reviewed by

Foussereau [1] and Lachapelle [2] A selection of

important forward steps has been made for this short

survey

1.2.1 The Pre-Jadassohn Period

During the seventeenth, eighteenth, and nineteenth

centuries [1], some researchers occasionally

repro-duced contact dermatitis by applying the responsible

agent (chemical, plant, etc.) to intact skin Most of the

observations are anecdotal, but some deserve special

attention

In 1847, Städeler [3] described a method devised to

reproduce the lesions provoked by Anacardium

occi-dentale (Städeler’s blotting paper strip technique) on

human skin, which can be summarized as follows:

“Balsam is applied to the lower part of the thorax on an

area measuring about 1 cm2 Then, a piece of blotting

paper previously dipped in the balsam is applied to the

same site Fifteen minutes later, the subject

experi-ences a burning sensation, which increases very

rap-idly and culminates after about half an hour The skin

under the blotting paper turns whitish and is

sur-rounded by a red halo As the burning sensation

decreases, the blotting paper is kept in place for 3 h.”

This observation is important because it was the first

time that any test was actually designed and described

in full detail [1]

In 1884, Neisser [4] reviewed a series of eight cases

of iodoform dermatitis triggered by a specific

influ-ence Neisser wrote that it was a matter of

idiosyn-crasy, dermatitis being elicited in these cases by

iodoform application The symptoms were similar to

those subsequent to the application of mercurial

deriv-atives, and a spread of the lesions that was much wider

than the application site was a common feature to both instances

In retrospect, this presentation can be considered an important link between casuistical writings of older times and a more scientifically orientated approach of skin reactions provoked by contactants It was a half-hidden event that heralded a new era, which blossomed

at the end of the nineteenth century

1.2.2 Josef Jadassohn, the Father

of Patch Testing in Dermatology

Josef Jadassohn (Fig 1.1) is universally acknowledged as

the father of patch testing (“Funktionelle Hautprüfung”),

a new diagnostic tool offered to dermatologists [5] At the time of his discovery, Jadassohn was a young Professor

of Dermatology at Breslau University (Germany); he most probably applied and expanded – in a practical way

Fig 1.1 Josef Jadassohn (1863–1936) (used with kind sion from the Institut für Geschichte der Medizin der Universität Wien)

permis-Core Message

Historical aspects of contact dermatitis are

›

indistinguishable from those of patch testing

and prick testing

caus-– the observations and interpretations previously made by

his teacher Neisser [4] Summing up the different sources

of information available, we can reasonably assume that:

(1) the birthday and birthplace of the patch test is Monday,

23 September 1895 at the Fünfter Congress der Deutschen

Dermatologischen Gesellschaft held in Graz (Austria),

where Jadassohn made his oral presentation “Zur Kenntnis

der medicamentösen Dermatosen”; (2); the birth

certifi-cate is dated 1896, when the proceedings of the meeting

were published [6

As recorded by Sulzberger in 1940 in his classic

textbook [7], the key message of Jadassohn’s paper

was the fact that he recognized the process of delayed

hypersensitivity to simple chemicals:

When put together, those two observations reflect a

double-winged discovery: the local elicitation of a

mercury reaction and the local elicitation of

refractori-ness to reaction

Concerning the technical aspects of the “Funktionelle

Hautprüfung,” the methodology was quite simple:

gray mercury ointment was applied on the skin of the

upper extensor part of the left arm and covered by a

5-cm2 piece of tape for 24 h Many comments can be

made at this point: (1) from the beginning, the patch

test appears as a “closed” or occlusive testing

tech-nique, (2) the size of the patch test material is large

(2.3–2.3 cm) compared to the current available als, (3) the amount of ointment applied is not men-tioned (the technique is therefore considered as qualitative), and (4) the duration of the application is limited in the present case to 24 h

materi-It should be remembered that soon after ing the patch test, Jadassohn was appointed as the Professor of Dermatology (1896) at the University of Bern (Switzerland) where he stayed for several years, before coming back (in 1917) to his native Silesia, in Breslau again One of his major accomplishments there was the observation of a specific anergy in patients suffering from sarcoidosis or Hodgkin’s dis-ease, for example

develop-1.2.3 Jean-Henri Fabre’s Experiments

Another description of a patch test technique was given by the French entomologist Jean-Henri Fabre (1823–1915), who lived in Sérignan-du-Comtat,

a village in Provence (Fig 1.2) This work was

Fig 1.2 Jean-Henri Fabre, French entomologist (1823–1915)

1 In his original publication, Jadassohn describes

the following two occurrences: A syphilitic

patient received an injection of a mercurial

preparation and developed a mercurial

derma-titis which involved all parts of the skin except

a small, sharply demarcated area It was found

that the spared area was the site previously

occupied by a mercury plaster which had been

applied in the treatment of a boil

2 In a second observation, a patient who had

received an injection of a mercurial preparation

developed an acute eczematous dermatitis

which was confined to the exact sites to which

gray ointment (Hg) had been previously applied

in the treatment of pediculosis pubis In this

patient, the subsequent application of a patch

test (Funktionelle Hautprüfung) with gray

oint-ment to unaffected skin sites produced an

eczematous reaction consisting of a severe

erythematous and bullous dermatitis

1 contemporaneous with Jadassohn’s experiments, but it is described here because it was not designed

pri-marily for dermatological diagnosis [8] Fabre

reported in 1897 (in the sixth volume of the

impres-sive encyclopedia Souvenirs entomologiques,

trans-lated into more than 20 languages) that he had studied

the effect of processionary caterpillars on his own

skin A square of blotting paper, a novel kind of

plas-ter, was covered by a rubber sheet and held in place

with a bandage The paper used was a piece of

blot-ting paper folded 4 times, so as to form a square with

1-in sides, which had previously been dipped into an

extract of caterpillar hair The impregnated paper

was applied to the volar aspect of the forearm The

next day, 24 h later, the plaster was removed A red

mark, slightly swollen and very clearly outlined,

occupied the area that had been covered by the

“poisoned” paper

In these and further experiments, he dissected

vari-ous anatomical parts of the caterpillars in order to

iso-late noxious ones (barbed hairs) that provoked burning

or itching Rostenberg and Solomon [9] have

empha-sized the importance of Fabre’s methodology to

dermatology, so often used in the past decades by

der-mato-allergologists For instance, many similar

attempts were made during the twentieth century to

isolate noxious agents (contact allergens and irritants),

not only from different parts of plants, woods, and

ani-mals, but also from various other naturally occurring

substances and industrial products encountered in our

modern environment

In my view, Fabre’s experiments are gratifying

for an additional reason: they reproduce another

common skin reaction of exogenous origin, contact

urticaria [10] It is well known today that a protein,

thaumetopoietin (molecular weight 28 kDa), is

responsible for the urticarial reaction In an attempt

to reproduce Fabre’s experiments, I applied

caterpil-lars’ barbed hairs to my skin, using a plastic square

chamber designed by Van der Bend as patch test

material, which was kept in place for 2 h After the

removal of the patch, two types of reactions were

recorded consecutively: (1) at 20 min, an urticarial

reaction (considered to be nonimmunological),

which faded slowly during the next 2 h, and (2) at

day 2, an eczematous reaction, spreading all around

the application site and interpreted as an

experimen-tally induced immunological protein contact

of each allergen, the time of reading, the reading score, etc., and (3) differential diagnosis between irritant and allergic contact dermatitis was very often unclear

It is no exaggeration to say that patch testers were acting like skilled craftsmen [11], though – step by step – they provided new information on contact dermatitis.When covering this transitional period, we should recall the names of some outstanding dermatologists who directly contributed to our present knowledge and

to the dissemination of the patch test technique throughout the world

1.2.5 Bruno Bloch’s Pioneering Work in Basel and in Zurich

Bruno Bloch is considered by the international nity as one of the more prominent pioneers in the field

commu-of patch testing, continuing and expanding Jadassohn’s clinical and experimental work In many textbooks or papers, patch testing is often quoted as the Jadassohn–Bloch technique

The major contributions made by Bloch to patch testing are the following:

he was working on processionary caterpillars

1 When he was in Basel, in 1911, he described [12] in detail the technique of patch testing The allergen should be applied to a linen strip

As far as we can understand by consulting various

sources of information, Bruno Bloch acted as a group

leader for promoting and disseminating the idea of

applying a limited standard series in each patient This

was made in close connection with Jadassohn in

Breslau (his former teacher when he was in Bern),

Blumenthal and Jaffé in Berlin, and – later on –

Sulzberger in New York In Bloch’s clinic, Hans

Stauffer and Werner Jadassohn worked on determining

the adequate concentration and vehicle for each

Allergen Concentration (%) Vehicle

Balsam of Peru 25 Lanolin Salicylic acid 5 Lanolin

Mercuric chloride 0.1 Water Potassium dichromate 0.5 Water

Primula obconica As is Sodium perborate 10 Water Brown soap As is

Coal tar Pure Wood tars Pure Quinine chlorhydrate 1 Water

expan-which is put on the back, covered with a slightly

larger piece of gutta- percha and fixed in place

with zinc oxide adhesive plaster; the test should

then be left for 24 h The size of the patch was

chosen to be 1 cm2 For the first time in the

his-tory of patch testing, he graded the stages of

the skin reaction from simple erythema to

necrosis and ulceration, and stressed that a

nor-mal and a sensitized subject differ

fundamen-tally in that only the latter reacts

2 In collaboration with the chemist Paul Karrer,

who first synthesized vitamin C and received

the Nobel Prize in 1937, Bloch discovered and

successfully synthesized primin, the specific

chemical in Primula obconica that is

responsi-ble for allergic contact dermatitis in persons

contacting the common plant [13]

3 He also conceived the concept of

cross-sensiti-zation in contact dermatitis by studying the

reactivity patterns of iodoform, a commonly

used topical medication at that time

4 He described the first cases of systemic contact

dermatitis, illustrated forever by moulages

of the Zurich collection (moulageur: Lotte

Volger)

5 The idea of developing a standard series of

allergens was also developed extensively by

Bruno Bloch in Zurich [14] The substances

with which standard tests were made were the

following: formaldehyde (1–5%), mercury (1%

sublimate or ointment of white precipitate of

mercury), turpentine, naphthalene (1%),

tinc-ture of arnica, P obconica (piece of the leaf),

adhesive plaster, iodoform (powder), and

qui-nine hydrochloride (1%)

1 on the experience gained at the Finsen Institute in Copenhagen regarding the occurrence of positive

reactions to various chemicals among patch-tested

patients It is remarkable that the list was used in

Copenhagen without any change from 1938 to 1955,

which allowed Marcussen to publish, in 1962 [16], a

most impressive epidemiological survey concerning

time fluctuations in the relative occurrence of contact

allergies Of the 21 allergens listed by Bonnevie, seven

are still present in the standard series of patch tests

used currently

1.2.7 A Controversial Period: The Pros

and Cons of a Standard Series

In the 1940s and 1950s, the standard series did not

blossom throughout Europe Some authors refused to

adhere to the systematic use of a standard series in all

patients and championed the concept of “selected

epi-cutaneous tests.” Two former assistants of Bruno

Bloch, Hans Stauffer and Werner Jadassohn, were

par-ticularly keen on this concept of selection

Werner Jadassohn (son of Josef), Professor of

Dermatology at Geneva University, had a strong

influ-ence on many colleagues in this respect The principle

of “choice” or “selection” was based upon a careful

recording of anamnestic data, especially in the field of

occupational dermatology [17]

A similar view was defended in France by

Foussereau; [18] this was a source of intense debates at

meetings This discussion is obsolete nowadays due to

a general agreement as regards the practical interest of

using standard and additional patch test series in daily

practice

1.2.8 Marion Sulzberger, the Initiator of Patch Testing in North America and Alexander Fisher, a World Leader in the Field of Contact Dermatitis

Sulzberger was one of the most brilliant assistants of Bruno Bloch in Zurich, and later of Josef Jadassohn in Breslau In both the places, he was considered as the beloved American fellow worker When Sulzberger came back to New York and became one of the Professors of Dermatology there, he modified consid-erably the spirit of the discipline, which was at that time very static in the New World

But it is acknowledged that the “master” in the field of contact dermatitis and patch testing in the United States is Alexander Fisher, through more than

50 years of pioneering work in New York City He has become more closely identified with this subject than any other physician in the world He has pub-lished countless papers, describing his methodology

in the search of new contact allergens, and also gesting hypoallergenic substitutes This proved to be

sug-a very useful sug-and stimulsug-ating sug-approsug-ach; when ing, he often recalled attention on “doing so patients are not doomed to repeated attacks.” His famous book: “Contact Dermatitis,” now in its sixth edition, actualized by Rietschel and Fowler [19], is an undis-puted source of insight for all clinicians

lectur-1.2.9 The Founding of Groups

A Scandinavian Committee for Standardization of Routine Patch Testing was formed in 1962 In 1967, this committee was enlarged, resulting in the formation

Core Message

Poul Bonnevie is the author of the first modern

›

textbook on occupational dermatology The

key role played by a standard series of patch

tests for investigating contact dermatitis is

obvious in his personal approach

of the International Contact Dermatitis Research Group

(ICDRG) The founder members of the ICDRG were

Bandmann, Calnan, Cronin, Fregert, Hjorth,

Magnusson, Maibach, Malten, Meneghini, Pirilä, and

Wilkinson The major task for its members was to

stan-dardize at an international level the patch testing

proce-dure, for example, the vehicles used for allergens, the

concentration of each allergen, and so on

Niels Hjorth (1919–1990) in Copenhagen was the

vigorous chairman of the ICDRG for more than 20-years

He organized the first international symposium on

con-tact dermatitis at Gentofte, Denmark, in October 1974;

this symposium was followed by many others, which

led to an increasing interest in contact dermatitis

throughout the world, and, consequently, to the

estab-lishment of numerous national and/or international

con-tact dermatitis groups Hjorth’s contribution to promoting

our knowledge of contact dermatitis was enormous; it is

true to say that he ushered in a new era in environmental

dermatology All the contributors to this textbook are

greatly indebted to him; he showed us the way forward

Etain Cronin wrote in 1980 an extensive book

enti-tled “Contact Dermatitis” [20], which can be compared

in its spirit to Alexander Fisher’s textbook

In the meantime, in the United States, the North

American Contact Dermatitis Group (NACDG) was

founded, working towards similar aims Howard Maibach

acted as a constant link between both the groups

1.2.10 The Founding of the European

Environmental and Contact

Dermatitis Research Group

(EECDRG) and the European Society

of Contact Dermatitis (ESCD)

During the 1980s, an increasing interest for all facets of

contact dermatitis was evident in many European

coun-tries This led some dermatologists and basic scientists

to join their efforts to improve knowledge in the field

The EECDRG was born and the first meeting initiated

by John Wilkinson, took place at Amersham, England (28 June to 1 July, 1985) Later, two meetings were organized each year At that time, the members of the group were: Andersen, Benezra, Brandao, Bruynzeel, Burrows, Camarasa, Ducombs, Frosch, Goossens, Hannuksela, Lachapelle, Lahti, Menné, Rycroft, Scheper, Wahlberg, White, and Wilkinson The main goal was to perform joint studies to clarify the allerge-nicity (and/or irritant potential) of different chemicals Studies were planned following the principles of “new-born” evidence-based dermatology The adventure was fruitful and many joint papers were published

From the early days of its founding, the group felt the need to disseminate the acquired expertise to other experienced colleagues Peter Frosch was the leader of this new policy, by organizing a Symposium in Heidelberg, Germany in May 1988, that – obviously – was a great success This event was the starting point

of the ESCD The new society was involved in the organization of congresses, on a 2-year schedule The first congress took place in Brussels, Belgium in 1992, under the chair of Jean-Marie Lachapelle and has been followed by nine others, so far!

Additional aims of the Society were: the

publica-tion of the Textbook of Contact Dermatitis (first edipublica-tion

in 1992) and the creation of subgroups of specialists, devoted to the study of specific research projects The

Journal Contact Dermatitis is the official publication

of the ESCD

1.2.11 Dermatochemistry

and Contact Dermatitis

The introduction of dermatochemistry in the scope of contact dermatitis proved to be of uppermost interest The leader in the field was Claude Benezra in Strasbourg (France) After his premature accidental death, new developments were achieved by his succes-sor, Jean-Pierre Lepoittevin

1.2.12 Recent Advances in the

Management of Patch Testing

Recent history has forwarded some new insights to reach a better significance of patch test results, either positive or negative First of all, in case of doubt,

Core Message

The founding of groups played a great part in

›

the development and standardization of patch

testing throughout the world

1 additional tests are available, among which the ROAT, standardized by Hannuksela and Salo [21] and

com-pleted by other variants of use tests, provides a more

accurate answer in some difficult cases

In addition, efforts have been made to determine

more precisely the relevance (or non relevance) of

pos-itive patch test results [22], which is the ultimate goal

in dermato-allergology

Much attention has been paid to the dose–response

relationships in the elicitation of contact dermatitis, a

concept that modifies our views in the matter

A new ready-to-use patch test system, the TRUE

test, was introduced in 1985 by Fischer and Maibach

[23] It represents a more sophisticated approach in the

technology of patch testing, taking into account the

parameter of optimal penetration and delivery of

aller-gens through the skin The alleraller-gens are incorporated

in hydrophilic gels The gel is adapted to each

indi-vidual allergen For protection against light and air, the

strips are contained in airtight and opaque aluminum

poaches

TRUE test represents an alternative way of patch

testing [24], which intends to avoid variations of the

allergens applied on the skin

1.3 Historical Aspects of Prick

Testing

The historical aspects of prick testing are rather

diffi-cult to circumscribe

Blackley [25] was probably the first to suggest that

allergens could be introduced into the skin to detect

sensitization Schloss [26] used a scratch technique in

the studies of food allergy between 1910 and 1920

The “codified” methodology of prick testing was

described as early as 1924 by Lewis and Grant, but

became widely used only after its modification by

Pepys [27], almost exclusively by allergologists and

pneumologists

In dermato-allergology, it was introduced routinely

in the late 1980s, in relation to expanding knowledge

on contact urticaria, immediate allergy to latex

pro-teins, and also protein contact dermatitis considered a

well-defined entity

Nowadays, it is an undisputed tool of investigation

in the field of contact dermatitis

References

1 Foussereau J (1984) History of epicutaneous testing: the blotting–paper and other methods Contact Dermat 11: 219–223

2 Lachapelle JM (1996) A century of patch testing First Jadassohn Lecture (ESCD) Jadassohn’s Centenary Congress, London, 9–12 Oct 1996

3 Städeler J (1847) Über die eigenthümlichen Bestandtheile der Anacardium Früchte Ann Chemie Pharmacie 63: 117–165

4 Neisser A (1884) Über Jodoform-Exantheme Dtsch Med Wochenschr 10:467–468

5 Adams RM (1993) Profiles of greats in contact dermatitis I: Josef Jadassohn (1863–1936) Am J Contact Dermat 4: 58–59

6 Jadassohn J (1896) Zur Kenntnis der medicamentösen matosen Verhandlungen der Deutschen Dermatologischen Gesellschaft, V Congress, Vienna (1895) Braumüller, Vienna,

11 Sézary A (1936) Méthodes d’exploration biologique de la peau Les tests cutanés en dermatologie Encyclopédie médico-chirurgicale, Paris, 12010, pp 1–8

12 Bloch B (1911) Experimentelle Studien über das Wesen der Jodoformidiosynkrasie Z Exp Pathol Ther 9:509–538

13 Bloch B, Karrer P (1927) Chemische und biologische suchungen über die Primelidiosynkrasie Beibl Vierteljahrs-

Unter-s chr NaturforUnter-sch GeUnter-sell Zürich 72:1–25

14 Bloch B (1929) The role of idiosyncrasy and allergy in matology Arch Dermatol Syphilis 19:175–197

der-15 Bonnevie P (1939) Aetiologie und Pathogenese der krankheiten Klinische Studien über die Ursachen der Ekzeme unter besonderer Berücksichtigung des Diagnostischen Wertes der Ekzemproben Busch, Copenhagen/Barth, Leipzig

Ekzem-16 Marcussen PV (1962) Variations in the incidence of contact hypersensitivities Trans St Johns Hosp Dermatol Soc 48: 40–49

17 Jadassohn W (1951) A propos des tests épicutanés “dirigés” dans l’eczéma professionnel Praxis 40:1–4

18 Foussereau J, Benezra C (1970) Les eczémas allergiques professionnels Masson, Paris

consid-19 Rietschel RL, Fowler JF Jr (2008) Fisher’s contact

dermati-tis, 6th edn BC Decker, Hamilton, Ontario

20 Cronin E (1980) Contact dermatitis Churchill Livingstone,

Edinburgh

21 Hannuksela M, Salo H (1986) The repeated open application

test (ROAT) Contact Dermat 14:221–227

22 Lachapelle JM, Maibach HI (2009) Clinical relevance of

patch test reactions, Chapter 8 In: Lachapelle JM, Maibach

HI (eds) Patch testing and prick testing A practical guide

Springer, Berlin, pp 113–120

23 Fischer T, Maibach HI (1985) The thin layer rapid use

epicu-taneous test (TRUE Test), a new patch test method with high

accuracy Br J Dermatol 112:63–68

24 Fischer T, Kreilgard B, Maibach HI (2001) The true value of the TRUE test for allergic contact dermatitis Curr Allergy Asthma Reports 1:316–322

25 Blackley CH (1873) Experimental research on the causes and nature of catarrhus aestivus Baillere, Tindall and Cox, London

26 Schloss OM (1920) Allergy in infants and children Am

J Dis Child 19:433–436

27 Pepys J (1975) Skin testing Br J Hosp Med 14:412

I Part

Basic Features

J.D Johansen et al (eds.), Contact Dermatitis,

DOI: 10.1007/978-3-642-03827-3_2, © Springer-Verlag Berlin Heidelberg 2011

Abbreviations

AFMU 5-acetylamino-6-formylamino-

3-methyluracilACD Allergic contact dermatitisACE Angiotensin-converting enzyme

AD Atopic dermatitisAla Alanin

D Deletion

DC Dendritic cellDNCB 2,4 dinitrochlorobenzeneDTH Delayed-type hypersensitivity

DZ DizygoteFLG FilaggrinGST Glutathione S-transferase

GWAS Genome wide association studies

Hg MercuryHLA Human leukocyte antigen

I InsertionICD Irritant contact dermatitisI/D Insertion/deletionIFN Interferon

IL Interleukin

LT LymphotoxinMDBGN Methyldibromo glutaronitrileMHC Major histocompatibility complexMMP Matrix metalloproteinase

MnSOD Manganese superoxide dismutase

IVDK-Zentrale, Institut an der Universität Göttingen,

von-Sieboldstraße 3, 37075 Göttingen, Germany

e-mail: aschnuch@med.uni-goettingen.de

B.C Carlsen

Department of Dermato-Allergology, Copenhagen University

Hospital Gentofte, Niels Andersens Vej 65, 2900 Hellerup,

2.3 Irritant Contact Dermatitis 28

2.3.1 Individual Variability in Irritant Responses in

Healthy Individuals 29

2.3.2 Predisposition Related to Specific Phenotypes 30

2.3.3 Genetic Predisposing Factors 33

References 34

2 NAT NDMA p-nitroso-dimethylanilin N-acetyltransferase

Ni Nickel

OR Odds ratio

PPD p-phenylenediamine

ROS Reactive oxygen species

SNP (“snip”) Single nucleotide polymorphism

TAP Transporter associated with antigen

presentationTEWL Transepidermal water loss

TNF Tumor necrosis factor

Val Valine

2.1 General Introduction

Contact dermatitis cannot develop without exposure

to substances in the environment Conversely, only a

part of individuals exposed to the same exogenous

stimulus develop contact dermatitis, allergic or irritant

In addition, several cofactors are involved Hence, the

notion of a complex disease, with probably many genes

and many environmental factors contributing to the

observed phenotypes There are essentially two

rea-sons to study genetic factors: (a) to get further insights

into the pathogenesis, and (b) to get information about

how and where to target preventive measures However,

there has been a lack of conclusive results in the study

of the genetics of allergic and irritant contact

dermati-tis, and even more, a complete ignorance of the

inter-play between endogenous factors of individual

susceptibility and exposure to noxious agents In some

instances, the environmental factor may override any

genetic predisposition In others, the genetic factor

may prevail, with the consequence that the disease is

confined to a specific subpopulation, the “noxious

agent” doing no harm to the vast majority of people

The problem becomes more complex, even

insur-mountable, if a quantitative approach is taken [1] One

should have in mind the critical remark of HARDY

and SINGELTON: “To state that most complex

dis-eases are caused by an interaction between genome

and environment is a cliché Such interactions, while

likely, have for the most part not been demonstrated,

and we should be cautious about universally

subscrib-ing to this belief without evidence” [2] This is the

challenge for those few dealing with the genetics of

contact dermatitis and a reminder for those (many)

being involved in research, treatment, and prevention

or decreased susceptibility to contact allergy (CA) (Table 2.1) One should have in mind or even exclude these confounding causes of different susceptibilities when studying the genetics of CA

High induction dose of the allergen [4]

Irritant contact dermatitis [59]

1 This article is partly based on A Schnuch, G Westphal, R Mössner,

K Reich: Genetic factors in contact allergy–Review and future goals Contact Dermatitis (submitted)

2.2.1 Early Studies in the Genetics

of Contact Allergy

In the past, different approaches were taken to study

the question of inheritance in CA in humans and

ani-mals (Table 2.2) Studies up to 1985 were

comprehen-sively reviewed by Menné and Holm [5], and recent

studies on nickel allergy by Shram and Warshaw [6]

2.2.1.1 Experimental Sensitization

After Sulzberger and Rostenberg had noticed vidual differences in experimental sensitization to

interindi-p-nitroso-dimethylanilin (NDMA) and 2,4

dinitrochlo-robenzene (DNCB), Landsteiner et al reanalyzed these data and concluded that the susceptibility to sensitization

is not general (equally expressed regardless of the nature

of the chemical), but most probably chemical-specific

Table 2.2 Summary of studies in the genetics of ACD

Reanalysis of the above study Susceptibility to sensitization is

chemical-specific Individuals sensitized to one allergen are more easily sensitized to others

[3]

Chase (1941) Sensitization of guinea pigs with

DNCB and poison ivy; tion of high and low responders

identifica-Controlled breeding of the two colonies

The offspring of the high reactors reacted also intensely; the other group reacted poorly, although induction was even higher

Sensitivities (to organic compounds) not substance specific

One strain could be sensitized to potassium dichromate, but not to mercury chloride; reverse sensitivity of the other strain Sensitivities (to metal compounds) substance specific

Sensitization of children more frequent if parents were sensitized (only NDMA, not DNCB)

with 23 standard allergens

Pos reactions in female relatives more frequent than in controls (30/18%)

[10]

Fleming, Burden and

Forsyth (1999)

Relatives (n = 209) of patients with

Ni – ACD (n = 39) were questioned

about intolerance to nickel

The risk ratio for first degree relatives of Ni positive patients was 2.83 (CI 2.45–3.27)

Remark: confounders were not controlled for!

[11]

Twin studies

Menné and Holm (1983) Based on a questionnaire on a

possibly nickel allergy mailed to 1.546 female twins from the Danish Twin register, 115 pairs were

investigated (patch test in n = 75)

Difference between concordance rate for Ni allergy among MZ and DZ pairs The heritability for nickel allergy was ~60% For a medium potent sensitizer (Ni), genetic factors may play a role (see Table 2.3 )

(continued)

[3, 7] Nevertheless, it was shown that individuals

sensi-tized to one allergen are more easily sensisensi-tized to others

However, the question of the cause of different

suscepti-bilities remained unsettled

2.2.1.2 Family Studies

A genetic influence became more evident through the

study done by Walker et al [8], probably one of the

most convincing human studies The authors studied

experimental sensitization with NDMA and DNCB in

99 families with a total of 301 individuals Interestingly,

children were sensitized to (the strong allergen) DNCB

independent of successful sensitization to their

par-ents, but in case of the weaker allergen NDMA,

chil-dren were sensitized significantly more often, when

their parents were sensitized (Table 2.3) One may

conclude that a very potent allergen can be considered

to overpower genetic influences [8] In contrast, in

sen-sitization to weaker allergens (like NDMA or nickel),

genetic factors may play a role [8, 9] With regard to

other types of family studies [10, 11], Menné and

Holm raise several shortcomings of such studies, e.g.,

difference in exposure time for parents and offspring,

or changing exposure patterns over time [5]

2.2.1.3 Twin Studies

Clustering of diseases in families may either be the result of shared genetic influences or shared family environment With regard to nickel CA, the results of twin studies are controversial [9, 12, 13] (Table 2.2) In

a more recent study, Bryld et al recruited a sample of female twins with hand eczema from the Danish twin register [13] In the final analysis, 630 females were

Status of parents Percentage of children sensitized

Bryld et al (2004) A sample of female twins with

hand eczema from the Danish twin register was patch tested with

nickel (n = 630)

Patch test positive to nickel: n = 146 Only a

small tendency for larger odds ratio in MZ (OR: 1.28, 95% CI 0.33–5.00) Ni allergy mainly caused by environmental factors

Cave: selection criterion!

[13]

Studies of immunogenetic markers

Ishii et al (1990-1998) Genetic control of metal

sensitiza-tion in mice

Various polymorphism in the I-A region [18, 20, 21, 19]

Asherson et al (1990) sensitization and IFNg release in

CBA (H-2k) and BALB/c (H-2d) mice

The H-2d haplotype determines contact sensitivity and poor IFNg response to several antigens

Walton et al (1986) Associations of nickel allergy with

RR for the alleles TAP2B increased, for TAP2C decreased (both significantly)

[27]

Table 2.2 (continued)

included, of which 146 had a positive patch test to

nickel There was a trend toward an increased risk for

nickel allergy among MZ (OR: 1.28, 95% CI 0.33–5.00)

The authors concluded that allergic contact dermatitis

(ACD) to nickel is mainly caused by environmental and,

only to a lesser degree, genetic factors [13] The

limita-tions of this study (admitted by the authors) included the

use of the heterogeneous phenotype “hand eczema” as a

selection criterion and a relatively small sample size per

age group [14] Furthermore, MZ and DZ twins might

share a different degree of allergen exposure leading to

a systematic error in twin studies [15]

2.2.1.4 Studies of Immunogenetic Markers

Early studies have used the proteins (HLA-“antigens”)

of the MHC class I (HLA-A/-B/-C) and MHC class II

(HLA-DP/-DQ/-DR) as serological immunogenetic

markers Meanwhile, they were complemented by the

typing of genomic (g) DNA, relating the phenotype

(serotype) to genotypes Up to now, >1,200 class I and

>336 class II alleles were identified [16]

MHC-variations (HLA-phenotype and/or genotype) were

found to be associated with disease susceptibility,

mainly in autoimmune and infectious diseases [17]

Studies of immunogenetic markers in CA were

per-formed in animals and humans It is generally believed

that the genetic control of delayed-type

hypersensitiv-ity (DTH) reactions in mice relies on the I-A subregion

of H-2, the murine MHC, and is antigen-specific, at

least in some instances, as was shown for nickel (Ni)

[18], Mercury (Hg) [19], Chromium (Cr) [20], Gold

(Au) [21], and organic haptens [22, 23]

Numerous studies on MHC I and MHC II in humans

with contact sensitization were performed during the

last three decades (reviews: [5, 24, 6]) Class I and

class II MHC molecules differ greatly among

individu-als Most of the associations of HLA loci with CA

were not significant, with the exception of HLA-B35

[25] and DQA1*061 [26], which were increased, and

DR15, which was decreased in nickel allergic patients

[26] In addition, polymorphisms of genes encoding

the TAP transporter proteins located in the HLA class

II region and of genes encoding complement factor B

(component of the C3 convertase enzyme activating

the alternative pathway), particularly the subtype

BF*FB, located in the MHC class III region, were

found to be associated with nickel allergy [27, 28] But

even if MHC-disease associations exist, they would not necessarily be causal, since they might be caused

by genetic linkage In almost all studies only nickel allergy was considered, which may be a further reason for the lack of significant findings, as nickel may bind

to nearly every HLA-molecule and may even act in an HLA independent manner [29, 30] Rarely, HLA poly-morphisms were studied in individuals sensitized to organic compounds, again with inconclusive results [31, 32, 33, 34]

2.2.2 In Search of the Phenotype

of Contact Allergy: Polysensitization

The phenotype, the observable characteristics of an individual, results from the interaction of genotype and environment In CA, the phenotype corresponds hypo-thetically to unknown genotypes For many reasons, the genes involved in CA have not yet been found One of them may be the variety of chosen (operationalized)

“phenotypes.” Most often, only sensitization to nickel (or to other metals) was considered (assuming that nickel allergy could be considered a valid paradigm for

CA in general) In other experiments, organic haptens were used, but they differed in sensitization potency, blurring the view on possible genetic influences The problem became more complicated through the notion that CA is not an all-or- none, but a graded phenomenon [35] Different doses (1), different potencies (2) of the allergen, and different susceptibilities of the individual (3) result together in different grades of sensitization (Review: [1]) As in principle, every human being is equipped with the immunological tools to mount a

combi-2 DTH reaction, such reaction cannot reasonably be understood as a “disease” (or its “phenotype”) On the

other hand, a carefully well-defined phenotype is of

utmost importance in genetic studies of a disease [2]

Therefore, the focus of research should be “increased

susceptibility to CA,” which could serve as the

pheno-type to be studied But what can we understand of

“increased susceptibility” [1]?

It was the seminal work of a group from the UK done

20 years ago that contributed essentially to the notion of

susceptibility [36] With a set of intriguing experiments

using DNCB sensitization they found (in a rather small

study group) that patients with multiple sensitization (to

three and more unrelated contact allergens) were more

easily (with lower doses) sensitized and exhibited

stron-ger reactions upon rechallenge Consequently, a study

was done to determine whether there was an association

between multiple sensitization and HLA molecules

[32] No statistically significant association was found

More recently, however, the concept of

polysensitiza-tion has experienced a new turn (review: [1]):

One will easily agree that all three elements (induction

and elicitation increased, sensitization even to weak

allergens) are suitable to make up the meaning of

“increased susceptibility.” There is sufficient evidence

that this increased susceptibility is unequivocally

indi-cated by polysensitization

Interestingly, the distribution of graded bility (as expressed by increasing polysensitization) follows the general distribution of quantitative traits of multifactorial disorders (i.e., complex diseases like blood pressure) (Fig 2.1) [39] (p 248)

suscepti-2.2.3 Polymorphisms in Allergic Contact Dermatitis

In many diseases, susceptibility loci on defined somes or polymorphisms (variation present at greater than 1% in the population) located in specific DNA sequences were detected and found to be associated with the disease (e.g., psoriasis [40]), thereby substantiating more and more the notion of disease genes However,

chromo-0 5 10 15 20 25

Number of + to +++ reactions

%

Fig 2.1 Distribution of the number of positive reactions (+, ++,

or +++) to allergens of the standard series 6+: 6 or more than

6 reactions Total number of patients n = 58,268 Number of

patients with no positive reaction to standard series allergens:

n = 31,865 (54.7%) [1]

1 The risk to be sensitized to an index allergen

gradually increased with the number of

cosensi-tization This was shown for a group of quite

heterogeneous allergens (neomycin, the

fra-grance mix, paraphenylendiamine (PPD),

bufex-amac, nickel, cobalt chromate)

2 The risk to react in patch testing to an index

allergen (the fragrance mix) with stronger

(++/+++) reactions increased with the number

of cosensitization

3 The risk to be sensitized to the weak allergen

paraben-mix (compared to sensitization to the

stronger allergen MDBGN) increased with the

number of cosensitization

4 The prevalence of polysensitization remained

stable over a 20-year periode [37], despite

generally decreasing sensitization rates in the

background population [38]

Core Message

Studies on the genetics of CA should focus on

›

increased susceptibility, and therefore, studied

in patients with polysensitization

genes at the root of ACD have not yet been identified

Linkage or association studies have been done until now

without convincing success, and thus, almost no putative

susceptibility loci were identified (with the exception of

a few HLA loci) Therefore, a group of investigators

from the University of Göttingen/Germany opted for the

“candidate gene” approach [41, 42, 43, 44, 45] Candidate

genes are those whose characteristics (e.g., protein

prod-uct) suggest that they may be responsible for a genetic

disease The existing knowledge on the biologic relevant

steps in CA may point the way [46, 47]

Contact allergens are low-molecular weight

chemi-cals, their permeation into the skin being a function of

the molecular structure of the allergen and of the skin

barrier (which is elsewhere discussed [48]) Some

molecules may require metabolic activation in the skin

to become an active prohapten Others may be

deacti-vated by early metabolic conversion (detoxication)

Sensitization to the allergen may then depend on the

capabilities of the organism to metabolize a chemical

to a protein-reactive metabolite [47] Individuals differ

with regard to these metabolizing capabilities This is

caused by various genetic polymorphisms of

xenobi-otic metabolizing enzymes, such as N-acetyltransferases

(NAT) and glutathione S-transferases (GST) [49, 50].

Sensitization itself – the immunological step – is a

complex process leading up finally to the activation of

allergen-specific T-cells (mainly CD8+) [46] One of the

pivotal steps is the activation, maturation, and migration of

antigen-presenting dendritic cells (DCs), namely dermal

DCs and (epidermal) Langerhans cells [51] The whole

process is orchestrated by several important changes in the

skin, involving cytokines and chemokines, adhesion

mol-ecules, and matrix metalloproteinases (e.g., MMP-9) [46]

Interleukin 1-beta (IL-1-beta) and tumor necrosis factor

(TNF) can be regarded as the key cytokines during this

process, although many other factors were shown to be

indispensable for sensitization to take place [51] However,

getting this gearing going is by no means allergy specific

[52] Unspecific stimuli (e.g., irritants), not to forget

microbes via activation of the innate immune system [53],

are able to start the machinery as well [52, 54, 55] Even

more, allergens need these nonspecifically activated

stim-uli by virtue of their own (most contact allergens dispose

of irritating properties) [56] or by interference of external

factors (preexisting or induced inflammation) [57, 58]

This interplay resulted in the concept of the “danger

model,” introducing, as indispensable elements,

inflam-matory processes into the pathogenesis of ACD [59]

As important elements within the pathogenetic evant steps of ACD, metabolically active enzymes and various cytokines were studied [41, 42, 43, 44, 45]

rel-2.2.3.1 Tumor Necrosis Factor (TNF)

Following a change in nomenclature in 1998, TNFa and TNFb were renamed TNF and LTa (lymphotoxin a) TNF is a proinflammatory cytokine, mainly produced

by macrophages, playing an essential role in host defense against infections [60] Its role is, however, far more

complex: This cytokine is involved in the physiological

regulation of a wide spectrum of biological processes (e.g., cell proliferation, differentiation, apoptosis, skin barrier homeostasis) and implicated in a diverse range of

pathological conditions, particularly inflammatory

(rheumatoid arthritis, psoriasis) and infectious (sepsis) [60, 61, 62]

The gene encoding TNF is located on chromosome 6p21.33, within the MHC Class III complex (Fig 2.2) Several gDNA variants or single nucleotide polymor-phisms (“SNPs”) have been identified, e.g., TNF – 238 G®A, TNF – 308 G®A, TNF – 857 C®T, TNF –

1031 T®C More than 90 case-control studies for the TNF-308 promoter SNP and disease were accumulated [63, 61]

Studies of TNF Polymorphisms in ACD (See Table 2.4)

1 The first study investigating the relationship between polymorphisms of the TNF gene and ACD found that the distribution of TNF – 308 genotypes, but not TNF-238, was significantly different in cases with ACD and healthy con-trols, with carriers of the A allele being more frequent among polysensitized patients [44]

2 Individuals from Germany and the Netherlands

sensitized to PPD (n = 181) and controls out history of ACD (n = 161), age- and gender-

with-matched to cases, were selected for genotyping for the TNF-308 gene polymorphism [64] The frequency of the rare A allele was significantly higher in cases than in controls (22.1 vs 12.4%) A logistic regression analysis, using

Genotype and phenotype of

NAT2*5b/2*6a (slow Acet) decreased Genetic linkage of NAT1*10 with NAT2*4

Glutathione S-transferases

(GST) M1 and T1

Combined deletion (GSTT1-/GSTM-1) in patients allergic to organic mercury compounds compared to controls and to para group allergics

Cytokines: ILB-511, ILB + 3953,

ILRN, IL-6-174, TNFA-238,

TNFA-308

[64] c

Cytokine IL-4 No difference between Cr allergics and controls with

regard to IL-4–590 polymorphism

Transcription start site

Fig 2.2 Scheme depicting the

Numbering is descending from

the +1 of the transcription start

site ([63], modified)

These consistent findings support the concept that the

promoter polymorphism at position – 308 of the TNF

gene might be a risk factor for acquiring ACD In

par-ticular, in one study, the rare TNFA – 308A

polymor-phism was more frequent among polysensitized

patients supporting the notion that polysensitization is

in fact the relevant phenotype Although DTH

reac-tions differ in some aspects from ACD, the finding of

an increased granulomatous (DTH) response to romin in carriers of the TNF – 308 A allele supports the above results [66] As TNF is also involved in irri-tant contact dermatitis (ICD), and as the TNF-308 A polymorphism was shown to be associated with an increased risk of ICD [67, 68], it is conceivable that this polymorphism might have an impact on ACD via unspecific trigger factors as suggested by the “danger model” [59]

lep-Despite quite a number of studies showing a tional relevance, albeit highly context specific (increase

func-of transcriptional activity or production func-of TNF), Bayley et al., summarized the results of functional

in vivo and in vitro studies and concluded that the –

308 G/A polymorphism is probably not functional [63] The definite functional role of this polymor-phisms remains to be elucidated [69, 70, 71]

The starting point of most studies was the hypothesis

that genetic variants of the TNF locus are likely to be involved in the disease because TNF is clearly involved

in pathogenesis However, this locus may be linked to other candidate SNPs within or outside the TNF gene

(e.g., LTA, encoding lymphotoxin a) or unknown

sus-ceptibility markers, which may extend over a large region of the MHC including many genes [72] Thus, it may be an extended haplotype (e.g., HLA A1, B8, DR3), and not the single SNP, that impact disease sus-ceptibility [73], indicating the need to study frequencies

of rather long-range haplotypes containing TNF*-308 together with other susceptibility marker (Fig 2.2)

sex, age, and TNF (A/A + A/G) vs GG as

explanatory variables, confirmed the risk

asso-ciated with the combined TNF (A/G + A/A)

genotypes

3 In a cohort study in cement workers (n = 153)

conducted in Taiwan [65], those sensitized to

chromate (cases, n = 19; 12.4%) were compared

to nonsensitized with regard to TNF – 308 G/A

and IL-4–590 (C/T) gene polymorphisms The

TNF – 308 G/A genotype was found to be a

significant risk factor for ACD to chromate

(RR: 3.9; CI: 1.14–13.2), whereas the

distribu-tion of genotypes of the IL-4 polymorphism

(C/T) did not differ between cases and controls

Assuming an identical exposure, the different

outcomes are most likely due to different

susceptibilities for which the genetic variation

found (TNF and GST (see below)) may partly

d sensitization not specified

Filaggrin null mutations

(combined genotypes for

R501× and 2282del4)

Results inconclusive

[149] d

Not associated with ACD d

when compared to other controls: risk increased [150] d

Associated with relevant sensitization to nickel only [152]

Table 2.4 (continued)

2.2.3.2 Interleukin-16

IL-16, originally described as a lymphocyte

chemoat-tractant factor, exerts a variety of proinflammatory

func-tions (review: [74, 75]) The active peptide (121 amino

acids) is cleaved from a precursor protein by caspase

three, and then self aggregates to an active

homote-tramer IL-16 has been identified at sites of

inflamma-tion associated with several different disease states [74]

Its role could be to mediate directed locomotion of

T-cells toward DC after these have captured antigen and

attract other DC to sites of antigenic challenge, resulting

in a tenfold higher accumulation of CD4+ T-cells [76]

Based on several studies, an important role for IL-16

during DTH reactions can be assumed [77, 78, 79]

The gene encoding IL-16 (IL-16) is located on

chromosome 15q26.3 One polymorphism in the

promoter region, a T/C SNP at position – 295, was

dissected in Crohn’s disease, atopic dermatitis (AD),

asthma, and periodontitis, with, however, conflicting

results [80, 81, 82, 83, 84] Due to different effects of

IL-16 in different types of disease, this polymorphism

may exert an enhancing (in Th1 driven-) or protective

effect (in Th2 driven- diseases) [82]

Studies of IL-16 Polymorphisms in ACD

Up to now, only one study investigated the IL-16–295

polymorphism in ACD It was found that the IL-16–295

genotypes were differently distributed among patients

with ACD and healthy controls [45] In particular, the

IL-16–295*C/C genotype was overrepresented among

polysensitized individuals (7.0 vs 1.0% in the control

group; odds ratio (OR) 7.68; 95% CI 1.59–48.12)

Association was found neither in monosensitized

patients (sensitized to para-arylic compounds) with

ACD nor in patients with AD [45]

The fact that the homozygous combination of the

rare allele IL-16–295*C appeared to be more common

among polysensitized patients with ACD adds, from the part of genetics, further support the concept of polysensitization as a phenotype of increased risk The observed association both in ACD and Crohn’s disease [80] thought to be driven by Th1 cytokines, as well

as the lack of association in AD [81], dominated by Th2 cytokines, at least in acute lesions, is compatible with the Th1/Th2 paradigm Despite these findings suggestive of being plausible, the study needs to be replicated

2.2.3.3 N-Acetyltransferase 1 and 2 (NAT1/NAT2)

Acetylation is a major route of biontransformation for several therapeutic arylamine and hydrazine drugs (review: [85] It plays an important role in the bioac-tivation as well as bioincativation of numerous poten-

tial carcinogens N-acetylation is in general regarded

as a detoxifying reaction, while N-O-acetylation (the

acetylation of the corresponding hydroxylamine) leads to highly reactive, toxic intermediates (review: [85, 50, 86] In humans these acetylation reactions are catalyzed by two closely related cytosolic

enzymes, N-acetyltransferase-1 (NAT1; EC 2.3.1.5) and N-acetyltransferase-2 (NAT2; EC 2.3.1.5) In

dermatology, the xenobiotic most studied with regard

to N-actelylation is the contact allergen para-

phenylenediamine (PPD) It was shown that PPD is metabolized to its mono- and dicacetylated derivatives and to oxidation products such as Brandowskis Base (BB, an end-product of oxidation) [87, 88, 89, 90] However, it can be expected that only a part of PPD is acetylated [91, 92] The remnant, PPD and its oxida-tion products, could still act as sensitizer [93, 94]

The human NAT1 and NAT2 genes are located in

close proximity on chromosome 8p22 and share 87%

nucleotide sequence identity within their protein

coding regions Until now (updated 16 Nov 2007 and

27 May 2008), 26 alleles of NAT1 and 53 of NAT2

have been identified (http://louisville.edu/medschool/

pharmacology/NAT.html; accessed 23 March 2009)

Both genes are polymorphic with regard to the “slow”

and “rapid” acetylator phenotype Epidemiological

studies have provided some clues concerning the

importance of variations in both NAT1 and NAT2 in

altering risk for a variety of disorders, most notably

cancers [50, 86], but also nonmalignant diseases

[95] and, in particular, atopic diseases [96, 97, 98,

99, 100]

Studies of NAT: Polymorphisms in ACD

1 Early studies investigated the NAT phenotype

in ACD A “slow acetylator” NAT1

pheno-type was reported to be associated with ACD

[101, 102, 103] As the studies (a)

com-prised patients with CA as controls, (b) used

a NAT2-substrate (caffeine), and (c) their

sample size was very small, no convincing

conclusion can be drawn from the results

with regard to the NAT1-phenotype in ACD

patients [102, 103]

2 Actually the first molecular-epidemiologic

study in CA determined the NAT2 genotype

and phenotype [41] Patients allergic to

para-substituted aryl compounds (but other

sensiti-zation not excluded) (n = 55) and healthy

controls (n = 85) were compared with regard to

their capacity to metabolize caffeine

(pheno-type) and with regard to the NAT2 genotype

Carriage of at least one NAT2*4 or NAT2*12A

allele encodes a rapid phenotype In addition, NAT2 phenotypes (rapid and slow) were deter-mined by the use of the ratio of the caffeine metabolites AFMU/1-MX (Fig 2.3) in urine Concordance between genotypes and pheno-types was >90% Concerning the NAT2 pheno-type, 48% of contact allergic patients were classified as rapid acetylators, compared to 24% in the control group (Fisher’s exact test

p < 0.001) (Fig 2.4) Genotypically, 51% of contact allergic patients were rapid acetylators, whereas in the control group only 31% “rapid” genotypes were found

3 In a second study on NAT in a similarly

charac-terized but extended group of patients (n = 88) and healthy controls (n = 123), we investigated polymorphism in the NAT1 and the NAT2 gene

[42] NAT2 rapid acetylators (carriers of at

least one NAT2*4, or NAT2*12A allele) were

more common in the disease group (45%) than

in the control group (30%) (p = 0.029) The riage rate of the NAT1*10 allele (encoding

car-probably the NAT1 rapid acetylator phenotype) was slightly but not significantly increased in patients (43 vs 36%; OR: 1.5; CI: 0.88–2.68)

The haplotype NAT2*4/NAT1*10 (rapid

acety-lators) was increased in patients (27 vs 15%; OR: 2.1; CI:1.04–4.04) This may be due a

genetic linkage between NAT2*4 and NAT1*10 (p = 0.0025).

4 These findings, namely an increased risk of ACD for the “rapid” NAT2 polymorphism, were corroborated in a study from Turkey [104] and Iraq [105], although the results of the latter study are compromised by a low sample size and an unconventional, not standardized patch test technique

N

N O

methylxan-thine indicates a phenotype

of NAT2 “rapid acetylator”

(AFMU: 5-acetylamino-

6-formylamino-3-metyhuracil)

At first sight, the concept of reduced detoxifying

com-petence (slow acetylators) associated with an increased

risk of CA seems intriguing [103, 87] However,

N-acetylation may be involved in the development of

CA through activation (e.g., N-O-acetylation of the

corresponding hydroxylamines), leading to higher

levels of reactive metabolites NAT enzymes may also

play a role beyond xenobiotic metabolism and may

address endogenous substrates (like folic acid and

derivatives or other unknown substrates), or internal

signaling pathways [106, 107, 108] Grant et al pointed

at the paradox that acetylated xenobiotics are less

water soluble than their parent compounds, which

would make it unlikely that these enzymes evolved

specifically in order to accelerate elimination of

foreign chemicals [85]

2.2.3.4 Glutathione Transferases

M1 and T1 (GSTM1 and GSTT1)

Cytosolic/soluble glutathione transferases (GST) are

a superfamily of phase II enzymes GST conjugate

electrophilic substrates with the nucleophilic tide glutathione (GSH) As a general rule, this leads to decreasing reactivity of toxicants The cytosolic GSTs are subdivided into seven main classes, including the most studied families GST m (mu, M) and q (theta, T) Although some substrates are metabolized by sev-eral GST, others are specific for particular isozymes (reviews: [50, 109]) The observed substrate speci-ficities (e.g., genotoxic aromatic epoxides, mono and dihaloalkanes, aminophenols) were found in the con-text of specific toxicological research (on canceroge-nicity) [109], and will probably not reflect the total of the activities of these enzymes GSH conjugation may result in toxification as well as detoxification And, similar to NATs, GSTs may act beyond xenobiotic metabolism, and may be involved in modulating inter-nal signaling pathways [110]

tripep-The genes encoding for the proteins GSTM1 and GSTT1 are organized on chromosome 1p13.3 and chromosome 22q11, respectively Although there are numbers of SNPs of GSTs of class m and q, many of these variations have no or little effect on enzyme activity Exceptions are the deletion polymorphisms

GSTM1*0 and GSTT1*0, leading to complete loss of

enzyme activity Variations (null deletions; phenotype:

“nonconjugators”) in both GSTM1 and GSTT1 were found to alter the risk for a variety of disorders, most notably cancers of different sites but also other dis-eases, such as chronic cardio vascular disease, rheuma-toid arthritis, drug eruptions, and atopic asthma [109,

Fig 2.4 Ratio of the caffeine metabolites AFMU and 1 MX

(Fig 2.3) in patients with ACD (n = 52) and healthy controls

(n = 85) The values were logarithmically transformed and the

cut-off point set at 0, separating slow (ratio <0) and rapid (ratio

>0) acetylators (p < 0.001) [41]

110, 111, 112, 113] Although the variation itself being

probably of moderate strength, these gene variations

lead to synergistic effects if they are combined with

other polymorphisms such as the highly active CYP1A1

patho-119, 120], playing a role in the pathobiology of ACD [121, 122, 123, 124] GSTM1 and GSTT1 exhibit GSH peroxidase activity, and thus, may protect against toxic effects of endogenous and exogenous reactive oxygens [125, 126]

2.2.3.5 Manganese Superoxide Dismutase

Manganese superoxide dismutase (MnSOD, EC 1.15.1.1) is a mitochondrial protein that scavenges potentially toxic superoxide radicals by dismuting superoxide (O2−) to O2 plus H2O2 The gene (SOD2)

was mapped to chromosome 6q25.3 A peptide morphism in the target sequence of MnSOD enzyme, Ala(16)Val, is known to disrupt proper targeting of the enzyme from cytosol to mitochondrial matrix Several diseases were suspected to be associated with this polymorphism, but with conflicting results (e.g., can-cer [127], rheumatic diseases [128], or asthma [129])

Studies of the MnSOD Polymorphisms

in ACD

In view of the pathogenetic role of ROS in ACD (see above), this polymorphism was studied in 157 patients with sensitization to PPD and compared to healthy

controls (n = 201) [130] No significant difference in

the distribution of allelic frequencies and genotypes between cases and controls was observed, although for subgroups defined by gender and age, there was a trend

1 GSTM1 and GSTT1 may be involved in

inac-tivation of the organic mercury compound

thiomersal and of its degradation products

(e.g., ethylmercury), as several organic

mer-cury compounds were detoxified by GSH

[115], these compounds may interact with

GSTs [116], and GSH was shown to inhibit

elicitation in patients allergic to thiomersal

[117] Therefore, the GSTM1 and GSTT1

polymorphisms were studied in patients

sensi-tized to mercury compounds (thiomersal,

phe-nylmercury acetate, and ammonium mercury

chloride, n = 100) [43] Healthy individuals

(n = 169) and patients with CA to

“para-substi-tuted aryl compounds” (n = 114) served as

con-trol GSTM1 deficiency was significantly more

frequent in thiomersal allergics, and GSTT1

deficiency more frequent in patients allergic to

mercury compounds other than thiomersal

More importantly, the combined deletion

(GSTM 1*0 and GSTT1*0) was significantly

more frequent in the thiomersal group than in

healthy controls (16/91 vs 11/169; p = 0.0093)

and the para-compound group (16/91 vs

7/114, p = 0.014) This finding suggests a

“syn-ergistic” effect of these enzyme deficiencies

(synthetic genetic interaction of two genes;

deletion of only one of them with no effect on

the phenotype)

2 A cohort study on cement workers [65] (see

above) investigated the GSTM1 and GSTT1

polymorphisms While the GSTM1 deletion

was equally distributed among cases (cement

workers sensitized to chromate (Cr)) and

con-trols (cement workers without sensitization to

Cr), there was a higher frequency of the GSTT1

2 toward a overrepresentation of the CC carriers (Ala/Ala) (OR: 1.3; CI: 0.8–2.1) [130] The authors

con-cluded that the SOD2 polymorphism studied has no

strong impact on the individual susceptibility to

develop sensitization to PPD

2.2.3.6 Angiotensin-Converting Enzyme

Angiotensin-converting enzyme (ACE, kininase II, EC

3.4.15.1) catalyzes the conversion of angiotensin I into

angiotensin II, a potent vasoconstrictor, and is involved in

the inactivation of bradykinin, a potent vasodilator

Beyond these well-known substrates, ACE cleaves

sub-stance P, beta-endorphins, and other peptides [131],

which may modulate Langerhans cells and T-lymphocyte

functions [132] In particular, it was shown in animal

experiments that ACE modulated the inflammatory

response to allergens, but not to irritants, by degrading

bradykinin and substance P [133] The gene, ACE, is

located on chromosome 17q.23.3 The presence or

absence of a 287 bp Alu repeat element in this gene (a

repeated DNA sequence that can be cut by the Alu

restric-tion enzyme), i.e., an “inserrestric-tion/delerestric-tion” (I/D)

polymor-phism), was found to be associated with the levels of

circulating enzyme, namely, that ACE levels were low for

I/I homozygotes and high for D/D homozygotes [134]

Studies of the ACE Polymorphisms in ACD

Based on this functional role of the polymorphism, it was

hypothesized that individuals with the I/I genotype would

be at greater and those with the D/D genotype at lower

risk for developing ACD In 90 patients with ACD (patch

test positive to PPD) and 160 controls, the I/D

polymor-phism was studied [135] Carriers of the I allele (OR: 1.6;

CI: 1.1–2.4), as well as the I/I genotype (OR 2.0; CI:

1.1–3.7), were found significantly more often in the ACD

group, and carriers of the “protective” D allele were found

less often in this study group (OR: 0.6 (CI 0.4–0.9)

These interesting results broaden our view on ACD beyond the chemical, immunological, and inflamma-tory aspects to a neuro-endocrinological network, rarely considered in the pathogenesis of ACD [136, 137] Furthermore, they underline the importance of structural variants beyond SNPs in the study of com-plex traits [138]

2.2.3.7 Filaggrin

Filaggrin (FLG) (filament-aggregating protein) is a key component of the stratum corneum (review: 139, 140]) Multiple FLG peptides are cleaved from profillagrin,

which is encoded by the FLG gene on chromosome

1q21 FLG aggregates keratins and filaments, is a major component of the cornified envelope, and contributes – after degradation – with a mixture of hygroscopic amino acids to the pool of amino acids, metabolites, and various ions, known as “natural moisterizing fac-

tor” [141, 142] In addition, the N-terminal portion

cleaved from profilaggrin is a calcium binding domain, which enters the nucleus of keratinocytes and

is thought to be involved in regulating the terminal ferentiation of the epidermis [143] More than 20 loss-

dif-of-function mutations within the FLG gene have been reported [139] These FLG mutations are nonsense or

frameshift mutations, each resulting in truncation

of the profilaggrin molecule Association of the FLG

null genotype (in particular R501× and 2282del4) with AD has now been replicated in numerous studies [144, 145, 146]

Studies of FLG Mutations in ACDFLG deficiency may lead to skin barrier defects,

as was shown in AD patients with and without FLG

mutations [141, 147] An increase of susceptibility to chronic ICD was recently shown to be associated with

Core Message

An “insertion/deletion” (I/D) polymorphism

›

of the ACE gene was found to be associated

with an increased risk of ACD This finding must be replicated

Core Message

The Ala(16)Val peptide polymorphism of the

›

MnSOD enzyme is probably not associated

with an increased risk of ACD

FLG null mutations (OR: 1.91; 1.02–3.59) [148] This

may also be true for ACD because a compromised

skin barrier will facilitate permeation of allergens and

contribute by itself to an inflammatory milieu, both

favoring an allergic response [48] A study based on a

population (n = 183) from the Danish twin register

included a small subpopulation with ACD (n = 45)

[149] It was reported that “FLG null alleles are not

associated with….CA” [149] A critical comment

referred to the inadequate choice of controls and lack

of statistical power, altogether denying a sound basis

to draw such conclusions [150] Even more, on using

data from a population-based study as controls (n = 249)

[151], a recalculated odds ratio (OR 2.87; 1.10–7.51)

indicated an increased risk for CA to be associated

with the combined FLG null genotype In 60% of

patients with ICD (out of n = 296), one or more type IV

sensitization (not specified) was diagnosed [148] No

association to FLG deficiency was found In a larger

population-based study in Germany (KORA C), the

FLG null mutations mentioned above had been

geno-typed in 1,502 adults [152] Neither sensitization to

specific allergens (nickel, the fragrance mix) nor

sensi-tization to at least one (39.3%) or two allergens (13.2%)

were significantly associated with the combined null

genotype In contrast, nickel patch test positivity

together with a history of intolerance to fashion

jewel-lery was significantly associated with the combined

null genotype (OR 4.04; 1.35–12.06) [152]

These results seem to point against a major role of

the FLG mutations as a risk factor for ACD However,

the results of patch testing (in terms of frequency and

pattern of sensitization) differ considerably with regard

to other population-based [153, 154, 155] and clinical

studies [156, 157] In particular, sensitization frequency

to at least one allergen was higher by a factor >2,

compared to other epidemiological studies, and

sur-prisingly almost as high as found in selected clinical

patch test populations The frequency of sensitization

to the fragrance mix exceeded that which was found in

probably all larger clinical studies [158] One

explana-tion could be a high proporexplana-tion of falsely positive cases,

which cannot be excluded totally in less professional

patch testing in epidemiological studies When the

diagnosis of nickel patch test positivity was

strength-ened by a positive history, and the patch test result thus

probably not falsely positive, a significant association

between ACD (to nickel) and FLG mutations was

observed

2.2.3.8 General Remarks on the Study

of “Candidate Gene” Polymorphisms

in ACD

In this review we have presented studies supporting the view that manifestation of ACD may be influenced by distinct polymorphisms The reason to investigate these polymorphism was guided by a pathogenetic hypothesis If a polymorphism is shown to be associ-ated with a disease, its functional relevance should be demonstrated In this regard, the functional role has not been proven experimentally, but the results could

be regarded as plausible, at least

Nevertheless, a number of limitations regarding the validity and the interpretation of the studies are to be addressed:

Many studies were done in individuals

sensi-•

tized to PPD only One may argue that greater phenotype homogeneity is achieved, albeit at the expense of generalization On the other hand, as explained above, a study group defined

by the mere presence of a sensitization would

be too heterogeneous with regard to tibility Hence, the suggestion to investigate genetic variation in a high-risk group [1], where genetic influences can probably be more read-ily identified [159, 2]

suscep-With the exception of Wang’s et al study [65],

•

there was no control for allergen exposure Individuals with high susceptibility but without allergen exposure (and no sensitization) may

be found in the control group

As cytokines (e.g., TNF/IL-1

IFNg [161]) and enzymes (cytochrome p450/GST [49]) interact in vivo, polymorphisms may act synergistically, e.g., the combination

The studies of polymorphisms in ACD reviewed that

all suffer essentially from a small sample size, and

p-values are rather poor All studies are essentially

underpowered, or false positive results cannot be

excluded Nevertheless, all studies offered tentatively

a plausible functional role for the polymorphisms,

not-withstanding the limitations outlined above It is

note-worthy that three polymorphisms first identified by the

Göttingen group to be associated with an increased

risk of ACD, namely TNF, NAT, and GST, were

replicated at least once, albeit with slightly different study designs

Taken together, the impact of the results presented here may support the view that ACD as a complex dis-ease is influenced by genetic factors, in addition to many well-known environmental factors However, some diseases are not simply present or absent, but can

be viewed as quantitative traits expressed on a sured continuum Only if a normal trait variation exceeds a defined threshold, it is considered as “dis-ease” (e.g., hypertension) Alike, a variety of anthtro-pometric and laboratory traits were also studied in GWAS (Genome Wide Association Studies), such as serum lipid levels, body mass index, and height [164]

mea-CA was considered here as a quantitative trait, and it was suggested to study the genetics in individuals where this trait is expressed at the extreme tail of the distribution of sensitization (Fig 2.1), namely as polysensitization [1]

2.3 Irritant Contact Dermatitis

Irritant contact dermatitis (ICD) has a multifactorial pathogenesis Exposure to irritants, e.g., water, alkalis, acids, oils, and organic solvents, is a necessity and generally considered the most important causal com-ponent Several exogenous factors influence the irritant reaction, (see Table 2.5) Certain phenotypes have an increased risk of irritant contact dermatitis under con-trolled experimental settings and are considered espe-cially susceptible These phenotypes are discussed below and an overview is given in Table 2.5

The irritant response shows great interindividual variability in healthy individuals [182–184] The

of CYP1A1 with GSTM1*0 may increase the

risk of lung cancer [109], or the combination of

NAT2 and TNF polymorphisms the

suscepti-bility for psoriasis [162] Although a synergism

between NAT1 and NAT2 and between GSTM1

and GSTT1 polymorphisms was demonstrated

(see above), no further analysis, in particular

between cytokine and enzyme-polymorphisms,

has been done

Often it is unresolved as to whether a

disease-•

associated polymorphism is itself functionally

important or acting only as a marker for a

coin-herited, perhaps as yet, unidentified

polymor-phism Thus, for instance, the association with

the TNF locus may be secondary and likely to

be caused by genetic linkage Furthermore,

sus-ceptibility markers may, as in the case of TNF,

extend over a large region of the MHC

includ-ing many genes [72], and it may be the extended

haplotype (and not the single SNP) that impact

disease susceptibility However, the structure of

the extended haplotype is still not fully

under-stood It was suggested that the – 308 G/A

poly-morphism together with the MHC 8.1 ancestral

haplotype (HLA A1, B8, DR3) may play a role

in the altered TNF gene expression

In view of the poor reproducibility of the

•

majority of studies – only six out of 600

asso-ciations were found to be consistently

repli-cated – BAYLEY at al refer to some basic

requirements of the editors of Nature Genetics:

Large sample size, small p-values, associations

that make biological sense, and alleles that

have a relevant physiological function An

ini-tial study should be accompanied by an

stud-underlying mechanism of this interindividual

variabil-ity and of the different phenotypes is poorly

under-stood It is possibly genetically determined [185]

Genetic factors examined in relation to ICD and details

of the interindividual variation are also presented

below

2.3.1 Individual Variability in Irritant

Responses in Healthy Individuals

Under well-defined test conditions and in relatively

homogenous populations, interindividual variability in

irritant responses has repeatedly been documented both

after acute irritant assaults and chronic irritant

expo-sure [182–184] This means that some individuals

develop irritant reactions at lower doses than others

and/or react more intensely on irritant exposure They

can be considered more susceptible The variation in

reaction mimics a normal distribution [184] The

inter-individual variations are not only apparent by visual

scoring of reactions, but also when assessing the skin

changes by noninvasive objective methods [186–188]

The great interindividual variation in irritant siveness is not explained by intraindividual variability Intraindividual variability is in all instances less than the interindividual variation [188,189] Increased sus-ceptibility toward one irritant is not always indicative

respon-of an increased susceptibility to other irritants [190].The clinical implication of increased susceptibility

to irritant reactions has been assessed in a few studies Development of clinical hand dermatitis, type IV aller-gies, and enhanced allergic reactivity on elicitation is linked to an increased irritant susceptibility [191–193] The association between type IV allergies and increased irritant susceptibility is consistent with the danger model, where an antigenic signal in itself is not enough

to produce sensitization [194] A nonantigen-specific irritant signal – danger signal – is a pivotal component for sensitization to occur This is supported by the observations that otherwise subclinical doses of aller-gen produce a clinical response only in combination with irritants [195] and irritants lower the threshold for sensitization [196] The effect on elicitation occurs both when the irritant is applied simultaneous with the allergen and when applied 24 h after allergen exposure [195] A danger signal may more easily be produced in individuals with an inherent increased irritant suscep-tibility, and thus, associate with CA

The irritant response depends on the skin barrier integrity and the inflammatory response Variations in the skin barrier construct, skin recovery ability, and the components in the inflammatory reaction may give rise

to the interindividual variations seen Skin penetration

of irritants and transepidermal water loss (TEWL) are measures of skin barrier integrity Both measures have been found to be predictive of the acute irritant response [187, 197–200], but not of the chronic irritant response [186, 201] Total consensus is not apparent since skin reactivity to acute irritant assault is not always related

to the baseline skin barrier function [202] Skin ness correlates with the irritant penetration rate which indicates that skin thickness plays a role in the perme-ability of the skin and possibly in the response to irri-tant exposure [187] Epidermal lipids are also important

thick-to the skin barrier integrity The level of ceramides in the stratum corneum at baseline in healthy volunteers was inversely correlated to the intensity of reaction to acute irritant exposure in one study [203]

Several cytokines are involved in the inflammatory response and considerable interindividual differences in cytokines baseline levels are also observed [186, 204]

Causal components in irritant contact dermatitis

Combined exposure to irritants [259]

Age [197, 226, 227]

Sex [207, 221, 224, 225]

Ethnicity [230]

Minimal erythema dosage [242]

Table 2.5 Causal components in irritant contact dermatitis

2 Baseline stratum corneum levels of two cytokines, interleukin-1 receptor antagonist and interleukin-8,

respectively, have been shown to be predictive of the

acute response to skin irritation [186] The

proinflam-matory cytokine interleukin-1a, which is generally

considered an important contributor to the early response

of ICD, was not predictive of the acute irritant response

under experimental settings [186] The predictive value

of the baseline level of TNF-a, another important

proin-flammatory cytokine in ICD, has not been assessed A

permeable skin barrier, perhaps caused by changes in

epidermal lipids and skin thickness, and variations in

the basal inflammatory cytokine levels seem associated

with the degree of susceptibility to irritant exposure

But skin barrier and the inflammatory response are

highly complex fields with innumerable components

and further investigation into the underlying biological

mechanisms of individually increased irritant

suscepti-bility is warranted

2.3.2 Predisposition Related

to Specific Phenotypes

Small variations in irritant responses might be ascribed

to ethnicity, age, sex, AD, and other skin diseases

Generally, studies on the endogenous factors sex,

eth-nicity, and age are marked by divergent results, whereas

studies on AD are more consistent Many of the

stud-ies on predisposing factors related to specific

pheno-types are small in size, and therefore, seem to lack

power to determine if any difference exists It can

explain the divergent results reported The great

inter-individual variability may also mask any small impact

of a certain phenotype making it difficult in small

stud-ies to determine if any difference exists When larger

studies are carried out, small differences seem to appear, e.g., when examining sex as predisposing fac-tor for ICD This indicates that variations in irritant responses related to phenotypes do exist, but the impact

of these phenotypes is relatively small The ing ability of the endogenous factors such as AD, sex, age, ethnicity, body mass index, and other skin dis-eases to ICD is discussed below

predispos-2.3.2.1 Atopic Dermatitis

It is firmly established that patients with AD represent

a phenotype with increased reactivity when mentally exposed to irritants [201, 205–207] Such increased hyperreactivity is both present in clinically nor-mal and dry skin of patients with AD with the dry skin showing the greatest susceptibility to irritants [201, 205] Patients with a history of AD but no active lesions do not show an increased reactivity compared with patients with active AD [208, 209] The hyperreactivity observed

experi-in AD patients may also be positively correlated with severity of disease [210]

The higher susceptibility toward irritant reactions

in AD might partly be explained by higher ity of the skin barrier and by a greater inflammatory response The baseline barrier function in atopic indi-viduals has been reported not to differ from nonatopics [186, 209], but most studies report a higher baseline level of TEWL than in controls [201, 206, 211], indi-cating an altered skin barrier Measures were per-formed in macroscopically unaffected skin Patients with AD also have a higher penetration rate of SLS in uninvolved skin compared with nonatopics [187, 211], especially those with active AD lesions Patients with inactive dermatitis showed intermediate values in skin diffusibility [211] The baseline level of TEWL does not seem to be correlated with skin thickness in patients with AD, which indicate that other factors than skin thickness play a role in permeability of the skin in AD [211] The lipid composition in stratum corneum in skin of AD is disturbed, and changes in the epidermal proliferation and differentiation in both nonlesional and lesional skin of AD have also been reported, reviewed in [212] The indications of a compromised skin barrier may also be related to the recently found FLG mutations and association with AD [213] Baseline cytokine levels in the stratum corneum do not differ between atopics and nonatopics in in vivo

permeabil-Core Message

Great

› inter individual variation in the irritant

response exists in healthy individuals and is

not explained by intraindividual variability An

altered skin barrier and variations in basal

inflammatory cytokine levels might contribute

to the explanation of the interindividual

vari-ability, but further investigation into the

underlying mechanism is warranted

studies [186, 209], but spontaneous release of

proin-flammatory cytokines from keratinocytes is greater in

atopics in one cultured cell study [214] Furthermore,

the cytokine response upon stimulation, including the

important proinflammatory cytokines TNF-a and IL-1,

seems greater in atopic patients than in controls [214]

Patients with AD also possess a higher number of

TNF-a positive mast cells in the dermis [215]

Additional reading in reference [216]

The genetic basis of AD has been reviewed in [217]

and [218] and common susceptibility genes between

AD and ICD may be an obvious explanatory

possibil-ity of the increased irritant sensitivpossibil-ity in AD patients

Thirty-three SNPs in different genes and null

muta-tions in the profilaggrin gene have so far been

associ-ated with AD, but only associations between AD and

five of the SNPs and the FLG mutations have been

replicated [217, 218] Besides FLG mutations, none of

the other genetic markers for AD – which have been

replicated – have been examined in relation to ICD

2.3.2.2 Sex

Conflicting data exist on the role of the sex as

predis-posing factor for ICD Epidemiological studies

consis-tently show a higher rate of women among patients

with irritant hand eczema, but most experimental

stud-ies cannot confirm any differences between the sexes in

acute or cumulative irritant reactivity [183, 198] Also

no differences in baseline TEWL or barrier recovery

rate has been observed between sexes [183, 219, 220]

This stands in contrast to the generally perception of

women having more sensitive skin Total consensus

does not exist since a few studies have reported an

increased irritant susceptibility in women compared

with men [207, 221] Cyclic variation in baseline TEWL

and acute irritant response has also been reported for

women in accordance with menstrual cycle [222, 223]

In more recent studies, men reacted to a greater

degree on irritant exposure than did women [224, 225]

One of these studies compiled data from previous ies and represents one of the largest studies regarding sex as predisposing factor A large number of test sub-jects may reveal an endogenous factor with a relatively small impact on the irritant response, which is not revealed by a smaller number of test subjects The finding has been confirmed in one recent study, where male sex was a risk factor for irritant reaction, but the effect of the male sex was relatively weak [225] Overall, no consensus on the role of the sex as predis-posing factor of ICD is yet reached

stud-2.3.2.3 Age

Few studies have been conducted on age and irritant reactivity and the results are not uniform Most studies point at a decreased reactivity in the elderly both after acute and chronic irritant assaults [197, 226, 227] In one study, this age difference was most apparent for strong irritants [224] Cultured cell studies show a decreased inflammatory cytokine production after irri-tant exposure in intrinsic aged skin supporting a reduced response in the elderly compared with younger age [228] The basal barrier function measured as TEWL in the elderly is not altered [220], but other histological abnormalities of the skin barrier are apparent and the recovery of elderly skin is slower than in younger skin, reviewed in [229] In contrast, age above 40 years was

a risk factor for irritant responses in one study; ever, a rather weak risk factor [225] Larger studies are needed for further elucidation

how-2.3.2.4 Ethnicity

Interethnic variations in irritant reactions have been assessed between Asians and Caucasians, Blacks and Caucasians, and Hispanics and Caucasians Divergent reports on interethnic variations in irritant reactions have been given and no consensus on the topic exists The topic is reviewed in [230]

When different irritants with differing potencies were compared, no consistent differences in the level

of response was observed between Caucasians and Asians [190] Both increased responsiveness in Japanese vs Caucasian skin and decreased responsive-ness in Chinese vs Caucasian skin have been reported [231, 232] Increasing the number of test subjects by

Core Message

AD is a risk factor for increased susceptibility

›

to ICD, which might be ascribed to an altered

skin barrier and greater cytokine release