"FUNCTIONAL" IMMUNOLOGY HOST RESPONSES TO INFECTIOUS DISEASE PAUL A. GULIG

"FUNCTIONAL" IMMUNOLOGY HOST RESPONSES TO INFECTIOUS DISEASE PAUL A GULIG "FUNCTIONAL" IMMUNOLOGY HOST RESPONSES TO INFECTIOUS DISEASE PAUL A GULIG April 7, 2008 CONCEPTS 1 Immunity works! (usually) M[.]

"FUNCTIONAL" IMMUNOLOGY

HOST RESPONSES TO INFECTIOUS DISEASE

PAUL A GULIG April 7, 2008

1 Immunity works! (usually) - Most infectious agents cannot

evade innate immunity or early induced responses Hardly any can evade the adaptive response

2 Levels of immunity/defenses

a Innate defenses

b Early induced response (cytokines, phagocytes,

complement, inflammation)

c Specific, adaptive immune response (Ig and CMI)

3 The relevant adaptive immune response depends on the

nature of the infectious organism, its anatomical site of

infection, and intracellular/extracellular nature of infection

Figure 2-1

INNATE DEFENSES OF SURFACES

INNATE DEFENSES OF SURFACES

antibacterial peptides in intestines

C Microbial - normal flora of gut, lower genital tract, upper respiratory tract

INNATE DEFENSES "INSIDE" THE BODY

Activation of Complement

Alternative pathway - stabilizing C3b,Bb

Classical pathway - IgM and IgG antibodies (not innate)

Mannan-binding Lectin – microbial carbohydrates

Polymorphonuclear leukocytes (PMNs)

- short lived (T 1/2 - hours)

- found in circulation and marginal zones of capillaries -

rapid recruitment

- can be recruited as part of early induced response by

chemotaxis – quickly

- more oxidative than macrophages

- granules with antimicrobial factors (defensins,

proteases, lysozyme, bacterial permeability factor, etc.)

Cellular - phagocytes

- long lived (T 1/2 - days)

- produced from bone marrow precursors - slower

- circulating monocytes , tissue macrophages in RES

- can be activated by adaptive response and certain cytokines to kill intracellular pathogens

- secrete cytokines to produce early induced

response

-antigen presentation

Dendritic Cells

• Mainly antigen presentation

• Not killing

Toll-Like Receptors (TLRs) – 10 (at least):

• TLR2 bacterial peptidoglycan, lipoproteins

cytoplasmic – recognize peptidoglycan components

Regulate cell activation and innate immune

response

EARLY INDUCED DEFENSES

• stimulated by relatively invariant receptors on

host cells (not antigen-specific)

• short lived

• no memory or secondary response

• boosts nonspecific cellular and humoral effectors

to fight infection until adaptive immunity can be produced

• symptoms : pain, swelling, redness, heat

• reasons : vasodilation, edema, increased permeability

• functions : increase access of cellular and humoral defenses to infection

• main action at vascular endothelium

Figure 1-12

Figure 2-45

Macrophage Cytokines

pro-inflammatory

a IL-1 - endogenous pyrogen ( fever

b IL-6 - stimulate acute phase response from liver (CRP, MBP, etc to opsonize microbes)

d IL-8 - chemokine to recruit PMNs

e IL-12 - potentiate IFN-γ production by NK cells with help of TNF-α

• endothelial and leukocyte surface proteins

(selectins, integrins) mediate extravasation, diapedesis, and migration in regulated

manners

• IFN-α and IFN-β

– from cells infected with viruses

– inhibit viral replication

– increase MHC class I (Ag-presentation)

– activate NK cells

• IFN-γ produced by NK cells and Th1 cells

– stimulates macrophages to kill intracellular pathogens

Figure 2-48

NK cells

• cytotoxic activity (like CTLs )

• secrete IFN-γ like Th1 and γδ-T cells

• stimulated by IFN-α and IFN-β; IL-12 + TNF-α

ADAPTIVE IMMUNITY

• antigen-specific:

– antibodies from B/plasma cells

– effector/regulatory T cells

• clonal expansion of effector cells

• potential for immunological memory

Which Type of Immunity is

Best?

Ask

where are the pathogens

anatomically (including production

of toxins)?

• epithelium

– (adherence factors and locally acting toxins) – sIgA

• "inside " body

– extracellular and circulating toxins

• IgG for opsonization, lysis (with C),

neutralization

• driven by Th2 response

• Th1 CMI via activated macrophages to kill

intracellular pathogens

• T cells recognize processed antigens of

pathogen in context of MHC class II , secrete cytokines (primarily, but not exclusively IFN-

γ ) to stimulate macrophages

Figure 8-27

Regulation Of The Type Of Response

Given this level of understanding of the process of infectious disease and the

range of immune defense mechanisms, you should be able to predict the type of defenses a microbe will encounter as

part of a given disease process and the type of adaptive immunity that will

protect against the infection and

disease.

Evasion of Host Defenses

You must know the opponent as

well as yourself

1 Do they spread beyond the mucosal surface to

the inside of the body?

2 Do they live extracellularly or intracellularly ?

3 If they are intracellular, do they infect

phagocytes or nonphagocytes ?

4 If they are intracellular, do they remain within a

vacuole , or do they invade to the cytoplasm?

Consider which host defenses they will encounter.

In tissues and fluids

1 Complement

virulence mechanisms for evasion

a do not bind and/or activate complement -

polysaccharide capsules

b cause inhibition of activation and amplification cascade

- bind factor H (M protein of streptococci)

c degrade complement - secrete proteases

d complement receptor homologs (viruses)

e secrete complement homologs

C4b homolog (vaccinia virus) inhibits C cascade

2 Phagocytes - beyond mucosal surface

i EXTRACELLULAR vs INTRACELLULAR pathogens

ii extracellular antiphagocytic functions

►inhibit recruitment - inhibit complement, cytokines

►kill the phagocytes - toxins

►prevent phagocytosis - prevent opsonization , prevent

binding (carbohydrate capsules)

iii intracellular pathogen functions

►inhibit phagosome-lysosome fusion (type 3 secreted proteins)

►escape phago(lyso)some into cytoplasm (lipases)

►inhibit oxidative burst (?)

►resist antimicrobial functions (catalase, altered LPS)

Cytokines

• IL-1

converting enzyme), preventing formation of IL-1β, down regulating inflammation and inhibiting apoptosis

– B15R protein of vaccinia virus - IL-1 receptor

– IFN-α/β receptor homologs secreted by vaccinia virus

– Vaccinia virus E3L and K3L proteins inhibit different parts of

IFN-mediated intracellular antiviral functions

Figure 11-5

Immune Host

c Antibodies

i at mucosal surface - degrade antibodies

►IgAse of Haemophilus influenzae

ii antigenic mimicry - surface components look like host

►polysialic acid capsule of Neisseria meningitidis

iii antigenic cloaking - bind host proteins to bacterial surface

►protein A of Staphylococcus aureus

c Antibodies (continued)

iii antigenic variation - change antigenic composition

►during infection of a single host:

- pili of Neisseria gonorrhoea

- variable surface proteins of Trypanosomes (protozoans)

►from year to year:

- Hemagglutinin of Influenza virus (shift and drift)

iv antigenic variety -numerous serological types among strains in the world (each strain is antigenically stable)

► M protein of Streptococcus pyogenes

► Rhinoviruses

Figure 11-3 part 2 of 2

Figure 11-1

d Cell-mediated immunity

i immunosuppression - HIV - affecting CD4/CD8 ratios

ii alter host response from cell-mediated (Th1) to antibody

(Th2) response - Mycobacterium leprae

• M leprae - intracellular pathogen of macrophages - replicates

within macrophages

• Antibodies (Th2-regulated) are ineffective and probably

detrimental

• Cell-mediated immunity (Th1 regulated) is protective

• M leprae causes some people to produce primarily an

antibody response by affecting cytokine gene expression (lepromatous leprosy)

• People who make CMI responses have mild disease

(tuberculous leprosy)

Figure 11-6

Humoral and Cell-mediated

• Latency of viruses

– hide out until the coast is clear (many Herpes

viruses)

– Varicella zoster (chicken pox) re-emerges

later in life as shingles after being latent in

nerve ganglia

Figure 11-4