"FUNCTIONAL" IMMUNOLOGYHOST RESPONSES TO INFECTIOUS DISEASE

"FUNCTIONAL" IMMUNOLOGY
HOST RESPONSES TO INFECTIOUS DISEASE

PAUL A. GULIG
April 7, 2008

CONCEPTS

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
A. Physical:
Epidermis - essentially impenetrable (except maybe some worms)
Epithelial Surface - mucus and flow of luminal fluid (tears, urine, food, etc.)
B. Chemical:
fatty acids of skin
lysozyme in secretions
digestion by enzymes of intestines
acid - stomach
antibacterial peptides in intestines
C. Microbial - normal flora of gut, lower genital tract, upper respiratory tract
INNATE DEFENSES "INSIDE" THE BODY
Humoral – complement

Functions:
Opsonization (C3b)

Lysis of some organisms (C5-9 - MAC)

Chemotaxis and anaphylaxis (C5a and C3a) - early induced function
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
Macrophages
- 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
Receptors
Toll-Like Receptors (TLRs) – 10 (at least):
TLR2 bacterial peptidoglycan, lipoproteins
TLR3 viral dsRNA
TLR4 bacterial LPS (with CD14)
TLR5 bacterial flagella
TLR9 bacterial CpG

Nucleotide-binding oligomerization domain (Nod) proteins (Nod1 and Nod2)
cytoplasmic – recognize peptidoglycan components

Regulate cell activation and innate immune response
Antimicrobial Effectors
Reactive Oxygen Intermediates (peroxide, superoxide)

Reactive Nitrogen Intermediates (nitric oxide)

Lysosomal/granule factors
defensins
proteases
lysozyme
bacterial permeability factor
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
Inflammation
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
c. TNF-α – inflammation – vascular endothelium

vasodilation
↑ vascular permeability
↑ adhesion molecules by endothelium
clotting of vasculature
systemic vs. local production can lead to damage (shock)
Macrophage Cytokines
pro-inflammatory
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
Chemokines
recruit and activate phagocytes

PMNs: IL-8
macrophages/monocytes: MCAF/MCP-1
other cells
endothelial and leukocyte surface proteins (selectins, integrins) mediate extravasation, diapedesis, and migration in regulated manners
Interferons
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
CHOICES
Antibodies
circulating humoral IgG/IgM
mucosal sIgA

Cell Mediated Immunity
cytotoxic CD8+ T cells (CTLs)
inflammatory CD4+ T cells (Th1)
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
intracellular
macrophages –

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

intracellular
non-phagocytes

CTL
lyse infected cells
MHC class I dependent
Figure 8-27
Figure 10-4
Regulation Of The Type Of Response
mucosal immunity
stimulated at mucosal associated lymphoid tissues

Th1 vs. Th2
early cytokines
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
Functions/stages of pathogens/disease

1. encounter
2. entry
3. spread (+/-)
4. multiplication
5. evasion of host defenses
6. damage
7. move to new host (+/-)
You must know the opponent as well as yourself
Do they spread beyond the mucosal surface to the inside of the body?
Do they live extracellularly or intracellularly?
If they are intracellular, do they infect phagocytes or nonphagocytes?
If they are intracellular, do they remain within a vacuole, or do they invade to the cytoplasm?
Consider which host defenses they will encounter.
Non-immune host
At mucosal surfaces: not many defenses –

antibacterial proteins
defensins
evasion – changes in LPS
lysozyme
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
B13R protein of vaccinia virus inhibits ICE (IL-1 converting enzyme), preventing formation of IL-1β, down regulating inflammation and inhibiting apoptosis
B15R protein of vaccinia virus - IL-1 receptor homologous
TNF-α
pox viruses secrete TNF receptor homologs that can bind TNF-α
Interferons
IFN-γ receptor homologs secreted by myxoma virus and vaccinia virus
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