Transcript Document

Lecture outline
• General principles of host defense
• Mechanisms of host defense against
different classes of microbes
• Immune evasion by microbes
• Injury caused by normally protective
immune responses
• Strategies for vaccines
Host defense against infections
• The physiologic function of the host
immune response is to combat infections
– Inherited and acquired immune
deficiencies are manifested by
increased susceptibility to infections
and activation of latent infections
– Defects in different components of the
immune response make individuals
susceptible to different infections
– Vaccines provide protection against
infections
Immunity to microbes: general principles-1
• Defense against infections is mediated by the early
reactions of innate immunity and the later responses
of adaptive immunity
– The innate immune response controls infection long
enough for adaptive responses to kick in, and can
often eradicate the infection
– Many pathogenic microbes resist innate immunity
– Adaptive immunity is able to combat these
microbes -- the lymphocyte expansion that is
characteristic of adaptive immunity helps to keep
pace with rapidly dividing microbes; specialized
immune responses are better able to deal with
diverse microbes
Immunity to microbes: general
principles-2
• The immune system is specialized to
generate different effector
mechanisms for different types of
microbes
– Extracellular microbes: antibodies,
phagocytes; TH17, (TH1)
– Intracellular microbes: phagocytes +
TH1; CTLs
– Helminthic parasites: IgE, eosinophils;
TH2
Immunity to microbes: general principles-3
• The evolutionary battle: microbes and their
hosts are engaged in a constant struggle for
survival
• The outcome of infections is determined by
the balance between host defenses and the
ability of microbes to evade or resist
immunity
• Immune responses to microbes are
themselves capable of causing tissue injury
Principal mechanisms of defense against microbes
Antibodies
Phagocytes
T cells (CTLs)
(may work with antibodies, T cells)
All microbes
All microbes
Intracellular
microbes, esp.
viruses
Phases of immune responses
Microbe
Naïve T cells
Effector T cells
Naïve B cells
Plasma cells
Memory T cells
Memory B cells
Rapid protection Long-lived protection
Immunological memory
Yet it was with those who had recovered from
the disease that the sick and the dying found
most compassion. These knew what it was from
experience, and had now no fear for themselves;
for the same man was never attacked twice -never at least fatally. And such persons not only
received the congratulations of others, but
themselves also, in the elation of the moment,
half entertained the vain hope that they were for
the future safe from any disease whatsoever.
Description of the plague in Athens 430BC, Thucydides
Properties and roles of memory cells
• Survive even after infection is cleared
• Numbers more than naïve cells
• Respond to antigen challenge (recall) more
rapidly than do naïve cells
• Memory T cells: migrate to tissues, some
live in mucosal tissues and skin
• Memory B cells: produce high affinity,
often isotype switched, antibodies
• Provide rapid protection against recurrent
or persistent infections
• Goal of vaccination is to induce effective
memory
Specialization of immune responses to microbes
Effector
Type of microbe Adaptive immune response mechanism
Extracellular microbe Endocytosed antigen stimulates
(bacteria, viruses)
CD4+ helper T cells (TH1, TH17)
--> antibody, inflammation
Neutralization,
phagocytosis
Intracellular microbe Antigen in vesicles or cytosol IFN-g activates
in phagocytes
--> CD4+, CD8+ T cells
phagocytes; killing
of infected cells
Intracellular microbe Antigen in cytosol -->
in non-phagocytic
CD8+ CTLs
cell (virus)
Helminthic
parasites
TH2 response --> IgE,
eosinophils
Killing of
infected cells
Eosinophil-mediated
killing of IgE-coated
parasites
Adaptive immunity to extracellular microbes -antibodies
The only one way of preventing most infections
High-affinity antibodies are the most effective
Isotype switched antibodies trigger multiple effector mechanisms
Long-lived plasma cells provide prolonged protection
Adaptive immunity to extracellular microbes -role of helper T cells
IL-17
Antibody responses to bacteria
• Major antigens of many bacteria are
polysaccharides, and defense is mediated only by
antibodies; these T cell-independent antibody
responses may be short-lived and weak:
– Low-affinity, poor memory, few long-lived plasma cells,
IgM>IgG
• Helper T cell-dependent antibody responses to
protein antigens are more effective:
– High affinity; IgG, IgA>IgM; long half-life of IgG; longlived plasma cells; good memory
– Reason for development of “conjugate vaccines”
• Critical role of the spleen in bacterial clearance
Injurious effects of anti-bacterial immunity
• Local: acute inflammation (innate response, Th17
cells, antibodies), tissue damage
• Systemic effects of inflammation (fever, metabolic
abnormalities): cytokine mediated
• In severe cases, septic shock
– Shock (hypotension), disseminated intravascular
coagulation, metabolic abnormalities
– Caused by cytokines (mainly TNF) induced by LPS
(endotoxin), enterotoxins (“superantigens”)
• Rare late sequelae: immune complex diseases (e.g.
post-streptococcal GN); cross-reactive responses
against self tissues (e.g. rheumatic heart disease)
Innate and adaptive immunity to
intracellular bacteria
Cell-mediated immunity against intracellular microbes
CD4+ T cells: make phagocytes
better killers of microbes
CTLs: eliminate the
reservoir of infection
CD4+ and CD8+ T cells cooperate in cell-mediated
immunity against intracellular microbes
CD4+ T cells: help to kill microbes
in vesicles of phagocytes
CD8+ CTLs: kill microbes that
have escaped into the cytoplasm
Co-existence of immunity and
hypersensitivity in tuberculosis
• Cell-mediated immunity: beneficial host
response
– T cells produce IFN-g, which activates
phagocytes to kill ingested bacteria
• Delayed type hypersensitivity: tissue injury
– Macrophages activated by IFN-g injure involved
tissues, e.g. granulomatous inflammation with
caseous necrosis
– A cause of pathology in tuberculosis
Innate and adaptive immunity to viruses
Innate and adaptive immune responses in viral infections
Innate
immunity
Adaptive
immunity
Antibody
Roles of antibodies and CTLs in adaptive
immunity to viruses
• Antibodies neutralize viruses and prevent
infection
– Block infectious virus early in course of infection
(before entering cells) or after release from
infected cells (prevents cell-to-cell spread)
• CTLs kill infected cells and eradicate
reservoirs of established infection
– In some latent viral infections (EBV, CMV), CTLs
control but do not eradicate the infection;
defective T cell immunity leads to reactivation
of the virus (in HIV, immunosuppression caused
by leukemias, treatment for graft rejection)
Immune evasion by viruses
• Antigenic variation
– Influenza, HIV, rhinovirus
• Inhibition of the class I MHC antigen processing
pathway
– Different viruses use different mechanisms
– NK cells are the host adaptation for killing
class I MHC-negative infected cells
Viruses inhibit the class I MHC pathway
of antigen processing
Immune evasion by viruses
• Antigenic variation
– Influenza, HIV, rhinovirus
• Inhibition of the class I MHC antigen processing pathway
– Different viruses use different mechanisms
– NK cells are the host adaptation for killing class I MHCnegative infected cells
• Production of immune modulators
– Soluble cytokine receptors may act as “decoys”
and block actions of cytokines (poxviruses)
– Immunosuppressive cytokines, e.g. IL-10 (EBV)
• Engagement of inhibitory pathways
– LCMV (mice), HIV (humans): PD-1
• Infection of immune cells
– HIV
Different components of the immune
system defend against particular infections
Inherited deficiency
Infection(s)
MyD88 (many TLRs)
Invasive bacterial
infection (e.g.pulmonary)
TLR-3 (viral RNA sensor)
Herpes simplex encephalitis
TH1 pathway
“Atypical” (environmental)
mycobacteria
TH17 pathway
Mucocutaneous candidiasis,
skin bacterial abscesses
These examples (albeit rare) illustrate the specialization and
redundancy of components of innate and adaptive immunity.
Adaptive immunity to parasites
Parasite
Immune response
Effector mechanism
Helminths
TH2 cells --> IL-4, IL-5 Eosinophils kill IgE-coated
--> IgE, eosinophils
parasites (form of ADCC)
Leishmania
T cells produce IFN-g --> Phagocytes kill parasites
activation of phagocytes
living in endosomes
Malaria
CD8+ T cells -->
secretion of cytokines
Role of antibody?
IFN-g, TNF activate
macrophages, neutrophils
to kill parasites
The role of TH2 responses in defense against helminths
Eosinophils are better at killing helminths than are other
leukocytes; the TH2 response and IgE provide a mechanism
for bringing eosinophils to helminths and activating the cells.
Principal adaptive immune responses to microbes
Immune response
Type of
microbe
Protective functions
Pathologic effects
Extracellular
bacteria
1. Antibody
2. Activated macrophages
1. Immune complexes
2. Inflammation,
septic shock
Intracellular
bacteria
1. T cell-mediated
macrophage activation
2. CTL-mediated killing of
infected cells
1. Granulomatous
inflammation
2. Injury to host cells
Viruses
1. Antibody
2. CTL-mediated killing
of infected cells
1. Immune complexes
2. Injury to host cells
Principles of vaccination strategies
• Purified antigens --> protective antibody
– Not effective against microbes that mutate
antigenic proteins or hide inside infected cells
• Attenuated microbes, viral vectors for antigens
--> antibodies + CMI
– Safety concerns
• Difficult to induce effective CTL responses with
purified protein antigens
– Potential of plasmid DNA vaccines
• Clinically usable adjuvants
Efficacy of vaccines
• Vaccines have been useful for generating
protective antibodies, but so far, not for
generating effective cell-mediated
immunity
• Vaccines work best against microbes that:
– Do not vary their antigens
– Do not have animal reservoirs
– Do not establish latent infection within
host cells
– Do not interfere with the host immune
response