Lecture outline General principles of host defense Mechanisms of host defense against different classes of microbes Immune evasion by microbes Injury caused.

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

Naïve T cells

Microbe

Effector T cells Memory T cells

Naïve B cells Plasma cells Memory B cells

Rapid protection Long-lived protection

Phases of immune responses

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.

Immunological memory

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

Type of microbeAdaptive immune responseEffector

mechanism

Extracellular microbe(bacteria, viruses)

Endocytosed antigen stimulatesCD4+ helper T cells (TH1, TH17) --> antibody, inflammation

Neutralization,phagocytosis

Intracellular microbein phagocytes

Antigen in vesicles or cytosol --> CD4+, CD8+ T cells

IFN-g activatesphagocytes; killingof infected cells

Intracellular microbe in non-phagocytic cell (virus)

Antigen in cytosol -->CD8+ CTLs

Killing ofinfected cells

Helminthicparasites

TH2 response --> IgE,eosinophils

Eosinophil-mediatedkilling of IgE-coatedparasites

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;

long-lived 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

CD4+ T cells: make phagocytesbetter killers of microbes

CTLs: eliminate the reservoir of infection

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

CD4+ and CD8+ T cells cooperate in cell-mediated immunity against intracellular

microbes

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

Antibody

Innate and adaptive immune responses in viral infections

Innateimmunity

Adaptiveimmunity

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

MHC-negative 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

HelminthsTH2 cells --> IL-4, IL-5 --> IgE, eosinophils

Eosinophils kill IgE-coated parasites (form of ADCC)

LeishmaniaT cells produce IFN-g -->activation of phagocytes

Phagocytes kill parasitesliving in endosomes

MalariaCD8+ T cells --> secretion of cytokinesRole of antibody?

IFN-g, TNF activate macrophages, neutrophilsto 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

Type ofmicrobe Protective functions Pathologic effects

Immune response

Extracellularbacteria

1. Antibody2. Activated macrophages

1. Immune complexes2. Inflammation,septic shock

Intracellularbacteria

1. T cell-mediated macrophage activation 2. CTL-mediated killing of infected cells

1. Granulomatous inflammation2. Injury to host cells

Viruses 1. Antibody2. CTL-mediated killingof infected cells

1. Immune complexes2. 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