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; T H 17, (T H 1) –Intracellular microbes: phagocytes + T H 1; CTLs –Helminthic parasites: IgE, eosinophils; T H 2

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 Intracellular microbes, esp. viruses

Naïve T cells Microbe Effector T cells Memory T cells Naïve B cells Plasma cells Memory B cells Rapid protectionLong-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 response Effector mechanism Extracellular microbe (bacteria, viruses) Endocytosed antigen stimulates CD4+ helper T cells (T H 1, T H 17) --> antibody, inflammation Neutralization, phagocytosis Intracellular microbe in phagocytes Antigen in vesicles or cytosol --> CD4+, CD8+ T cells IFN-  activates phagocytes; killing of infected cells Intracellular microbe in non-phagocytic cell (virus) Antigen in cytosol --> CD8+ CTLs Killing of infected cells Helminthic parasites T H 2 response --> IgE, eosinophils 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; 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 phagocytes better 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- , which activates phagocytes to kill ingested bacteria Delayed type hypersensitivity: tissue injury –Macrophages activated by IFN-  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 Innate immunity Adaptive immunity

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 deficiencyInfection(s) MyD88 (many TLRs)Invasive bacterial infection (e.g.pulmonary) TLR-3 (viral RNA sensor)Herpes simplex encephalitis T H 1 pathway“Atypical” (environmental) mycobacteria T H 17 pathwayMucocutaneous candidiasis, skin bacterial abscesses These examples (albeit rare) illustrate the specialization and redundancy of components of innate and adaptive immunity.

Adaptive immunity to parasites ParasiteImmune responseEffector mechanism Helminths T H 2 cells --> IL-4, IL-5 --> IgE, eosinophils Eosinophils kill IgE-coated parasites (form of ADCC) Leishmania T cells produce IFN-  --> activation of phagocytes Phagocytes kill parasites living in endosomes Malaria CD8+ T cells --> secretion of cytokines Role of antibody? IFN- , TNF activate macrophages, neutrophils to kill parasites

The role of T H 2 responses in defense against helminths Eosinophils are better at killing helminths than are other leukocytes; the T H 2 response and IgE provide a mechanism for bringing eosinophils to helminths and activating the cells.

Principal adaptive immune responses to microbes Type of microbe Protective functionsPathologic effects Immune response 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 Viruses1. 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