Innate Immunity Rui He Department of Immunology Shanghai Medical School Fudan University

Components of Immunity Innate Immunity: non-specific, also called natural or native immunity Adaptive Immunity: specific, also called acquired immunity

Features of Innate and Adaptive Immunity InnateAdaptive Characteristics Specificity For structures shared by groups of related microbes For antigens of microbes and for nonmicrobial antigens Diversity Limited; germline-encodedVery large; receptors are produced by somatic recombination of gene segments Memory NoneYes Nonreactivity to self Yes Components Cellular and chemical barriers Skin, mucosal epithelia; antimicrobial chemicals Lymphocytes in epithelia; antibodies secreted at epithelial surfaces Blood proteins Complement, othersAntibodies Cells Phagocytes (macrophages, neutrophils), natural killer cells Lymphocytes

The physiologic function of immune system Innate Immunity: the early reactions Adaptive Immunity: the later responses Defense against infectious microbes

 FUNCTIONS  COMPONENTS  Innate immunity recognition  The influence on adaptive immunity Innate Immunity

OVERVIEW The first line of defense against infection  An evolutionarily older defense strategy, found in all classes of plants and animals  Preexist infection or exposure to foreign antigen  Respond immediately after recognition of microbes  Respond in essentially the same way to repeated infection

 Initial response to microbes to prevent infection with elimination of danger  Innate components also important in adaptive immunity  Stimulates adaptive responses FUNCTIONS

Components of innate immune system ComponentsPrincipal Functions Epithelial barriers Epithelial layersPrevent microbial entry DefensinsMicrobial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells NeutrophilsEarly phagocytosis and killing of microbes MacrophagesEfficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cellsLysis of infected cells, activation of macrophages Circulating effector proteins ComplementKilling of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines

Epithelial barriers

 Skin  Mucosal surfaces of the gastrointestinal tracts (GI)  Mucosal surfaces of the respiratory tracts Physical barriers

Antimicrobial Peptides  Defensins Cystein-rich peptides with amino acids Present in the skin and abundant in neutrophil granules Broad-spectrum antibiotics Upregulated by inflammatory cytokines  Cryptocidines Secreted by the epithelium of the intestine Locally sterilize the lumen of intestine

Intraepithelial lymphocytes  Intraepithelial T cells Present in the epidermis of the skin and in mucosal epithelia  cells and NKT cells Serve as sentinels at common sites of microbial invasion  B-1 cells Present in peritoneal cavity Produce NATURAL antibodies

Components of innate immune system ComponentsPrincipal Functions Epithelial barriers Epithelial layersPrevent microbial entry DefensinsMicrobial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells NeutrophilsEarly phagocytosis and killing of microbes MacrophagesEfficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cellsLysis of infected cells, activation of macrophages Circulating effector proteins ComplementKilling of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines

Phagocytes  Cell types Neutrophils and Macrophages  Primary functions Identify, ingest, and destroy microbes

Neutrophils Polymorphonuclear neutrophils (PMNs)

 The most abundant population of circulating leukocytes  Mediate the earliest phases of inflammatory responses Neutrophils

Macrophages

Name of cell Location Alveolar macrophages pulmonary alveoluspulmonary alveolus of lungs lungs Histiocytesconnective tissue Kupffer cellsliver Microglianeural tissue EpithelioidEpithelioid cellsgranulomas Osteoclastsbone SinusoidalSinusoidal lining cellsspleen

 Dominant effector cells of the later stages of innate immune responses  Play central role in both innate and adaptive immune responses Macrophages

1.Active recruitment of the cells to sites of infection 2. Recognition of microbes 3.Phagocytosis 4. Destruction of ingested microbes The steps of functional responses of phagocytes

© 2005 Elsevier Recruitment of leukocytes

Phagocytosis  A cytoskeleton-dependent cellular process of phagocytes of engulfing large particles  Bound microbes are ingested into vesicles called phagosome

Destruction of phagocytosed microbes  Where Phagolysosome  Killing Mechanisms 1. Reactive oxygen intermediates (ROIs) 2. Reactive nitrogen intermediates: mainly NO 3. Preformed antimicrobials BUT, these mechanisms also can cause host tissue injury

Effector functions of macrophage

Natural Killer cells (NK cells)  A type of cytotoxic lymphocytes  The principal physiologic role 1.Defense against infections by viruses and some other intracelluar microbes 2. Rejection of tumors

The mechanism of effector function Perforin Granzyme

Components of innate immune system ComponentsPrincipal Functions Epithelial barriers Epithelial layersPrevent microbial entry DefensinsMicrobial killing Intraepithelial lymphocytesMicrobial killing Circulating effector cells NeutrophilsEarly phagocytosis and killing of microbes MacrophagesEfficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cellsLysis of infected cells, activation of macrophages Circulating effector proteins ComplementKilling of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines

The complement system  A complex series of some plasma proteins  Pathways of complement activation 1.Classical Pathway 2.Alternative Pathway 3.The lectin Pathway

Pathways of complement activation. The activation of the complement system may be initiated by three distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 14.

The effect of complement activation  Opsonization of pathogen  Recruitment of leukocytes  Killing of pathogens

Cytokines Cell source : macrophages, neutrophils, and NK cells, endothelial cells, some epithelial cells Functions 1.Recruit and activate leukocytes 2.Produce systemic alterations that contribute to potentiate antimicrobial responses Proteins secreted by the cells of innate and adaptive immunity that mediate many of the functions of these cells.

Cytokines TNF, IL-1Inflammation IFN-γMacrophage activation IL-12IFN-γ production by NK cells and T cells IL-15Proliferation of NK cells IL-10, TGF-βControl of inflammation In severe infection, excess systemic cytokine production is harmful and may even cause death of the host

The first line of host defense against microbes The mechanisms of innate immunity exist before exposure to microbes The components of the innate immune system include epithelial barriers,leukocytes, circulating effector proteins and cytokines Neutrophils and macrophages are phagocytes that kill ingested microbesby producing ROIs, nitric oxide, and enzymes in phagolysosomes NK cells are lymphocytes that defend against intracelluar microbes by killing infected cells and providing a source of the macrophage-activatingcytokine IFN-γ The complement system is activated by microbes, and products of complement activation promote phagocytosis and killing of microbes and stimulate inflammation Different cytokines of innate immunity recruit and activate leukocytes, enhance the microbicidal activities of phagocytes, and stimulate NK cells and T cell responses Summary

To be continued