Innate Immunity

Rui He

ruihe@fudan.edu.cn

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

  Innate AdaptiveCharacteristics

Specificity For structures shared by groups of related microbes

For antigens of microbes and for nonmicrobial antigens

Diversity Limited; germline-encoded Very large; receptors are produced by somatic recombination of gene segments

Memory None Yes

Nonreactivity to self

Yes Yes

Components

Cellular and chemical barriers

Skin, mucosal epithelia; antimicrobial chemicals

Lymphocytes in epithelia; antibodies secreted at epithelial surfaces

Blood proteins Complement, others Antibodies

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

Components Principal FunctionsEpithelial barriers

Epithelial layers Prevent microbial entry

Defensins Microbial killing

Intraepithelial lymphocytes

Microbial killing

Circulating effector cells

Neutrophils Early phagocytosis and killing of microbes

Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation

NK cells Lysis of infected cells, activation of macrophages

Circulating effector proteins

Complement Killing 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 29-34 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

Components Principal Functions

Epithelial barriersEpithelial layers Prevent microbial entry

Defensins Microbial killing

Intraepithelial lymphocytes

Microbial killing

Circulating effector cellsNeutrophils Early phagocytosis and killing of microbes

Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation

NK cells Lysis of infected cells, activation of macrophages

Circulating effector proteinsComplement Killing 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

NeutrophilsPolymorphonuclear neutrophils (PMNs)

The most abundant population of circulating leukocytes

Mediate the earliest phases of inflammatory responses

Neutrophils

Macrophages

Name of cell Location

Alveolar macrophagespulmonary alveolus of lungs

Histiocytes connective tissue

Kupffer cells liver

Microglia neural tissue

Epithelioid cells granulomas

Osteoclasts bone

Sinusoidal lining cells spleen

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

Components Principal Functions

Epithelial barriersEpithelial layers Prevent microbial entry

Defensins Microbial killing

Intraepithelial lymphocytes Microbial killing

Circulating effector cellsNeutrophils Early phagocytosis and killing of microbes

Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation

NK cells Lysis of infected cells, activation of macrophages

Circulating effector proteinsComplement Killing 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-1 Inflammation

IFN-γ Macrophage activation

IL-12 IFN-γ production by NK cells and T cells

IL-15 Proliferation of NK cells

IL-10, TGF-β Control 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