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Chapter 2:Innate

Immunity

Dr. Hafez Sumairi

Learning outcomes

1.How does the innate immune system recognizemicrobes and damaged cells?

2.How do the different components of innateimmunity function to combat different types ofmicrobes?

3.How do innate immune reactions stimulate adaptiveimmune responses?

Recognition ofmicrobes by the innateimmune systemInnate immunity also called natural, ornative, immunity, non specific

Adaptive or specific

Recognition of microbes by the innateimmune system• The components of innate immunity recognize structures that are shared by

various classes of microbes and are not present on host cellsPathogen-associated molecular patterns (PAMP)• Are shared by microbes of the same type

• Bacterial lipopolysaccharide (LPS)• Terminal mannose residues• Double-stranded RNA• Un-methylated CpG oligonucleotides

Pattern recognition receptors.• The receptors of innate immunity that recognize these shared structuresDamage-associated molecular patterns (DAMP)

Cellular receptors for microbes

• On phagocytes, dendritic cells,lymphocytes and epithelial andendothelial cells

• In different cellularcompartments

• Types• Toll-like receptors (TLRs)• Others

Cellular receptorsfor microbes typesToll-like receptors (TLRs)

Signal transduction

Components of innate immunity

1.Epithelia• Continuous epithelia that

provide physical andchemical barriers againstinfection

2.Cells in the circulation

3.Tissues4.Plasma proteins

Epithelia components

Cellular components of innate immunity

Phagocytes:• Neutrophils

• Polymorphonuclear leukocytes [PMNs]• Most abundant leukocytes in the blood• First cell type to respond, particularly bacterial

and fungal infections• Die after a few hours of ingestion

• Monocytes/macrophages• Survive in extravascular sites for long periods• Mononuclear phagocyte system• Produce cytokines

• Initiate and regulate inflammation,• Ingest and destroy microbes• Clear dead tissues• Initiate the process of tissue repair• APC

Cellular components of innate immunityMonocytes/macrophages

Cellular componentsof innate immunity• Monocytes/macrophages

• Activation• Functions

Cellular componentsof innate immunity• Monocytes/macrophages

Cellular components of innate immunity

• Dendritic Cells• Cytokines

• Initiate inflammation• Stimulate adaptive immune responses

• Mast Cells• Cytoplasmic granules

• Vasoactive amines such as• Histamine that cause vasodilation and increased capillary permeability• Proteolytic enzymes that can kill bacteria or inactivate microbial toxins.

• Skin and mucosal epithelium• Activated by

• Microbial products binding to TLRs• Special antibody

• Products• Synthesize and secrete

• Lipid mediators (e.g., prostaglandins)• Cytokines (e.g., TNF), which stimulate inflammation.• Products also provide defense against helminths and are responsible for symptoms of allergic diseases

Cellular componentsof innate immunity• Natural Killer Cells (NK) cells are

a class of (10%) lymphocytes that• Recognize infected and stressed

cells• Respond by killing these cells and

by secreting the macrophageactivating cytokine IFN-γ

• Cytoplasmic granules• Unique surface proteins• Eliminate cellular reservoirs of

infection

Cellular componentsof innate immunity• The activation of NK cells

is determined by a balancebetween engagement ofactivating and inhibitoryreceptors• IL12• IL15• Type I IFNs

Other classes of lymphocytes

1. Receptors have limited diversity2. Rapid responses• T cells

• γδ T cells are present in epithelia• NK-T cells• They recognize microbial lipids bound to a class I MHC–related molecule called CD1

• B cells• B-1 cells

• Found mostly in the peritoneal cavity and mucosal tissues• Natural antibodies (IgM)• Carbohydrates Ag

• Marginal-zone B cells• Carbohydrates Ag

Complement system• The complement system is a

collection of circulating andmembrane-associated proteinsthat are important in defenseagainst microbes.

• Proteolytic enzymes• Three functions

1. Opsonization2. C5a and C3a, are chemo-

attractants3. Formation of a polymeric protein

complex (MAC)

Other plasma proteins of innate immunity

Acute-phase response1. Plasma mannose binding lectin (MBL)

• MBL belongs to a family of proteins called the collectins, because they arestructurally similar to collagen and contain a carbohydrate-binding (lectin)domain.

2. Surfactant proteins• Belong to the collectin family and protect the airways from infection.

3. C-reactive protein (CRP)• Binds to phosphorylcholine on microbes and opsonizes the microbes for

phagocytosis by macrophages, which express a receptor for CRP

Cytokines of InnateImmunityInterleukins• These molecules are

produced by leukocytes andact on leukocytes.

• Are responsible forcommunications betweenleukocytes and betweenleukocytes and other cells

Innate immune reactions

1. The acute inflammatory response• Extracellular bacteria and fungi• Neutrophils and monocytes are recruited• Complement system

2. Antiviral defense mechanisms.• Type I interferons and natural killer cells.

Inflammation• It is a tissue reaction that rapidly delivers

mediators of host defense—circulatingcells and proteins—to the locations wherethey are needed, the sites of infection andtissue damage

Multiple steps

1. Recruitment of cells

2. Leakage of plasma proteins throughblood vessels

3. Engulfment of microbes and deadmaterial by phagocytes,

4. Destruction of these potentially harmfulsubstances.

Phagocytosis anddestruction ofmicrobes• Phagocytosis is a

process of ingestionof particles largerthan 0.5 µm indiameter.

• Chronicgranulomatousdisease (CGD)

Antiviral Defense• Type I interferons

induce resistance toviral infection andreplication, called anantiviral state

• Type I IFNs enhancethe ability of NK cellsto kill infected cells.

• Enhanced apoptosis

Microbial evasion of innate immunity

Regulation of innate immune responses

• Anti-inflammatory cytokines by macrophages and dendritic cells,• Interleukin-10 (IL-10), which inhibits the microbicidal and pro-inflammatory

functions of macrophages (classical pathway of macrophage activation),• IL-1 receptor antagonist, which blocks the actions of IL-1• Suppressors of cytokine signaling (SOCS), which block the responses of cells

to various cytokines, including IFNs.

Role of innate immunity in stimulatingadaptive immune responses• In experimental situations or for

vaccination the antigens need to beadministered with substances calledadjuvants that elicit the sameinnate immune reactions asmicrobes do.

• Types of second signals• T cells activation

1. Co-stimulators2. IL-12, IL-1, and IL-6

• B cells activation1. Complement product C3d serves as

the second signal for humoralimmune responses.

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