INNATE IMMUNITY

DR. PRASANNA HONNAVAR, PhD

1
 INNATE IMMUNITY

• General Features and Specificity of Innate Immune System

• Cellular Receptors for Microbes and Damaged Cells
• Components of Innate Immunity
• Innate Immune Reactions
• Evasion of Innate Immunity by Microbes
• Role of Innate Immunity in stimulating Adaptive Immune
Response
 Overview of immune system

Immune System

Adaptive
Innate
(Specific)
(Nonspecific)
2 line of defense
o
1o line of defense Protects/re-exposure

Cellular Components Humoral Components Cellular Components Humoral Components

 ISSUES

• How does the innate immune system recognize microbes

and damaged cells?

• How do the different components of innate immunity

function to combat different kinds of microbes?

• How do innate immune reactions stimulate adaptive

immune responses?

6
 General Features and Specificity of Innate
Immune System
• Principal types of reaction: inflammation , anti-viral defense
• Responds same way to repeat microbial encounters
• Recognizes structures shared by various classes of microbes and
not present on normal host cells
• Components evolve to recognize structures of microbes often
essential for survival and infectivity of these microbes (PAMP)
• Recognizes molecules released from damaged or necrotic cells
(DAMP)
• PRRs encoded in germline, not produced by somatic
recombination of genes; non-clonal distribution
• Does not react against host

7
Specificity and Receptors of Innate and
Adaptive Immunity

8
Cellular Locations of Receptors of the
Innate Immune System

9
Structure and Specificities of
Toll-like receptors (TLRs)

10
Signaling Functions of TLRs

11
The Inflammasome

12
 Components of Innate Immunity

• Epithelia

• Sentinel cells in the circulation and tissues

• NK cells

• Several plasma proteins

13
Functions of Epithelia in Innate Immunity

14
 Phagocytes

• Two types of circulating phagocytes:

• Neutrophils and Monocytes

• Recruited to sites of infection

• Recognize and ingest microbes for intracellular killing

15
16
Stages in the maturation of mononuclear
phagocytes

17
Activation and Functions of Macrophages

18
Classical and Alternative Macrophage
Activation

19
 Dendritic Cells

• Respond to microbes by producing numerous cytokines

• Cytokines recruit leukocytes initiating inflammation and

stimulate adaptive immune responses

• Constitute an important bridge between innate and

adaptive immunity

20
 Mast Cells

• BM-derived cells with abundant cytoplasmic granules

present in the skin and mucosal epithelium
• Can be activated by microbial products binding to TLRs
• Granules contain vasoactive amines, proteolytic enzymes
• Synthesize and secrete lipid mediators (e.g., prostaglandins)
and cytokines (e.g., TNF), which stimulate inflammation

21
 Natural Killer (NK) Cells

• Class of lymphocytes that recognize infected and stressed

cells

• Respond by killing these cells and by secreting the

macrophage-activating cytokine IFN-γ

• Activation determined by a balance between engagement of

activating and inhibitory receptors

22
Functions of NK Cells

23
Activating and Inhibitory receptors of
NK cells

24
 Other Classes of Lymphocytes

• Have some features of T and B lymphocytes

• Function in the early defense against microbes
• Express somatically rearranged antigen receptors (like
classical T and B cells) but limited diversity

• γδ T cells (epithelia)
• NK-T cells (epithelia, lymphoid organs)
• B-1 cells (peritoneal cavity, mucosal tissue)
• Marginal zone B cells (edges of lymphoid follicles)

25
 The Complement System

• Collection of circulating and membrane-associated proteins

important in microbial defense

• Proteins are proteolytic enzymes

• Activation involves sequential activation of these enzymes

• Enzymatic Cascade

26
Pathways of Complement Activation

27
 Other Plasma Proteins of Innate Immunity

• Mannose Binding Lectins (MBL)

• Surfactant Proteins
• C-Reactive Proteins (CRP)

• Circulating levels of many of these plasma proteins increase

rapidly after infection
• Protective response called the acute phase response to
infection

28
 Cytokines of Innate Immunity

• Dendritic cells, macrophages, and other cells secrete

cytokines in response to microbes
• Mediate many of the cellular reactions of innate immunity
• Soluble proteins mediate immune and inflammatory
reactions
• Responsible for communications between leukocytes and
between leukocytes and other cells (Interleukins)
• Also produced in cell-mediated immunity, major sources
being helper T lymphocytes

29
Cytokines of Innate Immunity (contd..)

30
Cytokines of Innate Immunity (contd..)

31
 Innate Immune Reactions

• Extracellular bacteria and fungi combated mainly by the

acute inflammatory response, in which neutrophils and
monocytes are recruited to the site of infection, and by the
complement system
• Defense against phagocytosed and intracellular bacteria
mediated by macrophages, which are activated by TLRs
and other sensors as well as by cytokines
• Defense against viruses provided by type I interferons and
natural killer cells
•

32
Acute Inflammatory Response

33
 Recruitment of Phagocytes to Sites of
Infection and Tissue Damage

• Extravascular migration

• By binding to venular endothelial adhesion molecules

• In response to chemoattractants produced by tissue cells in

response to PAMPs and DAMPs

34
35
 What Phagocytes do?

• Use several types of receptors to recognize microbes in the

blood and extravascular tissues

• Initiate responses that function to destroy the microbes

• Ingest (phagocytose) microbes

• Destroy the ingested microbes in intracellular vesicles

36
Phagocytosis and intra-cellular killing of
microbes

37
Phagocytosis and intra-cellular killing of
microbes

38
 Antiviral Defense
• Type I IFNs (several forms of IFN-α and one IFN-β), secreted by
many cell types infected by viruses
• Major source plasmacytoid dendritic cell
• Bind to IFN receptor on adjacent uninfected cells, signaling
pathways activated that inhibit viral replication and destroy viral
genomes
• Basis for use of IFN-α to treat some forms of chronic viral
hepatitis
• Enhance ability of NK cells to kill virus-infected cells
• Part of innate response to viral infections includes enhanced
apoptosis of infected cells
• Death of infected cells eliminates reservoir of infection

39
 Regulation of Innate Immune Responses

• Designed to prevent excessive tissue damage

• Antiinflammatory cytokines produced by macrophages and
dendritic cells, IL-10, inhibit microbicidal and
proinflammatory functions of macrophages
• IL-1 receptor antagonist, which blocks actions of IL-1
• Many feedback mechanisms in which signals that induce
proinflammatory cytokine production also induce
expression of inhibitors of cytokine signaling
• TLR signaling stimulates expression of proteins called
suppressors of cytokine signaling (SOCS), blocking responses
of cells to various cytokines, including IFNs

40
Evasion of Innate Immunity by Microbes

41
 Role of Innate Immunity in Stimulating
Adaptive Immune Responses

• Innate immune responses provide second signals for the

activation of B and T lymphocytes

• Requirement for these second signals ensures that adaptive

immunity is elicited by microbes and not by nonmicrobial
substances

42
Two-signal requirement for
lymphocyte activation

43
 REVIEW QUESTIONS

• How does the specificity of innate immunity differ from that of adaptive
immunity?
• What are examples of microbial substances recognized by the innate
immune system, and what are the receptors for these substances?
• What is the inflammasome, and how is it stimulated?
• What are the mechanisms by which the epithelium of the skin prevents
the entry of microbes?
• How do phagocytes ingest and kill microbes?
• What is the role of MHC molecules in the recognition of infected cells by
NK cells, and what is the physiologic significance of this recognition?
• What are the roles of the following cytokines in defense against
infections: (a) TNF, (b) IL-12, and (c) type I interferon?
• How do innate immune responses enhance adaptive immunity?

44