Immune System Overview

Dr J.O.Akande

Introduction

• Functional system rather than organ system

– Hematopoetic

– Vasculature

– Lymphatic

• There are 2 major lines of defense;

1. Non-specific (Innate Immunity)

2. Specific (Adaptive Immunity)

Cont’d

• Definition: The study of the physiologic mechanisms that allow the body to recognize materials as foreign or abnormal and to neutralize or eliminate those foreign materials.

• 3 general principles

1. Recognition of self versus non-self

2. SELECTIVITY and SPECIFICITY—The immune system is highly selective and specific for each pathogen

3. MEMORY—Once having met a pathogen, the immune system never forgets it.

Cont’d

Innate

• Surface Defenses

• Internal Defenses: Based on recognition of surface carbohydrates (glycocalyx)

• Glycocalyx is recognized as “self” or “non-self”

Surface Defenses• Skin

– physical barrier to microbes– Keratin resistant to most bacterial enzymes & toxins– secretions are acidic pH 3-5

• Mucosa – physical barrier and produces a variety of protective chemicals

• Gastric mucosa – very acidic and produces proteolytic enzymes

• Saliva & lacrimal fluid contain lysozyme• Mucous

– traps bacteria & moves them away from epithelial surface

Internal Defenses• Phagocytes

– Macrophages: derived from monocytes

• Free Macrophages: roam through tissues

• Fixed Macrophages: Kupffer cells (liver) & microglia (brain)

• Ingest cellular debris, foreign material, bacteria, fungi

– Neutrophils: ingest pathogens

– Eosinophils: weakly phagocytic of pathogens. Attack parasites (degranulation)

– Mast Cells: phagocytic of various bacteria

Cont’d• Phagocytic mechanisms:

– Adherence: cell binds to invader

• Aided by opsonization (a chemical process that enhances binding via complement & antibodies)

– Ingestion: formation of phagolysosomes

• Respiratory Bursts: merge phagosome with lysosome & flood phagolysosome with free radicals (macrophage)

• Defensins: proteins that crystallize out of solution & pierce pathogen membranes (neutrophils)

Mechanism of Phagocytosis

Figure 21.2

Cont’d

• Natural Killer Cells:

– Small population of large granular lymphocytes

– Non specific for “non-self”

– Not phagocytic: attack is by release of perforins that perforate the target cell plasma membrane.

• Shortly after perforation the target nucleus disintegrates.

– Release chemicals that enhance the inflammatory response

Inflammation• Tissue response to injury

• Triggered by injury – trauma, heat, chemical irritation, infection, etc.

• Beneficial effects

–Prevents spread of injury

–Disposes of cellular debris & pathogens

–Promotes repair

Cont’d

• cardinal signs of inflammation

–Redness

–Heat

– Swelling

–Pain

– (functional impairment Rigor)

Inflammatory Response

• Mechanisms causing vasodilation & vascular permeability

– Injured cells release inflammatory mediators• Histamines

• Kinins

• Prostaglandins

• Complement

• Cytokines (also activated by receptors on macrophages in response to microbial glycocalyx)

Cont’d

• Edema

– Dilutes harmful substances

– Provides nutrients (& O2) for repair

– Enhances entry of clotting protein

• Epithelial breaches also stimulate b-defensin release from epithelial cells

Cont’d

• Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages

• Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow

• Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing).

Cont’d

• Diapedesis: neutrophils migrate through capillary walls

• Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first)

• As the process continues, monocytes diapedesinto the area & become macrophages. With chronic inflammation, macrophages predominate

Cont’d

• Macrophages clean up cellular debris & pathogens

• If pathogens were associated with the injury, activation of the complement cascade occurs & elements of adaptive immunity join the process

Antiviral proteins

• Interferon and complement

• Interferon: some cells produce and release interferons (IFNs) when invaded by virus

• Released interferons stimulate nearby cells to produce proteins (PKR) that interfere with viral replication by disrupting protein synthesis and the ribosome

• Not virus specific.

Complement• A group of plasma proteins (20) that are

activated in the presence of foreign substances

• Complement activation enhances and amplifies inflammation

• Bacteria and some other cell types are lysed by complement activation

• Complement activation enhances both innate and adaptive defenses

Cont’d• Complement activation pathways

– Classical pathway: requires antibodies

• Antibodies bind to target (antigen)

• Complement protein C1 binds to the antibody-antigen complex (complement fixation)

– Alternative pathway: complement factors interact with microorganism glycocalyx

• Both pathways lead to a cascade of protein activation, leading to activation of C3

Cont’d

• C3 is the start of the; Final Common Pathway– C3 cleaves to form C3a & C3b– C3a (& C5a) enhance inflammation by increasing histamine

release, increasing vascular permeability & stimulating chemotaxis

– C3b coats bacterial membrane supplying adhesion points (opsonization)

– C3b initiates the cascade forming the membrane attack complex (MAC)

– The MAC forms a hole in the cell membrane & enhances Ca2+ influx cell lysis

Cont’d

• C-reactive proteins (CRP) produced by the liver in response to inflammatory molecules can activate the classical pathway by binding to membrane & activating C1. Also participates in opsonization.

• Fever – a systemic response to infection. Leukocytes & macrophages release pyrogensthat raise the hypothalamic “set point” for temperature

ADAPTIVE DEFENSES

• Characteristics;

• Specificity: directed at specific targets

• Systemic: not restricted to initial site of infection / invasion

• Memory: after initial exposure and activation, a more rapid and more vigorous response is made to subsequent exposures to pathogens

–(secondary response)

Components

• Humoral Immunity: (antibody mediated immunity) provided by antibodies floating free in body fluids

• Cell mediated immunity:

– lymphocytes directly attack specific invaders by lysis or indirect attack by initiating inflammation and/or activating other lymphocytes & macrophages

Humoral Immunity

• Antigen = any substance that can mobilize the immune system and provoke an immune response.

• Complete antigens (proteins, nucleic acids, lipids, polysaccharides):– Immunogenicity: the ability to stimulate specific lymphocytes

and specific antibodies

– Reactivity: the ability to react with activated lymphocytes and antibodies

• Hapten (an incomplete antigen): a smaller molecule that is not immunogenic until attached to proteins

Cells

• Lymphocytes

– T-cells

– B-cells

• Antigen Presenting Cells (APCs)

Cont’d

• Lymphocytes: initially uncommitted

• T-cells: are sorted in the Thymus

– Positive selection: recognize MHC survive

– Negative selection: react against to self-antigens on MHC killed

– 2% of initial T-cell precursors

– T-cells manage the immune response

• B-cells: are sorted in the marrow by an incompletely understood process

Cont’d• Immunocompetence: as T- or B-cells mature they

become immunocompetent,

• They display receptors on their cell membrane for a specific antigen.

• All of the receptors on one cell are identical; immunity depends upon genetic coding for appropriate receptors.

Antigen Presenting Cells (APCs)

• APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells

– T-cells: respond to antigen only if it is displayed on plasma membrane.

• APCs: Macrophages & B lymphocytes

• Interactions between APCs & lymphocytes & lymphocyte-lymphocyte interactions are critical to immune response

Humoral response

• Humoral response (clonal selection)

• B-cells: Antigen challenge to naïve immunocompetent B-cell

• Antigen binds to B-cell receptors & form cross-links between receptors

• Cross linked antigen-receptor complex undergoes endocytosis; B-cell presents to T-cell

Cont’d

Humoral Immunity

• Active humoral immunity:

– B-cells encounter & respond to antigen to produce an antibody

• Passive humoral immunity:

– Introduced “non-native” antibody

Active Humoral Immunity

• Naturally acquired: natural exposure to antigen (i.e. infection)

• Artificially acquired: vaccines; dead/attenuated or fragmented pathogen injected to elicit an immune response– Bestow immunity without disease; primary response

– Booster shots (secondary response); intensify response

– Shortcomings – adverse reactions & the immunity is less durable (poor memory) & has less cell mediated component

Passive Humoral Immunity

• Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months)

• Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins , gamma globulin, etc.)

Cell Mediated Immune Response

• T-cell activation: involves recognition of PM surface antigens only

– Antigen is combined with MHC & displayed on PM

– T-cell receptors: bind to the MHC & are stimulated by the associated antigen

– The addition of a co-stimulator (cytokines, interleukins, etc) prompts the T-cell to form a clone

– In the absence of a co-stimulator the T-cell becomes tolerant to antigen (anergy)

Cell Mediated: MHC

• MHC occurs as two classes

– MHC I on virtually all tissue cells

– MHC II only on PM some immune system cells

MHC display properties

• MHC I on virtually all tissue cells

– Display only proteins produced inside the cell

– Endogenous antigens = foreign proteins produced by the cell (viral / cancer)

– Stimulate the CD8* cell population

• form cytotoxic T-cells (Killer T, TC)

• *formerly T8 cells

Cont’d

• MHC II found only on PM of B-cells, some T-cells & APCs

– Display proteins derived from a phagocytized target

– Exogenous antigen: foreign protein from outside the cell –presented to PM surface

– Stimulates the CD4* cell population

• form Helper T-cells (TH)

• *formerly T4 cells

Figure 21.16b

T-cell roles• Helper T-cells (TH) stimulate B-cells & other T-cells to

proliferate

• Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody

• TH cells also produce cytokines that promote TC cells

• TH cells recruit other WBCs & amplify innate defenses (inflammatory)

• Subpopulations of TH cells specialize in specific sets of activations

• Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody

Cont’d

• TH cells also produce cytokines that promote TCcells

• TH cells recruit other WBCs & amplify innate defenses (inflammatory)

• Subpopulations of TH cells specialize in specific sets of activations

• TH cells also produce cytokines that promote TCcells

• TH cells recruit other WBCs & amplify innate defenses (inflammatory)

• Subpopulations of TH cells specialize in specific sets of activations

Cont’d

• Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen

• Activated TC cells are co-stimulated by TH cells

• TC mechanism (Cytotoxic T-cells, Killer T)– TC binds to cell & releases perforin & granzymes

– In the presence of Ca2+ perforin forms pores in target cell PM

– Granzymes enter through pores & degrade cellular contents

– TC then detaches & moves on

– Macrophages clean up

Cont’d

• Other T-cells

– *Regulatory T-cells (TReg): release inhibitory cytokines that suppress B-cell & T-cell activity• Help to prevent autoimmune events

• *formerly Suppressor T (TS)

– Gamma Delta T-cells (Tgd): live in the intestine. Function in surveillance & are triggered much like NK cells

Organ Transplants/Rejections

• Types of Organ Transplants

–Autograft: tissue graft from one body site to another (same person)

– Isograft: graft received from a genetically identical donor (identical twin)

–Allograft: graft received from genetically non-identical donor (same species)

–Xenograft: graft received from another species of animal

Organ Transplants/Rejections

• Transplant rejection: mediated by the immune system (especially TC, NK, antibodies)

–Auto/Isograft: MHC compatible

–Xenograft: most MHC incompatible

–Allograft: attempt to obtain the best MHC match

Organ Transplants/Rejections

• Immunosuppressive therapy: used to delay/prevent rejection

– Corticosteroids: suppress inflammation

– Antiproliferative: prevent/kill rapidly dividing cells

– Immunosuppressant: prevent/kill rapidly dividing cells

– Side effects tend to be harsh

– Increased risk of infection

Immunologic Dysfunction

• Immunodeficiency

Congenital/Genetic: varied inborn errors

Acquired

• Autoimmune disease: production of antibody & TH against self tissues

• Hypersensitivities (Allergies): the immune system responds to a harmless substance as if it were a threat.