Cell mediated immunity

Dr.T.V.Rao MD

CELL MEDIATED IMMUNITY

DR.T.V.RAO MD 1

Duality of Immune System

. Cell Mediated Immunity

• Involves specialized set of lymphocytes called T cells that recognize

foreign antigens on the surface of cells, organisms, or tissues:

• Helper T cells

• Cytotoxic T cells

• T cells regulate proliferation and activity of other cells of the

immune system: B cells, macrophages, neutrophils, etc.

• Defense against:

• Bacteria and viruses that are inside host cells and are inaccessible to

antibodies.

• Fungi, protozoa, and helminthes

• Cancer cells

• Transplanted tissue

DR.T.V.RAO MD 2

Relationship Between Cell-Mediated and Humoral Immunity

Antibody Production

T-Dependent Antigens:

• Antibody production requires assistance from T helper cells.

• A macrophage cells ingest antigen and presents it to TH cell.

• TH cell stimulates B cells specific for antigen to become plasma cells.

• Antigens are mainly proteins on viruses, bacteria, foreign red blood cells, and hapten-carrier molecules.

T-Independent Antigens:

• Antibody production does not require assistance from T cells.

• Antigens are mainly polysaccharides or lipopolysaccharides with repeating subunits (bacterial capsules).

• Weaker immune response than for T-dependent antigens.

CELL MEDIATED IMMUNE RESPONSES • Primary Function Of Cell Mediated Response

• Eliminate Intracellular Pathogens

• Eliminate Tumor Cells

• Both Ag Specific And Non-specific cells Are Involved

• Ag Specific: CD8+ Cells (TC) And TH (DTH)

• Non-specific: M, Neutrophils, NK

• Both Specific And Non-specific Require Cytokines

• Humoral And Cell Mediated Do Collaborate

• Ex. M Use Abs As Receptors To Recognize Target Cells

DR.T.V.RAO MD 4

CELL MEDIATED IMMUNITY

* CMI may play a role in some harmful conditions:

- Hypersensitivity reactions type IV (contact dermatitis) - Graft rejection

- Autoimmune diseases

* Cell mediated cytotoxicity mediated by:

- T-cytotoxic cells cells

- Natural killer cells

- Activated macrophages

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CELL MEDIATED IMMUNITY WORKS BY COMPLEX

MECHANISMS

LEAST UNDERSTOOD ???

DR.T.V.RAO MD 6

CMI HELPS IN • Delayed hypersensitivity • Immunity in infections caused by Obligate and facultative

intracellular parasites

• Eg – Tuberculosis, Leprosy

Listeriosis, Brucellosis,

Fungi – Histoplasmosis, Cocccidiomysosis,Blastomycosis,

Parasites – Trypanosomiasis

In transplantation immunity,

Immunologioly in Transplantation, malignancy,

Pathogenesis of Autoimmune diseases

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IMPORTANCE OF CELL MEDIATED IMMUNITY

• DiGeorge Syndrome Proves The Importance

• No Thymus, No T-cell Mediated Immunity

• Extracellular Infections Are Effectively Addressed

• Intracellular Infections Are NOT (viruses, intracellular bacteria)

• Cell Mediated Immunity Can Be Divided Into 2 Major Categories

• Effectors lyse target

• 2 groups of cells: CTLs (specific) and NK, M (non-specific)

• Effectors which are CD4+ and mediate DTH

DR.T.V.RAO MD 8

INDUCTION OF CELL MEDIATED

IMMUNITY • Depends on Nature of Antigenic stimulus

• Best developed after following infection with intracellular parasites

• Live vaccines highly stimulating

• Killed vaccine not very effective

• But effective if contains Freund type adjuvant.

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FUNCTIONS OF T CELLS

• Cytotoxic T cells

recognize antigen on

surface of virus

infected cells, tumor

cells, allograft cells

with MHC I and

sectored Lymhokines

and destroy target

cells

DR.T.V.RAO MD 10

• Only T cell dependent antigens

lead to development of CMI

• Certain chemicals which come in

contact with skin induces

Delayed hypersensitivity

• T Cell contain the specific

receptor ( TCR )

• One epitope ( Antigen ) on

contact with receptor undergoes

blast transformation

• Leads to Clonal proliferation

FUNCTIONS OF T CELLS

DR.T.V.RAO MD 11

FUNCTIONS OF T CELLS

• The stimulated cells undergoes blast transformation, Clonal proliferation

• Leads to Effectors cells and Memory cells

• T cell react on presentation with MHC

• Helper T cells when presented on surface of macrophages or other cells complexes with MHC II

molecule – leads to release of Biological Mediators Lymhokines – activate Macrophages and kills intracellular parasites

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T Cells and Cell Mediated Immunity Cellular Components of Immunity:

• T cells are key cellular component of immunity.

• T cells have an antigen receptor that recognizes and

reacts to a specific antigen (T cell receptor).

• T cell receptor only recognize antigens combined with

major histocompatibility (MHC) proteins on the surface of

cells.

• MHC Class I: Found on all cells.

• MHC Class II: Found on phagocytes.

• Clonal selection increases number of T cells.

DR.T.V.RAO MD 13

BROAD VIEW ON CYTOKINES

• Cytokines are a category of

signalling proteins and

glycoproteins that, like hormones

and neurotransmitters, are used

extensively in cellular

communication 14 DR.T.V.RAO MD

T CELLS ONLY RECOGNIZE ANTIGEN ASSOCIATED

WITH MHC MOLECULES ON CELL SURFACES

CENTRAL ROLE OF HELPER T CELLS

CYTOKINES • Cytokines have been classed as

Lymhokines, interleukins, and chemokine's,

based on their presumed function, cell of

secretion, or target of action. Because

cytokines are characterised by considerable

redundancy and pleiotropic, such

distinctions, allowing for exceptions, are

obsolete.

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DEFINITIONS

• Lymhokines Biologically active substance released by

activated T Lymphocytes

• Monokines – Substances secreted by Monocytes and

Macrophages

• Interleukins – Produces by lymphocytes which exert a

regulatory effect on other cells

• All above grouped under cytokines

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DEFINITIONS

• Autocrine, if the cytokine acts on the cell that secretes it.

• Paracrine, if the target is restricted to the immediate vicinity of a cytokine's secretion.

• Endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).

• It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

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• They are peptide mediators, intracellular messengers, which regulate immunological, inflammatory and reparative host cell responses

• They are potent hormones Active even at Fetomolar concentrations produced by widely distributed cells

( Lymphocytes, Macrophages, Platelets, and Fibroblasts.

WHAT ARE CYTOKINES

DR.T.V.RAO MD 20

CYTOKINES WORK ON MULTIPLE

LINEAGES

DR.T.V.RAO MD 21

CYTOKINES HAVE

• Paracrine effect – acts

locally – near the

producing cells

• Having pleotrophic

effects – Multiple

effects on growth and

differentiation of

various cell types.

DR.T.V.RAO MD 22

IMPORTANT CYTOKINES

• Interleukin I 1979

• Interleukin I divided into Alpha and Beta

• IL1 is secreted by Macrophages, Monocytes other nucleated

cells.

• Stimulated by Antigens, Toxins, Injury, Inflammation,

• Inhibited by

• Cyclosporins,Corticosteiods,Prostaglandins

23 DR.T.V.RAO MD

HOW CTLS KILL • Phases In CTL Killing

• Conjugate formation

• LFA-1 (CTL) binds ICAMs (Target)

• LFA-1 changes to high avidity if Ag Is Recognized

• Activated LFA-1 persists for 5-10 mins

• Membrane attack

• Requires Ca2+ and energy

• Granules release Perforins (65 kDa) and Granzymes (serine proteases) at the junctional space

• Perforins polymerize forming cylindrical pores (5-20 nm), Ca2+ is needed

• Granzymes enter target cell

• Granzyme B can enter thru mannose-6-phosphate receptor in a vesicle

• DNA fragmentation

• CTL dissociation

• Target cell destruction

• Apoptotic death within a few hours

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FUNCTIONS OF INTERLEUKIN 1

DR.T.V.RAO MD 25

• IL1 stimulates T cells and Produces IL2 and other Lymhokines

• Helps B cell proliferation

• Synthesizes Antibodies

• Helps Neutrophils in Chemo taxis

• Promotes Phagocytosis

• Promotes Metabolic Physiological and inflammatory responses by action on Bone marrow

IL1 INITIATES FEVER

• IL1 is crucial in promoting fever and called as Pyrogens.

• With the help of Tumor Necrosis factor causes hematological changes in Septicemias, Shock and bacterial meningitis

DR.T.V.RAO MD 26

OTHER INTERLEUKINS

• Interleukins 2 Modulates the immune

response

• Major activator of T and B Lymphocytes

• Stimulates cytotoxic T cells and Natural Killer

cells.

• Interleukin 3 Stimulates multilineage

cells of the Hematopoietic system. 27 DR.T.V.RAO MD

OTHER INTERLEUKINS

• Interleukin 4 Acts as a Growth factor for T Lymphocytes

• Interleukin 5 Causes the proliferation of activated B Lymphocytes

• Interleukin 6 Produced by Stimulated B and T Lymphocytes Induces the production of Immunoglobulin synthesis Stimulates the Hepatocytes, nerve cells,Hematopoetic cells

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INHIBITORY CYTOKINES

• Some cytokines are predominantly inhibitory. For example, IL-10 and IL-13 inhibit inflammatory cytokine production by macrophages.

DR.T.V.RAO MD 29

• Cells Capable of Cytotoxicity Express Fc Receptors

• Antibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of Ab

• Antibody Provides The Specificity

• Examples Of Cells Capable Of ADCC

• M, NK, Neutrophils, eosinophils

• Killing Of Target Is Accomplished

• Thru perforin, granzyme (NK, Eosinophils)

• TNF (M, NK)

• Lytic enzymes (M, Neutrophils, Eosinophils, NK)

ANTIBODY DEPENDENT CELL MEDIATED

CYTOTOXICITY (ADCC)

DR.T.V.RAO MD 30

DR.T.V.RAO MD 31

• Primarily identified as Antiviral agents

• Now classified as Cytokines

• Interferons play an important role in the first line of defence against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond..

INTERFERONS

DR.T.V.RAO MD 32

• Interferons are made by

cells in response to an

appropriate stimulus, and

are released into the

surrounding medium; they

then bind to receptors on

target cells and induce

transcription

of approximately 20-30

genes in the target cells,

and this results in an anti-

viral state in the target

cells.

DYNAMICS OF INTERFERONS

DR.T.V.RAO MD 33

CLASSIFICATION OF INTERFERONS

• There are three

classes of

Interferons: Alpha,

Beta and Gamma.

Interferon Alpha and

Beta are produced

by many cell types

DR.T.V.RAO MD 34

FUNCTIONS OF INTERFERONS

• Interferons are within the cytokine

family of proteins. Interferons are

especially important because they

enhance the immune system’s ability

to recognize foreign invaders,

enabling the system as a whole to

function more effectively

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TYPES OF INTERFERONS • Interferon-alpha (leukocyte interferon) is produced

by virus-infected leukocytes, etc

• Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells.

• Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells.

• Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.

36 DR.T.V.RAO MD

• Interferon-Gamma is

involved in the regulation of

immune response

throughout the body.

Interferon-Gamma is the

signalling protein that gets

the immune system as a

whole ready for attack and

fine tunes it to quickly and

effectively get rid of foreign

and unwanted intruders

INTERFERON GAMA

DR.T.V.RAO MD 37

• Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis. Since interferons have anti-proliferative effects, they have also been used to treat certain tumours such as melanoma and Kaposi’s sarcoma.

USES OF INTERFERONS

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THEORIES OF IMMUNE RESPONSE

• Several theories are considered

1 Direct template theory

2 Indirect template theory

3 Natural selection theory

4 Clonal selection theory

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JERNE’S NETWORK HYPOTHESIS

• It explains the mechanism of antibody response

• The variable region of an immunoglobulin molecule carrying the antigen combining site is different in different antibodies

• The distinct Aminoacid sequence at antigen combing site and the adjacent parts of the variable regions are termed as idiotype

• Produce antiidotypic antibodies

• Which in turn produce antibodies to them

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• Burnet proposed the theory 1957

• The theory emphasizes the immunological specificity to cellular level

In this theory the cell are formed by somatic mutation, the cells that react with self antigens are eliminated and called as Forbidden clones.

Their persistence in later life leads to Autoimmune process

WHAT IS CLONAL SELECTION THEORY

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NOBEL PRIZE WINNING THEORY

• Which in turn produce antibodies to them

• Forms a idiotype network

• The above process controls the amount of antibodies

• The above theory by Niels K.Jerne was awarded Nobel Prize for Medicine in 1984

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DR.T.V.RAO MD 43

• Now genetic basis of antibody

diversity is identified.

• The recent theory of Split

genes explains many

unknown mechanisms

• The theory says the

information occurs in

discontinuous stretches of

DNA, each coding for

separate regions of the

antibody molecule

RECENT THEORIES

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