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CELL MEDIATED IMMUNITY

Dr.T.V.Rao MD

DR.T.V.RAO MD

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

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 T H 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 (T C) 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

CELL MEDIATED IMMUNITY


* CMI

may play a role in some harmful conditions:

- Hypersensitivity reactions type - Graft rejection

IV (contact dermatitis)

- Autoimmune diseases * Cell mediated cytotoxicity mediated by: - T-cytotoxic cells cells

- Natural killer cells


- Activated macrophages
DR.T.V.RAO MD

CELL MEDIATED IMMUNITY WORKS BY COMPLEX MECHANISMS

LEAST UNDERSTOOD ???

DR.T.V.RAO MD

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
DR.T.V.RAO MD

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

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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.
DR.T.V.RAO MD

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
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FUNCTIONS OF T CELLS
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

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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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DR.T.V.RAO MD

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.
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BROAD VIEW ON CYTOKINES

Cytokines are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communication
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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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WHAT ARE CYTOKINES


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.
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CYTOKINES WORK ON MULTIPLE LINEAGES

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CYTOKINES HAVE
Paracrine effect acts locally near the producing cells Having pleotrophic effects Multiple effects on growth and differentiation of various cell types.
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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
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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 Ca 2+ and energy
Granules release Perforins (65 kDa) and Granzymes (serine proteases) at the junctional space Perforins polymerize forming cylindrical pores (5-20 nm), Ca 2+ 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


DR.T.V.RAO MD

Apoptotic death within a few hours

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FUNCTIONS OF INTERLEUKIN 1
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

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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
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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.


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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.
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ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY (ADCC)


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)

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INTERFERONS
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..

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DYNAMICS OF INTERFERONS
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 antiviral state in the target cells.
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CLASSIFICATION OF INTERFERONS There are three classes of Interferons: Alpha, Beta and Gamma. Interferon Alpha and Beta are produced by many cell types
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FUNCTIONS OF INTERFERONS
Interferons are within the cytokine family of proteins. Interferons are especially important because they enhance the immune systems 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.
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INTERFERON GAMA
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

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USES OF INTERFERONS
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 antiproliferative effects, they have also been used to treat certain tumours such as melanoma and Kaposis sarcoma.

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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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JERNES 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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WHAT IS CLONAL SELECTION THEORY


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


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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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RECENT THEORIES
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

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Programme created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World
Email doctortvrao@gmail.com

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