Immune response deepa babin
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IMMUNE RESPONSE
DEEPA BABIN TMC KOLLAM
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A tribute to
A TRIBUTE TO (L-R) 2011 Nobel Prize winners for Physiology or Medicine Bruce A. Beutler, Jules A. Hoffmann , Ralph M. Steinman
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Nobel Prize winners Bruce A. Beutler, Jules A. Hoffmann
for their discoveries concerning the activation of innate immunity" Ag binds the Toll like receptors in body cells and activates innate immunity-inflammation
and the other half to Ralph M. Steinman "for
his discovery of the dendritic cell activates T cell and its role in adaptive immunity".
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The Immune response An immune response is what the
immune system does when confronted by an antigen.
An immune response is an elaborate interplay between antigen, non-specific defenses, and B and T lymphocytes.
The process involves direct contact (cells, molecules bind to receptors on cell surfaces) and cytokines (messenger molecules) that also bind to receptors on cell surfaces
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Immune Response
Innate response – by birth, limited in its response (cannot handle too much invasion)
Adaptive Immune response– Matures over person’s lifetime– Takes time to start up– More effective and very powerful– Important Hallmark : MEMORY– Complex, involves a network of cells:
cytokines, B cells, T cells, antibodies
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Adaptive Immune Response
2 types
- Humoral/ antibody mediated (AMI) immunity
- Cell mediated immunity (CMI)
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Humoral Immunity - Applications
Defense against most extracellular bacterial pathogens viruses that infect through the
respiratory or intestinal tracts
Prevents recurrence of viral infections.
Takes part in the pathogenesis of Immediate (Types 1, 2 & 3) hypersensitivity & certain autoimmune disorders.
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Humoral Immunity
Cells taking part in immune response - Antigen presenting cells
(APCs) - B cells & - T cells
Production of antibodies consists of following stages :
1. Ag capture & processing by APCs2. Ag presentation3. TH cell activation4. B cell stimulation & differentiation5. Ab production by plasma cells
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1. Antigen Capture & Processing
Captured by APCs (macrophages & dendritic cells) – broken down in to small peptides.
The immune response begins when a white blood cell called a macrophage encounters a virus and consumes it. Meanwhile, other viruses look for nearby cells to infect.
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Next, the macrophage digests the virus and displays pieces of the virus called antigens on its surface. Nearby cells have now become infected by theattacking viruses.
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2. Antigen Presentation
Peptides derived from1. Exogenous Ags – presented with MHC
class II molecule, recognised by TH cells.
2. Endogeous Ags – presented with MHC class I molecule, recognised by TC cells.
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Capture, Processing and Presentation of Antigen by an Antigen presenting cell (APC)
Capture, Processing and Presentation of Antigen by an Antigen presenting cell (APC)
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This union stimulates the production of chemical substances -- such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) by the macrophage, and interleukin-2 (IL-2) and gamma interferon (IFN-y) by the T cell – that allow intercellular communication
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3. Helper T cell Activation Activation requires 2 signals:1. Combination of TCR with the Ag
peptide-MHC class II complex.2. Co-stimulatory signal : combination
of B7 on APC & CD28 on the T cell with release of IL-1 .
Activated TH cells now produce IL-2 which supports the growth of itself & other T cells.
Also produce IL-4, IL-5 & IL-6 which stimulates the growth & differentiation of B cells into
- Plasma cells & Memory B cells
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KILLER CELLS
The killer T cells now begin shooting holes in host cells that have been infected by viruses.
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B Cells
The antibodies released by the B cells bind to antigens on the surfaces of free-floating viruses. Besides making it easier for macrophages to destroy viruses, this binding signals blood components called complement to puncture holes in the viruses.
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Finally, as the infection is brought under control, the activated T and B cells are turned off by suppressor T cells.
However, a few "memory cells" remain behind to respond quickly if the same virus attacks again.
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4. B cell activation & differentiation4. B cell activation & differentiation
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5. Ab production
Ab production follows a characteristic pattern consisting of :
1. Lag Phase – immediate stage following antigenic stimulus during which Ab is not detectable in the circulation.
2. Log Phase – steady rise in the titre of Abs.
3. Plateau or Steady Phase – equilibrium between Ab synthesis & its catabolism.
4. Decline Phase – catabolism exceeds production, fall in Ab titre.
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Primary & Secondary ResponsePrimary Response
Initial contact with the Ag
Slow, sluggish & short lived.
Long lag phase.
Low titres of Ab, does not persist for long.
IgM – predominant.
Secondary Response Response to
subsequent exposure to the same Ag.
Prompt, powerful & prolonged.
Short or negligible lag phase.
Very high levels of Ab, lasts for long periods.
IgG - predominant
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Phases
1. A single injection of an Ag helps in sensitising / priming the immunocompetent cells producing the particular Ab.
2. Subsequent injections of an Ag – Boosters – induce effective levels of Ab.
Hence multiple doses of non living vaccines are administered to achieve effective levels of immunity.
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Phases
With live vaccines, a single dose is sufficient as multiplication of the organism will provide a continuous stimulus.
“Negative Phase” – when an Ag is injected into an animal already carrying the specific Ab in circulation, a temporary fall in the level of Ab occurs due to the combination of Ag with the Ab. It is then followed by a rise in Ab titre.
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A B C
Negative phase
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Cell Mediated Immunity
Refers to the specific immune responses that do not involve antibodies.
CMI response 1st described by Jenner in 1798.
1890 - Koch described the exaggerated cutaneous reaction of tuberculous guinea pigs to the I.D. injection of tubercle bacillus – Delayed hypersensitivity (DH).
DH- skin lesions appear 48-72 hrs after administration of the Ag.
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Applications of CMI CMI participates in following
immunological functions :1. Delayed hypersensitivity.2. Immunity in infectious diseases
caused by obligate & facultative intracellular parasites
Bacteria – Mycobacteria, Listeria Fungi – Histoplasma, Blastomycetes Protozoa – Leishmania,Trypanosoma Viruses – Measles, Mumps
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Applications of CMI
3. Transplantation immunity & graft-versus-host reaction.
4. Immunological surveillance & immunity against cancer.
5. Pathogenesis of certain autoimmune diseases
e.g. Thyroiditis
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Cells involved in CMI
CD8+T cells - recognise antigenic peptides in association with MHC class I molecule on a target cell.
CD4+T cells - MHC class II restricted, secrete cytokines which help in the growth & differentiation of T lymphocytes.
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Scheme of Immune response
against T cell dependent Ags
http://in.youtube.com/watch?v=4kNsYa20EJU&eurl=http://rufusrajadurai.wetpaint.com/page/3D+Medical+Animations?t=anon
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Factors influencing Ab production
1. Genetic factors2. Age3. Nutritional status4. Route of administration of Ag & site of
injection5. Size & number of doses6. Multiple Ags7. Adjuvants8. Immunosuppressive agents9. Effect of antibody
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1. Genetic Factors
Different individuals within a species show differences in immune response to the same Ag.
This is determined by the genetic differences.
Controlled by the gene Ir.
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2. Age
Embryo – immunologically immature - the developing lymphoid cells come into contact with all the tissue Ags of the body – Self Tolerance.
Up to 3-6 mths of age – protection provided by maternal Abs.
B cell responses to most protein Ags develop early.
Responses to polysaccharides & other Ags develop later, by 2 years of age.
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3. Nutritional Status
Protein calorie malnutrition – suppress humoral as well as cell mediated immunity.
Deficiency of amino acids & vitamins – decrease in Ab synthesis.
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4. Site & Route of Administration of Ag
Parenteral – better humoral response. Influence the type of Ig produced : Oral / Nasal – Ig A Inhalation of pollens – Ig E Parenteral administration of Ags – Ig G
Site of administration – relevant with some Ags Hepatitis B vaccine – deltoid (highly
immunogenic) - gluteal (less: paucity of APCs in gluteal fat – delays Ag presentation)
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5. Size & Number of Doses Ag is effective only above a
minimum critical dose. Low dose – fails to induce immune response. High dose – develops tolerance. - do not respond to
subsequent doses of same Ag.
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Multiple Ags
When 2 or more Ags are administered simultaneously, the effects may vary ;
Abs produced against different Ags just as though they had been given separately.
e.g. When 2 bacterial vaccines (typhoid & cholera) are given in a mixed form, the Ab response of one is not influenced by the other.
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Multiple Ags
Ab response to one or the other Ag may be enhanced or diminished.
e.g. When toxoids are given with bacterial vaccines (DPT), the response to toxoid is enhanced.
When 2 toxoids (DT) given together with one in excess, response to other is inhibited.
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Adjuvants
Any substance that enhances the immunogenicity of an Ag.
e.g. aluminium hydroxide
Increase the concentration and persistence of circulating antibody by:
1. Increasing the size of Ag - promotes phagocytosis & presentation by macrophages.
2. Stimulating the influx of macrophages & other immune cell types to the injection site.
3. Promoting local cytokine production
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Types of Adjuvants Freund’s incomplete adjuvant : water-in-
oil emulsion with protein Ags in water phase.
Freund’s complete adjuvant : incomplete adjuvant along with a suspension of tubercle bacilli.
Repository adjuvants – aluminium hydroxide or phosphate.
Gram negative bacilli (lipopolysaccharide fraction) – Bordetella pertussis – acts as an adjuvant for diphtheria & tetanus toxoid in DPT vaccine.
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Immunosuppressive Agents Inhibit immune response – useful in
transplantation procedure to prevent graft rejection.
e.g.corticosteroids,antimetabolites, cyclosporine
Corticosteroids – depletion of lymphocytes -inhibits histamine
release & inflammatory process
Cyclosporine –commonly used for immunosuppression
- selective inhibition of helper T cell activity
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SUPERANTIGENS Class of bacterial toxins (staphylococcal
enterotoxins) & retroviral proteins that can activate very large number
of T cells irrespective of their antigenic specificities.
Features of super Ags :1. Not processed2. Interact with the MHC class II molecule
outside of the peptide - binding groove.
3. Bind only to the Vβ segment of TCR.
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Monoclonal Antibodies (mAb)
Abs produced by a single clone of cell and directed against a single antigenic determinant are called Monoclonal Antibodies.
Very useful for diagnostic & research techniques.
Method for large scale production of mAb was developed by Kohler & Milstein in 1975.
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Monoclonal Ab
Production is based on Hybridoma technology.
Hybridomas are somatic cell hybrids produced by fusing Ab forming spleen cells with myeloma cells.
It retains - Ab producing capacity of spleen cell. - ability to multiply indefinitely.
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ADCC: Antibody Dependent Cell-mediated Cytotoxicity
Cytotoxic response is mediated by cells in the presence of Ab.
Cells carry receptor for the Fc portion of Ig – able to bind Ab coated targets.
Such cells are also referred to as Killer cells.
* In the absence of Ab, the same cell could destroy the target by natural killing – NK cells.
e.g. Eosinophils are very efficient mediators of ADCC against parasitic worms.
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IMMUNOLOGICAL TOLERANCE
STATE OF SPECIFIC IMMUNOLOGIC UNRESPONSIVNESS TO A PARTICULAR Ag TO WHICH A PERSON HAS BEEN EXPOSED EARLIER.
Self Ag Embryonic life
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TRANSFER FACTOR
Transfer of cell mediated immunity Nucleopeptide Non antigenic Stimulate release of lymphokines
from sensitised T cells Used in CMI deficiency-TB,
Lepromatus leprosy,MELANOMA,Wiskott-Aldrich syndrome
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Theories of Immune Response
Side Chain Theory – Ehrlich (1900) Abandoned - Landsteiner demonstrated
that Abs can be formed against natural Ags as well as synthetic chemicals.
Direct Template Theory Ag act as a template for Ab synthesis. Indirect Template Theory – Burnet &
Fenner (1949) Entry of an Ag - Incorporation of some
of the genes from the antigenic determinant into the genome of Ab producing cells - Heritable changes occur in Ab producing cell
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Theories Natural Selection Theory – Jerne
(1955)1. Embryonic life – formation of a
million diff. Abs (covers full range of Ags) – Natural Abs.
2. Entry of an Ag – selective combination with Ab having complementary fit – natural selection of cells forming that particular Ab.
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Theories Clonal Selection Theory – Burnet (1957)1. During immunological development,
cells capable of reacting with different Ags are formed by somatic mutation.
2. Clone of cells having reactivity against self Ags - eliminated – called forbidden clones
3. Persistence of forbidden clones or redevelopment in later life – Autoimmunity
* most widely accepted theory
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CYTOKINES Biologically active substances
(intercellular messengers) which are – produced transiently - exert their effects at very low (10–15)
conc. & - regulate immunological, inflammatory &
reparative host responses.
Includes – Interleukin (product of leucocytes)
- Interferons - Growth factors & others
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Features of Cytokines Mediate their actions by binding to specific
cell- surface receptors. Produced by wide variety of cells like
lymphocytes, macrophages, platelets & fibroblasts.
Cytokines can have 1.Paracrine effect – act locally near the
producing cells 2.Autocrine effect – act directly on the
producing cells 3.Pleiotropic effect – multiple effects on
growth & differentiation of various cell types.
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Cytokines: Source & Function
CytokineCytokiness
Source : Immune cellsSource : Immune cells Effects of CytokinesEffects of Cytokines
IL-1IL-1 Monocytes, Monocytes, macrophagesmacrophages
Activation of T & B cellsActivation of T & B cells
IL-2IL-2 T cellsT cells Proliferation and/or activation Proliferation and/or activation of T & B cellsof T & B cells
IL-4IL-4 T & B cells, mast cells,T & B cells, mast cells, Activation of B cells, Activation of B cells, differentiation of Th2 cellsdifferentiation of Th2 cells
IL-6IL-6 T cells, macrophagesT cells, macrophages Differentiation of T & B cellsDifferentiation of T & B cells
IL-10IL-10 T & B cells, T & B cells, macrophagesmacrophages
Suppression of macrophages, Suppression of macrophages, activation of B cellsactivation of B cells
IL-12IL-12 B cells, macrophagesB cells, macrophages Differentiation of Th1 cellsDifferentiation of Th1 cells
IFN IFN LeucocytesLeucocytes Antiviral activityAntiviral activity
IFN IFN FibroblastsFibroblasts
IFN IFN T cellsT cells
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