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8/7/2019 Immunology for Sx Dd
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Immunology for SurgeryProf Anura Weerasinghe
MBBS(Col), MD(Col), DCH(Col),
DTM&H(London), MRCP(UK),FRCP(Edin) & PhD(Japan)
Professor of Physiology
Faculty of Medicine
University of Kelaniya
Ragama
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Topics
Immunity to cancer and transplantation
Immunodeficiency
Hypersensitivity Tolerance and autoimmunity
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Immune response againsttumours and transplants
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Objectives
Tumour and transplant antigens
Immune surveillance against tumour
cells Immunological mechanisms of rejection
and graft-versus-host disease (GVHD)
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Tumour antigens
Sparse evidence to support protective
immunity elicited by tumour antigens
May be used as tumour markers May be used as targets for tumour
vaccines
May be used as targets for antibodiesand effector T cells generated against
these antigens (Immunotherapy)
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Types of tumour antigens
Mutated self protein In melanoma
Product of oncogene
Her-2/neu in breast cancer Products of mutated tumour suppressor
gene
p53 in colon, breast & lung cancers
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Carcinogenesis
Defect in DNA
Chemical Physical
Biological
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DNA defect
Point mutationGene deletion
Chromosomal
translocation
DNA repair
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Types of tumour antigens
Mutated self protein In melanoma
Product of oncogene
Her-2/neu in breast cancer Products of mutated tumour suppressor
gene
p53 in colon, breast & lung cancers Aberrantly self protein
onco-foetal antigens
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Oncofetal antigens
Although highly associated with some
tumours, both on their cell surface and
in the serum, oncofetal antigens are not
unique to tumour cells since they are
also found on cells during embryonic
development and are found at very low
levels in normal human serum.
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Oncofetal antigens
Carcinoembryonic antigens (CEA)
- GI cancers
Alpha-fetoprotein
- Hepatoma
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Types of tumour antigens Mutated self protein
In melanoma
Product of oncogene
Her-2/neu in breast cancer
Products of mutated tumour suppressor gene p53 in colon, breast & lung cancers
Aberrantly self protein onco-foetal antigens
Oncogenic virus
HPV in cervical cancer EBV in lymphoma / Nasopharyngeal carcinoma
Hepatitis B in hepatoma
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That the immune system surveys constantly
for neoplastic cells and destroys them, is
suggested by the observation of increased
incidence of tumours of lymphoid or
epithelial cells in immunodeficient animals
and humans.
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Immune surveillance
The immune system surveys constantly
for neoplastic antigens associated with anewly developing tumour and destroys
the cells bearing them.
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Immune mechanisms operating
against tumours Activated macrophages
NK cells
Antibody and complement Antibody dependent cellular toxicity
Cytotoxic T cells
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Molecules involved in the
first-line defenseComplements - Promote action of
macrophages- lysis of the target cell
Cytokines - augment immune response
Eg; INF-K activate both macrophages
and NK cells
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Antibody mediated tumour
rejection
Play a role in leukaemia
Not very effective in solid tumours
Complementdependent
cytotoxicity
Antibody-dependentcellular cytotoxicity
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Complement mediated
cytotoxicity
Mediated by antibodies
Particularly IgM
Tumour cell + Antibody
Trigger classical complement pathway
C3b and C5b
Opsonization Lysis
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Antibody-dependent cellular
cytotoxicity
NK cells
+IgG
Sensitized tumour cell Release of cytotoxicmolecules
eg; perforin
Direct interaction
with tumour cells
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scuss t e ro e o o ow ng
cells/molecules in immune
response to tumours
T lymphocytes
NK cells
Macrophages
Antibodies
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Immunology of Transplantation
Immune Response to graft cells
Immunology of graft dysfunction
Strategies to prevent rejection
Treatment of acute rejection
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Immune response to graft
cells
Recognition
Self from non-self
Transplantation antigens
Histocompatibility Complexes
MajorMinor
Blood group antigens
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Immune Response to graft
cells
Presentation ofTransplantation antigens
APC T cell
T cell
T cell
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Immunology of Graft
Dysfunction
Hyperacute rejection (Within
minutes)
Unrecognized ABO incompatibility
Antibodies to HLA class I (positive
cross-match)
Acute (days or weeks)
CTL (CD8) mediated
Chronic (months or years)
CD4 mediated
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Humoral rejection
Antigen antibody Complexes
Activation of Complement cascade
Chemotaxis & Inflammation
Occlusion of capillaries & prevent vascularization
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Strategies to Prevent Rejection
Hyperacute/Acute- ABO compatibility
Tissue matchingImmunosuppresive
Therapy
Chronic - Careful tapering of
ImmunosuppressiveTissue matching
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GVHD
A disease occurring in BMT recipientsthat is caused by the reaction of mature
T cells in the marrow graft against
alloantigen in host cells. Requirements for GVHD;
Immuno-competent graft cells &
immuno-incompetent hostEg; blood transfusion in SCID
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Summary
Tumour and transplant antigens
Immune response in immune
surveillance against tumour cells Immunological mechanisms of rejection
and graft-versus-host disease
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Immunodeficiency
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Objectives
Classification of Immunodeficiency When to suspect
How to investigate
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Classification of
immunodeficiencies Primary usually congenital (inherited) The result of a failure of proper development
of the humoral or cellular immune system
Secondary acquired
The consequences of other diseases and
their treatments.
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Primary immunodeficiency
Complements Recurrent meningococcal meningitis
Phagocytes
Recurrent Staphylococcal skin sepsis Humoral immunity
Severe or recurrent extracellularbacterial
infections
Cellular immunity
Recurrent intracellularbacterial or viral
infections.
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Complement deficiency C3 deficiency
Recurrent infections with encapsulatedorganisms
Pneumococcus, Streptococcus & Neisseria
Deficiencies in Membrane Attack
Complex (MAC) components
Increased susceptibility to infections with
Meningococcus eg; Neisseria
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Extrinsic Phagocytic defects
resulting from
Deficiency of antibody or complement
Defective opsonization
Suppression of phagocytic activity
Eg by Glucocorticoids or autoantibodies
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B ll d fi i i
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B cell deficiencies Abnormal B cell maturation
Lack of Stem cells Severe Combined Immunodeficiency (SCID)
B cells fail to develop from B cell
precursors
Brutons agammaglobulinaemia
B cells do not switch antibody classes from
IgM
Hyper-IgM syndrome
B cells that do not respond to signals
from other cells
Common Variable Immunodeficiency
Transient h o amma lobulinaemia
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B cell deficiencies
Severe Combined Immunodeficiency
(SCID)
Functional impairment ofboth B and T
lymphocyte limbs of the immune response. Inheritance is either X-linked or autosomal
recessive
Brutons Agammaglobulinemia
X-linked inheritance
Isolated immunoglobulin defects
IgA deficiency is the commonest
C ll l I d fi i
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Cellular Immunodeficiency Result in recurrent viral, fungal,
mycobacterial and protozoan infections
Lack of Thymus
Di Georges syndrome
Stem cell defect
SCID
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DiGeorge syndrome;cellular immunodeficiency
Failure of the parathyroids
and thymus to develop
Appearance ofhypocalcemic tetany
shortly afterbirth
Occurs in both males and
famales A number of physical
abnormalities
P ti l C bi d I
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Partial Combined Immune
Deficiency
Wiskott-Aldrich Syndrome X-linked recessive disorder
Characterized by the presence of eczema,
thrombocytopenic purpura, and increasedsusceptibility to infection.
Ataxia-Telangiectasia
Autosomal recessive disorder
Ataxia
Telangiectasia
Recurrent sinopulmonary infections
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Molluscum contangiosum
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Secondary (acquired)
immunodeficiency
Commonest immunodeficiency
Contributes a significant proportion to
hospital admissions Mainly affects the phagocytic and
lymphocytic functions
Results from infection (HIV),malnutrition, aging, cytotoxic therapy
etc.
Factors causing secondary
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Factors causing secondary
immunodeficiency
Malnutrition - Protein-calory malnutritionand lack of certain dietary elements (eg; Iron,Zinc); world-wide the major predisposingfactor for secondary immunodeficiency.
Tumors direct effect of tumors on theimmune system by effects onimmunoregulatory molecules or release ofimmunosppressive molecules, eg TGFF.
Cytotoxic drugs/irradiation widely usedfor tumor therapy, but also kills cells importantto immune responses, including stem cells,neutrophil progenitors and rapidly dividing
lymphoyctes in primary lymphoid organs.
Factors causing secondary
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Factors causing secondary
immunodeficiency
Aging decreased T and B cell responsesand changes in the quality of the response.
Trauma increased infections probably
related to release of immunosuppressivemolecules such as glucocorticoids.
Diabetes mellitus
Immunosuppressive microbes malaria,measles and HIV.
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When to suspect
Recurrent infections
Severe infections not responding to
appropriate antibiotics
Unusual infections
Opportunistic infections
Opportunistic cancers
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Investigations to assess
quantitative or qualitativedefects of
the antibody-mediated immunity
the cell-mediated immunity
the complement cascade
the phagocytes
Evaluation of antibody
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Evaluation of antibody
mediated immunity
Simple electrophoresis Quantitative estimation of immunoglobulins
IgA, IgG, IgM
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Evaluation of cell-mediated immunity
DTH skin tests to common antigens candida, tuberculin
Determine
Total lymphocyte count T cell number in blood
T cell subpopulation percentages
(eg; CD4 & CD8)
E l i f ll di d
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Evaluation of cell-mediated
immunity
Delayed type of
hypersensitivity
skin tests tocommon
antigens eg;
Tuberculin
Mantoux test
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Flowcytometer
Evaluation of the complement
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Evaluation of the complement
cascade
Quantitative estimation of individualcomplement components
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Evaluation of the phagocytic
functions
Determine total granulocyte and
monocyte count
Assay for
Phagocytosis
Nitroblue tetrazolium (NBT) assay
Chaemotaxis
Diagnosis and treatment of
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Diagnosis and treatment of
immunodeficiency
Family history Since defective genes canbe inherited, an investigation into the family
history is especially important in the diagnosis
of primary immunodificiencies
Evaluation of specific immune
components
Antibiotics and antibodies Antibiotic
therapy is the standard treatment forinfections. In addition, antibodies from a pool
of donors are used for antibody deficiencies
Bone marrow transplants and gene
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Summary
Classification
When to suspect
How to investigate
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Hypersensitivity
Obj i
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Objectives
List hypersensitivity reactions anddescribe
Immunopathological basis
Clinical presentations
Principles of management of each type
Describe the management of
anaphylactic shock
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Immune response
Protective Damage to
host tissues
Hypersensitivity
Autoimmunity
Original Classification of
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Original Classification of
hypersensitivity by Gell and
Coombs
Type Immune mechanisms
I IgE antibodies
II Ab & complement
III Ag/Ab complexes
IV T cell mediated
P t l ifi ti f
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Present classification of
hypersensitivity
Gell & Coombs classification
of hypersensitivity
+
Type V Antibody mediated(stimulatory or blocking)
Ti f
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Time of appearance
Type I 2 to 30 minutes(immediate)
Type II
(Cytotoxic)
5 to 8 hours
(Intermediate)
Type III
(Immune complex)
2 to 8 hours
(Intermediate)
Type IV 24 72 hours
(delayed)
IgE mediated Type 1
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IgE mediated Type 1
hypersensitivity: Allergy
Commonest type of hypersenisivity Range from mild to fatal (anaphylaxis)
Some individuals (atopic) have a
genetic predisposition to make highlevels of IgE
Allergy affects 17% of the population
Allergic reaction can occur to normally,harmless antigens (such as pollen or
foodstuffs) and microbial antigens (fungi
or worms)
Mechanism of type 1
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Mechanism of type 1
hypersensitivity
Degranulate:
Histamine
Products of
cell membrane
lipids:
Leukotrienes
Cytokines
PreformedB cell
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Mast cell
IgE
Allergen
Preformed
metabolites
- histamine
Products of
membrane lipids
- Leukotrines- ProstaglandinsIL-5
Eosinophil
IL-4B cell
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Clinical examples of type 1
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Clinical examples of type 1
hypersensitivity
Rhinitis
Anaphylaxis
Bronchial asthma
Urticaria/angio-oedema
Food allergy
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Urticaria Agio-oedema
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Diagnosis
History
Specific IgE antibody level
Skin prick test Food elimination & challenge
Note; Patch test is done in Type IV hypersensitivity
Skin Prick Test
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Skin PrickTest
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Treatment
Antigen avoidance
Antihistamine
Corticosteroids Leukotriene receptor antagonists
Mast cell stabilizers
Adrenaline
Type II hypersensitivity
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Type II hypersensitivity Cytotoxic hypersensitivity
IgG and IgM mediated
Antibodies are directed mainly
to cellular antigens (e.g. onerythrocytes) or surface
autoantigens
Causes damage through
opsonization, lysis or antibody
dependent cellular cytotoxicity
Clinical examples of type II
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hypersensitivity
Rhesus incompatibility IgG against RhD antigen
Transfusion reactions
Isohaemaglutinins against majorbloodgroup antigens (A & B)
Autoantigens
Basement membranes of lung & kidney -
Goodpastures syndrome Acetylcholine receptor Myasthenia gravis
Erythrocytes Haemolytic anaemia
Drugs
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SDL
Principles of Coombs test
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Treatment
Exchange transfusion
Plasmapheresis
Immunosuppressives/cytotoxics
Type III hypersensitivityI l di d
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Immune-complex mediated
IgG against non-self or self antigens
Eg; microbes, drugs including antisera &autoantigens (eg; SLE)
Activation of complement cascade
Local damage: Arthus reaction Inhalation ofbacterial spores Farmers
lung
Avian serum/faecal proteins Bird
fanciers lung Systemic damage:
Serum sickness
Vasculitis
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T
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Treatment
Corticosteroids
Immunosuppressives/cytotoxics
Plasmapheresis
Monoclonal antibodies
T IV h iti it
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Type IV hypersensitivity
Delayed type (Occurs 24 hours after
contact with antigens)
Mediated by cells (T cells together with
dendritic cells, macrophages and
cytokines)
Persistence presence of antigen leads to
the formation of granuloma
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Clinical examples for type IV
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Clinical examples for type IV
hypersensitivity Contact dermatitis with
Small molecular weight chemicals
Eg: Nickel, silica
Molecules from some plants Eg; poison ivy
Post primary tuberculosis
Tuberculin test (Mantoux test)
T t t
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Treatment
Immunosuppressives
Corticosteroids
Removal of antigen
T V h iti it
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Type V hypersensitivity
Blocking antibodies
Anti-AChR antibodies in myasthenia gravis
Blocks muscle contraction
Stimulating antibodies
Anti-TSHR antibodies in Graves disease
Excess thyroid hormone secretion
T t t
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Treatment
Treatment of individual disease
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S
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Summary
Classification of hypersensitivity
Immunopathogenesis
Clinical features
Principles of management
of each type
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Tolerance & Autoimmunity
Objectives
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Objectives Define tolerance
Mechanisms of tolerance
Define autoimmunity and
autoimmune disease
Mechanisms of autoimmunity
Factors contributing to
autoimmunity Spectrum of autoimmune diseases
Principles of treatment
Immunologic Tolerance
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Immunologic Tolerance
The unresponsiveness of the immune
system to self-antigens.
Mechanisms of tolerance
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Mechanisms of tolerance
Mechanisms that prevent immune
response to self antigens.
Mechanisms of tolerance
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Central
Negative selection T cells in the thymus
B cells in the bone marrow
PheripheralT cells
Functional unresponsiveness (Anergy)
Death of the effector cell (apoptosis)B cells
High concentration of self antigens in
peripheral lymphoid tissues become
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Regulatory T cell
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Regulatory T cell
CD4+CD25+ T cells
Maintains tolerance to self-antigens
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Autoimmune disease
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A disease caused by tissue damageresulting from a breakdown of
self-tolerance mechanisms.
Autoimmune diseases can be
organ-specific or systemic.
Mechanisms of autoimmunity
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y A defect in the mechanisms of self-tolerance
Molecular mimicry Eg; a cross-reactive antigen between heart muscle and
Group A Streptococcipredisposes to the development of
rheumatic fever
Modification of cell surface by microbes and drugs
(hapten-like manner) Drug-induced autoimmune haemolytic anaemia
Thrombocytopenia following viral infections
Presence of self reactive T cell in peripheral blood
Extrathymic T cell development Failure of negative selection
AIRE gene defect
Mechanisms of autoimmunity
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Mechanisms of autoimmunity
Polyclonal activation via microbial
antigens
Eg; endotoxin and EBV
Availability of normally sequestered selfantigens
Eg; lens of eye, central nervous system,
thyroid and testes Dysregulation of idiotype network
Eg; antibodies to insulin, TSH and
acetylcholine receptors
Factors contributing to
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autoimmunity
Age
Higher incidence in aged population Less stringent immune regulation by the ageing
immune system
Gender
Women have a greater risk than in men Neuroendocrine system influence
Male:Female SLE 10:1 Graves disease 7:1
Ankylosing spondylitis is almost exclusively amale disease
Factors contributing to
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autoimmunity
Infections
Eg; EBV, Mycoplasma, Streptococci,Borrelia burgdoferi(Lyme arthritis) and
malaria
Drugs
Eg; Procainamide (10% develop SLE likesyndrome)
Immunodeficiency
Eg: C2, C4, C5, C8 & IgA deficiency
Factors contributing to
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autoimmunity Genetic factors
Disease HLA Risk
Ankylosing spondylitis B27 90
Reiters disease B27 36SLE DR3 15
Myasthenia gravis DR3 2.5
IDDM DR3/DR4 25
Psoriasis DR4 14
Multiple sclerosis DR2 5
Rheumatoid arthritis DR4 4
Spectrum of autoimmune
diseases
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diseases
Organ specific Addisions disease - Adrenalcortex
Autoimmune haemolytic anaemia
Graves disease - TSH receptors Guillain-Barre syndrome - Peripheral
nerves
Hashimotos thyroiditis - Thyroid
peroxidase IDDM - F cells in
pancrease
PBC - pyruvate
deh dro enase
Spectrum of autoimmune
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diseases Several organs affected
Goodpastures syndrome
Basement membrane of kidney and lung
Polyendocrine Multiple endocrine organs
A group of cells affected
Autoimmune haemolytic anaemia Autoimmune thrombocytopenia
Spectrum of autoimmune
diseases
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diseases Systemic
Ankylosing spondylitis - vertebral
Chronic active hepatitis - DNA
Rheumatoid arthritis - IgG
(Rheumatoid factor) Scleroderma - nuclei &
centromeres
SLE - dsDNA
Wegerners granulomatosis Cytoplasm ofthe neutrophils
PAN - Cytoplasm of the neutrophils
Antiphospholipid syndrome
Principles of treatment
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Metabolic control
Graves disease Pernicious anaemia
Immune modulators NSAID
SAID Immunosuppressive cytotoxic drugs
Removal of offending antibodies or immunecomplexes - plasmapheresis
Surgical Thymectomy & Splenectomy
Screen for associated disorders
Objectives
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Define tolerance
Mechanisms of tolerance
Define autoimmunity and
autoimmune disease
Mechanisms of autoimmunity
Factors contributing to
autoimmunity Spectrum of autoimmune diseases
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Immunofluorescence technique
ANA
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Diagnostic,prognostic &
monitoring
Anti ds-DNA
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Anti ds DNA
SLE >90%
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Ankylosing spondylitis
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Achilles tendonitis in seronegative arthropathy
Oral ulceration in Behcets disease
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Circinate balanitis in Reiters disease
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