Autoimmunity
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Transcript of Autoimmunity
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AUTOIMMUNITY
Prof. Emad A Koshak
Professor and Consultant
Internal Medicine, Allergy & Immunology
King Abdulaziz University- Faculty of Medicine
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The immune system normally acquires self tolerance by clonal deletion of autoreactive T cells in the thymus before birth and by functional suppression of autoreactive T and B cells at later stages of development.
The immune system normally acquires self tolerance by clonal deletion of autoreactive T cells in the thymus before birth and by functional suppression of autoreactive T and B cells at later stages of development.
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Background on inflammationBackground on inflammation
The word inflammation literally means "burning."
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Inflammation occurs in response to a range of traumas from sunburn and wounds, to infection and auto-immune conditions. Whatever the cause, this process is basically the same....
Inflammation occurs in response to a range of traumas from sunburn and wounds, to infection and auto-immune conditions. Whatever the cause, this process is basically the same....
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“SHARP”“SHARP”
Pain
Swelling
Heat
Redness
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Heat and redness result from dilation of the small blood vessels in the injured area and increased local blood flow.
Because blood vessels become more permeableduring inflammation, protein rich exudate escapes from blood plasma to the damaged tissue and causes swelling.
Pain is believed to result from such chemical substances as serotonin, specific cytokines or from tension of tissue over the inflamed area.
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Autoimmune disorders are a diverse group of conditions, which occur due to abnormal stimulation and signaling within the immune system. "Self" versus "non-self" recognition is altered.
Autoimmune disorders are a diverse group of conditions, which occur due to abnormal stimulation and signaling within the immune system. "Self" versus "non-self" recognition is altered.
An autoimmune response occurs because, for some reason, helper T cells recognize a cell of the body (or self cell) as foreign, and mark it for destruction.
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Examples of Autoimmune
Diseases:
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Multiple sclerosis
Myasthenia gravis (acetylcholine receptor autoantibodies)
Autoimmune neuropathies such as Guillain-Barré
Autoimmune uveitis
Nervous System: Nervous System:
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Gastrointestinal System:Gastrointestinal System:
Crohn's DiseaseUlcerative colitis
Primary biliary cirrhosis
Autoimmune hepatitis
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Blood:Blood:
Autoimmune hemolytic anemia
Pernicious anemia
Autoimmune thrombocytopenia
Meisha, a lab/terrier/spaniel mix, was 3 years old when she was diagnosed with autoimmunue hemolytic anemia in January of 1992.
Antiphospholipid antibody
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Skin:Skin:
Psoriasis
Dermatitis herpetiformis
Pemphigus vulgaris
Vitiligo
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Endocrine:Endocrine:
DM
Hashimoto thyroiditis
Graves diseases
Addison disease
DM
is an example of an autoimmune disorder in which Beta cells of the pancrease show destruction.
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(pancreatic beta-cell autoreactive T cells and autoantibodies)
Type I (insulin -dependent) diabetesType I (insulin -dependent) diabetes
Endocrine:Endocrine:
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Grave’s DiseaseGrave’s Disease
Graves Disease is an autoimmune condition that strikes more women than men at a rate of 7:1. It affects the functioning of the thyroid and causes hyperthyroidism, but it can also affect the tissue surrounding the eyes.
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Rheumatology:Rheumatology:
SLE
RA
Systemic Scelerosis
Dermatomyocytis
Progressive systemic sclerosis
is an example of an autoimmune disorder in which skin cells show extensive dermal fibrosis.Ankylosing spondylitis
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Malar rashMalar rash
SLE is the most commonly known autoimmune disorder.
This characteristic “butterfly” rash is made worse by exposure to sunlight.
Lupus is a potentially fatal autoimmune disease that strikes 1 in 2,000 Americans and 10 times as many women as men.
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Rheumatoid arthritisRheumatoid arthritis
Among the most serious and disabling types of arthritis, 2.1 million Americans live with rheumatoid arthritis.
About one out of seven Americans exhibit some form of arthritis.
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Many chronic inflammatory diseases have been shown to occur preferentially in individuals carrying certain variants of MHC (major histocompatibility complex) genes.
Many chronic inflammatory diseases have been shown to occur preferentially in individuals carrying certain variants of MHC (major histocompatibility complex) genes.
A Genetic Connection?A Genetic Connection?
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MHC GenesMHC Genes
There are two classes of HLA antigens:
class I antigens (HLA A, B, Cw) class II antigens (HLA DR [and DQ & DP])
There are:
22 different HLA A antigens 42 different B antigens 9different Cw antigens 18 different DR antigens
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Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes.
This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.
Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes.
This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.
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Ankylosing spondylitis (Bechterew's Disease), a joint inflammation mainly affecting the spine, occurs only in individuals carrying a certain variant of MHC molecule (HLA-B27). Much evidence suggests that molecules derived from microorganisms interact with the B27 molecule in causing the destructive immune reactions
Ankylosing spondylitis (Bechterew's Disease), a joint inflammation mainly affecting the spine, occurs only in individuals carrying a certain variant of MHC molecule (HLA-B27). Much evidence suggests that molecules derived from microorganisms interact with the B27 molecule in causing the destructive immune reactions
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Individuals with the DR2, DR3 variant of MHC genes are most susceptible to MS.
Individuals with the DR2, DR3 variant of MHC genes are most susceptible to MS.
Multiple sclerosis (MS)Multiple sclerosis (MS)
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Some populations, such as Gypsies, Eskimos, andBantus, never get MS.
Some populations, such as Gypsies, Eskimos, andBantus, never get MS.
Multiple sclerosis (MS)Multiple sclerosis (MS)
However, for susceptible populations, if one person in a family has MS, that person's first-degree relatives -- parents, children, and siblings -- have a one to three percent chance of getting the disease.
However, for susceptible populations, if one person in a family has MS, that person's first-degree relatives -- parents, children, and siblings -- have a one to three percent chance of getting the disease.
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MS
In MS, tumor necrosis factor-alpha (TNF), interLeukin (IL)-2, and IL-6 lead to the activation of most peripheral T-Cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways.
MS
In MS, tumor necrosis factor-alpha (TNF), interLeukin (IL)-2, and IL-6 lead to the activation of most peripheral T-Cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways.
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Family members with autoimmune diseases may inherit and share a set of abnormal genes, although they may develop different autoimmune diseases.
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Other genetic connections:
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(APL), traditionally associated with rheumatic autoimmune diseases such as SLE (lupus anticoagulant)
APL has been identified as a "common thread" in families where at least one member suffers from an autoimmune disorder.
Antiphospholipid antibodyAntiphospholipid antibody
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Antiphospholipid antibody syndrome
•(APS) is associated with recurrent clotting events (thrombosis):
•premature stroke CVA•repeated miscarriages•Phlebitis•Venous thrombosis (clot in the vein)•pulmonary thromboembolism
•Also associated with low platelet or blood elements that prevent bleeding.
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How to establish the Diagnosis
• History: characteristic symptoms
• Classical physical findings and signs
• Laboratory:– General: CBC, ↑ESR, ↑CRP, C3, ↓C4, ↑IgG– Specific auto-antibodies– Hormonal assay– Radiological– ? HLA
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What are some of the treatments for autoimmune diseases?
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Diminishing of the activity of the immune system
This necessitates a delicate balance, controlling the disorder while maintaining the body's ability to fight disease in general.
Drugs most commonly used are corticosteroid drugs.
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Cyclosporin A (CsA) inhibits a signal transmission pathway in T lymphocyte cells.
Cyclosporin A (CsA) inhibits a signal transmission pathway in T lymphocyte cells.
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Treatment1- Metabolic control:
a. Graves’ disease: antithyroid drugs, surgical, radiationb. Hashimoto’s thyroiditis: Thyroxin.c. Pernicious anemia: vitamin B12.d. IDDM: insulin
2- Antiinfalamtory and cytotxic drugs:Nonsteroidal antiinflamatory (NSAID)CorticosteroidsCytotoxic drugs: Cyclophosphamide, Azothioprine, Cyclosporin
3- Thymectmy:Myasthenia gravis after anticholinesterase
4- Plasmapheresis or Plasma exchange:GBS, SLE, Goodpasture’s
5- Spleenectomy:Hemolytic anemia, ITP
6- Intravenous Gammaglobulin therapyGBS, Dermatomyositis
7- Cytokines and inhibitors: anti-TNF
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Intravenous immunoglobulin
IVIG therapy is used in the treatment of various autoimmune diseases to reduce circulating immune complexes.
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Another treatment approach is to manipulate immune system messenger molecules called cytokines.
Another treatment approach is to manipulate immune system messenger molecules called cytokines.
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examples: Interferons and InterLeukins
examples: Interferons and InterLeukins
CytokinesAre low molecular mass proteins, secreted by lymphocytes, which activate other immune system cells to regulate:
Cell Growth, Cell Activation,Inflammation, Immunity, Tissue Repair, Fibrosis and Morphogenesis.
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Some cytokines (for example, IL-8) are also chemotactic for specific cell types, and are called “chemokines”.
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Example of inflammation and cytokines
Tumor necrosis factor-a TNF-a: Released by macrophages, increases vascular permeability, adhesion molecule expression on blood vessel endothelium, increases MHC expression, platelet activation (clots keep infection from the blood, and direct products to the lymphatic system).
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If the infection reaches the blood, TNF-a causes septic shock and death. Release into joints leads to Rheumatoid arthritis.
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New treatments
Use a chimeric monoclonal antibody against TNF-a, or a new drug, Etanercept, which is a recombinant protein with TNF receptor and the constant region of an antibody. Blocking TNF-a shows great promise as a new treatment for RA.
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Thanks