AUTOIMMUNITY Prof. Emad A Koshak Professor and Consultant Internal Medicine, Allergy & Immunology King Abdulaziz University- Faculty of Medicine

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.

Background on inflammation The word inflammation literally means "burning."

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....

“SHARP” Pain Swelling Heat Redness

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 permeable during 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.

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.

Examples of Autoimmune Diseases:

Multiple sclerosis Myasthenia gravis (acetylcholine receptor autoantibodies) Autoimmune neuropathies such as Guillain-Barré Autoimmune uveitis Nervous System:

Gastrointestinal System: Crohn's Disease Ulcerative colitis Primary biliary cirrhosis Autoimmune hepatitis

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 Antiphospholipid antibody

Skin: Psoriasis Dermatitis herpetiformis Pemphigus vulgaris Vitiligo

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.

(pancreatic beta-cell autoreactive T cells and autoantibodies) Type I (insulin - dependent) diabetes Endocrine:

Grave’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.

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

Malar 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.

Rheumatoid 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.

Many chronic inflammatory diseases have been shown to occur preferentially in individuals carrying certain variants of MHC (major histocompatibility complex) genes. A Genetic Connection?

MHC 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

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.

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

Individuals with the DR2, DR3 variant of MHC genes are most susceptible to MS. Multiple sclerosis (MS)

Some populations, such as Gypsies, Eskimos, and Bantus, never get MS. Some populations, such as Gypsies, Eskimos, and Bantus, never get 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.

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.

Family members with autoimmune diseases may inherit and share a set of abnormal genes, although they may develop different autoimmune diseases.

Other genetic connections:

(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 antibody

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.

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

What are some of the treatments for autoimmune diseases?

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.

Cyclosporin A (CsA) inhibits a signal transmission pathway in T lymphocyte cells.

Treatment 1- Metabolic control: a. Graves’ disease: antithyroid drugs, surgical, radiation b. Hashimoto’s thyroiditis: Thyroxin. c. Pernicious anemia: vitamin B12. d. IDDM: insulin 2- Antiinfalamtory and cytotxic drugs: Nonsteroidal antiinflamatory (NSAID) Corticosteroids Cytotoxic 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 therapy GBS, Dermatomyositis 7- Cytokines and inhibitors: anti-TNF

Intravenous immunoglobulin IVIG therapy is used in the treatment of various autoimmune diseases to reduce circulating immune complexes.

Another treatment approach is to manipulate immune system messenger molecules called cytokines.

examples: Interferons and InterLeukins Cytokines Are 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.

Some cytokines (for example, IL-8) are also chemotactic for specific cell types, and are called “chemokines”.

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).

If the infection reaches the blood, TNF-a causes septic shock and death. Release into joints leads to Rheumatoid arthritis.

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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