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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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autoimmunity

AUTOIMMUNITY

Prof. Emad A Koshak

Professor and Consultant

Internal Medicine, Allergy & Immunology

King Abdulaziz University- Faculty of Medicine

slide23

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.

slide33

Background on inflammation

The word inflammation literally means "burning."

slide34

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....

slide35

“SHARP”

Swelling

Heat

Redness

Pain

slide36

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.

slide37

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.

slide39

Nervous System:

Multiple sclerosis

Myasthenia gravis

(acetylcholine receptor

autoantibodies)

Autoimmune neuropathies

such as Guillain-Barré

Autoimmune uveitis

slide40

Gastrointestinal System:

Crohn's Disease

Ulcerative colitis

Primary biliary cirrhosis

Autoimmune hepatitis

slide41

Blood:

Autoimmune hemolytic anemia

Pernicious anemia

Autoimmune thrombocytopenia

Antiphospholipid antibody

Meisha, a lab/terrier/spaniel mix, was 3 years old when she was diagnosed with autoimmunue hemolytic anemia in January of 1992.

slide42

Skin:

Psoriasis

Dermatitis herpetiformis

Pemphigus vulgaris

Vitiligo

slide43

Endocrine:

DM

Hashimoto thyroiditis

DM

is an example of an autoimmune disorder in which Beta cells of the pancrease show destruction.

Graves diseases

Addison disease

slide44

Endocrine:

Type I (insulin -dependent) diabetes

(pancreatic beta-cell autoreactive T cells and autoantibodies)

slide45

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.

slide46

Rheumatology:

SLE

RA

Progressive systemic sclerosis

is an example of an autoimmune disorder in which skin cells show extensive dermal fibrosis.

Systemic Scelerosis

Dermatomyocytis

Ankylosing spondylitis

slide47

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.

Malar rash

slide48

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.

slide49

A Genetic Connection?

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

slide50

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

9 different Cw antigens

18 different DR antigens

slide51

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.

slide52

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 B27molecule in causing the destructive immune reactions

slide53

Multiple sclerosis (MS)

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

slide54

Multiple sclerosis (MS)

Some populations, such as Gypsies, Eskimos, and

Bantus, never get 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.

slide55

MS

In MS, tumor necrosis factor-alpha (TNFa), 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.

slide57

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

slide59

Antiphospholipid antibody

(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.

slide60

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
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
slide63

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.

treatment
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

slide66

Intravenous immunoglobulin

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

slide67

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

slide68

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.

examples: Interferons and InterLeukins

slide69

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

slide70

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).

slide71

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

slide72

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.