Tolerance And Autoimmune Diseases

Tolerence
* It is a specific immunologic unresponsiveness

i.e. the absence of specific immunoresponses to a particular antigen in a fully immunocomptent person * Unresponsiveness to self antigens is known as auto tolerance
* Both B-cells and T-cells participate in tolerence * But T-cells play the primary role

Peripheral Tolerance
* T-cell tolerance (clonal anergy):
* Some self-reactive T cells are not killed in

thymus

* Functional inactivation of surviving selfreactive T cells

Tolerance
* B-cells become tolerant to self by two mechanisms:

1) Clonal deletion Probably while B-cell precursors are in bon marrow 2) Clonal anergy B cells in the periphery
* Tolerance in B-cells is less complete than in T-cells * The most autoimmune diseases are mediated by antibodies

Factors Influencing The Induction Tolerance

1) Immunologic maturity of the host: Neonates are immunologically immature and well accept allograft that would be rejected by mature host 2) Structure and dose of antigen: a- Simple molecules induce tolerance more readily than complex ones

b- Very high and very low doses of antigen may result in tolerance

Factors Influencing The Induction Tolerance

3) T-cells become tolerant more readily and remain tolerant longer than B-cells 4) The continuous presence of antigen helps to maintain tolerance 5) Administration of immunosuppressive drugs enhances tolerance as in transplantation

Clinical Importance of Tolerance

1) Organ transplantation: Introduction of tolerance may help in prevention of rejection 2) Tumor development: Tolerance to tumor antigen results in growth of the tumor without being detected by the immune mechanisms 3) Autoimmune disorders: Disturbance of self-tolerance results in autoimmune disease

Autoimmune Diseases

Autoimmune Diseases
* Autoimmune diseases occur due to breakdown of the mechanisms that maintain auto tolerance * Auto-antibodies and self reactive T-cells are produced, resulting in tissue damage by several mechanisms

Etiology Of Autoimmune Diseases

1) Genetic predisposition:
- Familial incidence of autoimmune diseases - Most of them appear to be associated with certain MHC genes, specially MHC II genes

e.g. Rheumatoid arthritis is associated with DR4

Thyroditis with DR5 Multiple sclerosis with DR2 SLE with DR2/DR3 Type I diabetes with DR3/DR4 Ankylosing spondylitis with B27

Rheumatoid Arthritis

Etiology Of Autoimmune Diseases

2) Exposure to infectious antigens that cross react with self antigens

- An immune response to these antigen will result in immune attack against self antigens
e.g. Antibodies against M protein of Streptococcus pyogens may react with heart valves and cause Rheumatic fever 3) Alteration of self antigens or the appearance of new antigens under the effect of drugs, chemicals, or viral infections 4) Hormonal influences play a role e.g. SLE affects women 10 times more than men

Mechanisms Of Disease Production

* The disease may be organ specific e.g Hashimoto thyroditis * The disease may be systemic e.g. SLE or rheumatoid arthritis 1) Binding of an autoantibody to host cells result in complement fixation and tissue destruction e.g. Haemolytic anemia (Type II hypersensitivity)

Mechanisms Of Disease Production

2) Formation of immune complexes and their deposition in tissues, joints, kidney and skin The immune complexes fix complement resulting in tissue damage e.g. SLE and rheumatoid arthritis (Type III hyper.) 3) DTH reactions (Type IV)) due to auto reactive T-cells e.g. Ulcerative colitis, multiple sclerosis and type I diabetes

Laboratory Diagnosis
1- There is elevated serum immunoglobulins

2- Complement levels may be decreased

3- Immune complexe detected in serum or organ biopsy 4- Auto antibodies can be detected in serum e.g. anti-nuclear, anti-smooth muscles, Rh factor and anti-mitochondrial Ab 5- Testing for antibodies specific to particular Ag, involved in organ specific diseases (anti-thyroid Ab)

Thanks

Autoimmune Disease
Self tolerance is lost Specific adaptive immune responses mounted against self antigens Inability to eliminate antigen leads to chronic inflammatory process Ehrlich termed this horror autotoxicus

Autoimmune diseases mediated by cytotoxic antibodies (Type II)

Syndrome
Autoimmune hemolytic anemia

Autoantigen
Rh blood group antigens, I antigen

Consequences
Destruction of red blood cells by complement and phagocytes, anemia Abnormal bleeding

Autoimmune thrombocytopenic pupura Goodpastures syndrome

Platelet integrin GpIIb:IIIa Non-collagenous domain of basement membrane collagen type IV Epidermal cadherin

Glomerulonephritis, Pulmonary hemorrhage

Pemphagus vulgaris

Blistering of skin

Acute rheumatic fever

Streptococcal cell-wall antigens, Antibodies cross-react with cardiac muscle

Arthritis, mycocarditis, late scarring of heart valves

Autoimmune diseases mediated by immune complexes (Type III)

Syndrome
Mixed essential cyroglobulinemia

Autoantigen
Rheumatoid factor IgG complexes (with or without hepatitis C antigens) DNA, histones, ribosomes, snRNP, scRNP

Consequences
Systemic vasculitis

Systemic lupus erythematosis

Glomerulonephritis, vasculitis, arthritis

Autoimmune diseases mediated by T-cells (Type IV)

Syndrome
Insulin-dependent diabetes mellitus

Autoantigen
Pancreatic -cell antigen

Consequences
-cell destruction Joint inflammation and destruction Brain invasion by CD4 T cells, paralysis

Rheumatoid arthritis Unknown synovial joint antigen Experimental autoimmune encephalomyelitis (EAE), multiple sclerosis Myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

Autoimmune disease susceptibility

Genetic predisposition
Twin studies (Diabetes: 20% monozygotic vs. 5% dizigotic) Family studies

Association with MHC genotype

HLA genotyping

Genetic organization of the MHC in humans and the mouse

Detailed map of the human MHC region

Association between HLA and susceptibility to autoimmune disease

Population studies show association of susceptibility to insulindependent diabetes mellitus (IDDM) with HLA genotype

Family studies show strong linkage of susceptibility to insulindependent diabetes mellitus (IDDM) with HLA genotype

Autoimmunity involves T cells

Ability of a T cell to respond is determined by MHC genotype It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of allelic variants of MHC molecules to present autoantigenic peptides Alternatively, self peptides may drive the positive selection of developing thymocytes that are specific for particular autoantigens.

Levels of autoantigens may drive T cell selection

If antigens are expressed at too low a level, they may not drive negative intrathymic selection, but sufficient to drive positive selection Insulin genes transcribed at high level in thymus protect against diabetes

Peripheral B-cell anergy

Elimination of autoreactive B cells in germinal centers

Several ways in which infectious agents could break self tolerance

Association of infection with autoimmune disease

Some body sites are immunologically priviledged

Damage to an immunologically privileged site can induce an autoimmune response