Autoimmune disease

• Autoimmune is a disorder of the body’s defense mechanism in which an immune response is generated against component or products of its own tissues treating them as foreign material and attacking them.
• The disorder caused by inflammation and destruction of tissues by the body’s immune response as a result of autoimmunity is known as autoimmune disease.

Proposed mechanism for induction of autoimmunity

• A variety of mechanisms have been proposed to account for the T-cell mediated generation of autoimmune disease. And it is likely that autoimmune disease does not develop from  a single event rather from a number of different events.

Some of the proposed mechanisms are

1. Forbidden clone
2. Altered antigen
3. Sequestered antigen
4. Immunological deficiency theory
5. Genetic influence

1. Forbidden clone

• Mutation in the lymphocytes may result in the formation of changed or altered clone. These altered clone may recognize host as foreign and lead to development of autoimmunity.

2. Altered antigen

• Some of the antigen on the host cell get altered by chemical, biological or physical means. Thus formed new antigenic determinants which may be recognized as foreign by the host.

3. Sequestered antigen

• Some of the antigen in the body are hidden from cells of immune system.
• If the organs containing such antigen are damaged, it causes exposure of sequestered antigen thus an immune reaction to these antigen may occur.

4. Immunological deficiency theory

• According to this theory, mutation or loss of immune regulatory power. i.e. deficiency in immune system results in a condition in which self-antigen behaves as foreign.

5. Genetic influence

• This was determined by family studies. It is well recognized that certain immune disorder predominate in females and families.
• This has strongly supported the role of genetic influence in autoimmunity.
• Genetic links have occurred between disease and HLA antigens.

Types of autoimmune disease:

On the basis of pathogenic mechanism, autoimmune disease are classified into two types:

1. Organ specific autoimmune disease:

• This autoimmune disease is directed against a component of one particular type of organ.
• The organ specific autoimmune disease can further be divided into two groups:

• i. Autoimmune disease  mediated by direct cellular damage:
• This type of damage occur when lymphocytes or antibodies bind to cell membrane antigens, causing cellular lysis or inflammatory response in affected organ.
• The damaged cellular structure is then replaced by connective tissue (fibrous) & it losses its function.
• Examples: Hasimoto’s thyroiditis, autoimmune anaemia, Good pasteur’s syndrome, Insulin dependent diabetes mellitus.

• ii. Autoimmune disease mediated by stimulating or blocking auto antibodies:
• In some cases, antibodies act as antagonist & bind to hormone receptor stimulating inappropriate activity. This usually leads to overproduction of mediators or increase cell growth.
• They also bind to hormone receptor function and thereby block receptor function. This causes impaired secretion of mediators and gradual atrophy of the affected organ.
• Examples: Grave’s disease, Myasthenia gravis.

 2. Systematic autoimmune disease :

• It is the type of autoimmune disease which is directed against an antigen that is present in many different sites and can include involvement of several organs and tissues.
• These disease reflect a general defect in immune regulation that result in hyperactive T-cells and B-cells.
• Examples: Rheumatoid arthritis, Systematic lupus erythematosus (SLE), multiple sclerosis.

Some examples of autoimmune diseases:

Grave’s disease:

• The production of thyroid hormones is carefully regulated by thyroid stimulating hormone (TSH) produced by pituitary gland. The binding of TSH to receptor on thyroid cell activates adenylate cyclase enzyme stimulating synthesis of thyroxine and tri-iodo thyroxine.
• A patient with Graves’ disease produces autoantibody (LATS) that bind to receptor of TSH & mimic the normal action of TSH, activating adenylate cyclase & resulting in production of thyroid hormones. Unlike TSH, however autoantibody are not regulated and consequently they overstimulate the thyroid gland.

Myasthenia gravis:

• It is an autoimmune disease mediated by blocking antibodies.
• A patient with this disease produces auto antibodies that bind the acetylcholine receptor on motor end plates of muscles, blocking the normal binding of acetyl choline.  The result is progressive weakening the skeletal muscles.
• It also inducing complement mediated lysis of cells and the antibodies cause the destruction of the cells bearing receptors.

Hashimoto’s Thyroiditis:

• In Hashimoto thyroiditis, an individual produces antibodies & sensitized TH1 Cell specific for thyroid antigens.
• An attending delayed type hypersensitivity (DTH) response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages and plasma cells which form lymphocytic follicles and germinal centers.
• The ensuring inflammatory response cause goiter or visible enlargement of the thyroid gland, a physiological response to hypothyroidism.
• Hypothyroidsm is caused when antibodies are formed to a number of thyroid proteins including thyroglobulin and thyroid peroxidase, both of which are involved in the uptake of iodine.
• Binding of auto-antibodies to these protein interfere with thyroid gland functioning.

Goodpasture’s Syndrome:

• In Goodpasture’s syndrome, auto-autobodies specific for certain basement membrane antigen bind to basement membrane of kidney glomeruli and alveoli of lungs.
• Subsequent complement activation leads to direct cellular damage and an ensuring inflammatory response meditated by a buildup of complement split products.
• Damage to the glomerulus and alveolar basement membrane leads to progressive kidney damage and pulmonary hemorrhage.
• Death may ensure within several month of the onset of symptoms.

Autoimmune anemias:

• Autoimmune anemias include pernicious anemia, autoimmune hemolytic anemia (AIHA) and drug induced hemolytic anemia.
• Pernicious anemia is caused by auto- antibodies to intrinsic factor, a membrane bound intestinal protein on gastric parietal cells which facilitate uptake of vitamin B12 from small intestine. Binding of auto-antibody to intrinsic factor block absorption of vitamin B12. In absence of sufficient vitamin B12, which is necessary for proper hematopoiesis, the number of functional mature RBC decrease below normal.
• Autoimmune hemolytic anemia: An individual with autoimmune hemolytic anemia makes auto-antibody to Red- blood cell antigen, triggering complement mediated lysis or antibody-mediated opsonization & phagocytosis of RBC.
• In drug induced hemolytic anemia, certain drugs such as penicillin or anti-hypertensive agents like methyldopa interact with RBC, the cells become antigenic.

Insulin Dependent Diabetes mellitus (IDDM):

• IDDM is caused by an autoimmune attack on pancreas.
• The attack is directed against specialized insulin producing beta-cell that are location in spherical cluster islets of Langerhans, scattered throughout the pancreas.
• The autoimmune attack destroys beta cell resulting in decreased production of insulin and consequently increased level of blood glucose.
• Several factors are important in destruction of beta cells, first activated CTLs migrate into an islet and begin to attack the insulin producing cells.
• The CTL infiltration & activation of macrophages, frequently referred to as insulitis which is followed by cytokine release and presence of auto antibodies which leads to a cell mediated DTH.
• The auto-antibodies to beta cells may contribute to cell distribution by facilitating either antibody-mediated complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC).

Systemic Lupus erythematosus:

• One of the best example of a systemic autoimmune disease is systemic lupus erythematosus (SLE).
• The individual affected by SLE may produce auto-antibodies to a vast array of tissues, antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors.
• Interaction of these auto-antibodies with their specific antigens produces various symptoms.
• Auto antibody specific for RBC and platelets for examples, can lead to complement mediated lysis resulting in hemolytic anemia and thrombocytopenia, respectively.
• When immune complex of auto antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III hypersensitivity reaction develops.
• The complexes activates the complement system and generate membrane- attack complexes and complement split produces that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis.

Multiple sclerosis (MS):

• Multiple sclerosis (MS) is the most common cause of neurologic disability associated with autoimmune disease in western country.
• With this disease production of auto-reactive T-cell that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers.
• The cerebrospinal fluid of patient with active MS contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflammatory lesions, destroying the myelin.
• Since myelin function to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions.

Rheumatoid arthritis:

• Rheumatoid arthritis is common autoimmune disorder.
• Many individuals with rheumatoid arthritis produce a group of auto-antibodies called rheumatoid factors that are reactive with determinants of Fc region of IgG antibody.
• The classic rheumatoid factor is an IgM antibody with that reactivity. Such auto-antibodies bind to normal circulating IgG, forming IgM –IgG complexes that are deposited in the joints.
• The immune complexes can activate the complement cascade, resulting in type III hypersensitive reaction which leads to chronic inflammation of the joints.

Autoimmune Disease: Mechanism of autoimmunity, Types and examples