AUTOIMMUNE DISEASES

Autoimmune diseases are of 2 types:

1)organ specific autoimmune disease, 2)systemic autoimmune disease

ORGAN SPECIFIC AUTOIMMUNE DISEASES:

In an organ specific autoimmune disease; the immune response is directed to an antigen unique to a single organ or gland so that the manifestations are largely limited to that organ.

cells of a given organ may be damaged in two ways:

1) either by humoural or CMI effector mechanisms,
2) Antibodies may overstimulate or block the normal functions of the target organ.

Autoimmune diseases mediated by direct cellular damage:

When lymphocytes or antibodies  bind to antigens then cellular lysis or an inflammatory response is  generated in the affected organ. Manytimes,  the damaged cellular structure is replaced by connective tissues (fibrosis) and the function of the organ declines.

e.g.: hashimoto's thyroiditis
         Autoimmune anaemias
         Goodpasteure's syndrome,
         Insulin dependent diabetes mellitus

 HASHIMOTO'S THYROIDITIS-

Most frequent in middle aged women;  the individual produces autoantibodies and sensitized T-helper 1 cells against thyroid antigens.

As a reslut, DTH response occurs and thyroid gland is infiltrated by  lymphocytes,  macrophages and plasma cells which form lymphocytic follicles and germinal centers.

This leads to hypothyroidism  because autoantibodies bind to a number of thyroid proteins and interfere with uptake of iodine. This ,in turn, is manifested by GOITRE.

AUTOIMMUNE ANAEMIAS:

Autoimmune anaemias include :

1)pernicious anaemia 2)autoimmune hemolytic anaemia 3)drug induced hemolytic anaemia

1)pernicious anaemia

 Intrinsic factor is a membrane bound protein on gastric parietal cells; they help in the absorption of vit.B 12 from small intestine. This vit.B 12 is used in the process of hematopoiesis.

 Pernicious anaemia occurs when antibodies are formed to intrinsic factor. As a result, the host becomes incapable of absorbing vit.B12 from small intestine and hematopoiesis is  compromised leading to number of functional RBC below normal.
Pernicious anaemia is treated sith vit.B 12  injections.

2)Autoimmune hemolytic anaemia

In this case, autoantibodies to antigens present on RBC is made. This leads to complement mediated lysis or antibody mediated opsonization and phagocytosis of RBC ,lowering it's number below normal.

3)drug induced  hemolytic anaemia -

 in this case, drugs such as penicillin or the hypertensive agent like methyldopa interact with RBC and makes it antigenic.
 To diagnose this disease, RBC is incubated with antibodies against auto-antibodies present in RBC. If agglutination takes place; then presence of autoantibodies is confirmed and patient is diagnosed eith drug induced hemolytic anaemia.

GOODPASTEUR'S SYNDROME:

Basement membrane is found in kidney glomeruli and the alveoli of the lungs and they contain antigens specific to them against which auto-antibodies are produced in this disease .
Due to accumulation of  auto-antibodies ;  complement activation takes place and leads to direct cellular damage and inflammation.
This results in progressive kidney damage and pulmonary haemorrhage. Death may occur after few months.
For diagnosis; biopsies from patients stained with fluorescent  labelled anti-IgG and anti-C3b   reveal linear deposits if IgG and C3b along the basement membranes.

INSULIN-DEPENDENT DIABETES MELLITUS 

it occurs due to autoimmune attack on the  beta cells of pancreas  due to which insulin production is hampered and blood glucose level increases.
At first, beta cells are infiltrated by CTL and macrophages. Activation of macrophages release cytokines. Lytic enzymes of macrophages and cytokines destroys beta cells. Additionally,  autoantibodies contribute to cell destruction by facilitating ADCC or antibody mediated complement lysis.

 Symptoms : Initially,  ketoacidosis  and increased urine production occurs; in later stages atherosclerotic vascular lesions may occur which may result in gangrene of extremities due to impeded blood flow, renal failure and blindness.
If untreated, death may occur.
Treatment : insulin injections are administered  or transplantation of putified islet cells  is equally promising.

AUTOIMMUNE DISEASES DUE TO STIMULATING OR BLOCKING AUTOANTIBODIES:

antibodies may bind harmone receptors instead of ligand and stimulate or block the process concerned . This leads to increase or decrease in the production of mediators and increase in cell growth or gradual atrophy of the affected organ.

EXAMPLES OF SUCH DISEASES ARE :

1) greave's disease 2)myasthenia gravis

1) GRAVE'S DISEASE

As we know, production of thyroid hormone is regulated by TSH.
actually, when TSH binds to receptor on thyroid cell then adenylate cyclase is activated and two thyroid hormones namely thyroxine and tri-iodothyronine is stimulated.
but in case of grave's disease; autoantibodies are produced that bind the receptor for TSH and mimic the normal action of TSH thus producing throid hormones.
but these autoantibodies are not regulated like TSH and consequently, thyroid production is overstimulated and thus overproduced.
for this reason, these antibodies are called LATS antibodies (long acting thyroid stimulating antibodies).

MYASTHENIA GRAVIS

In this case, autoantibodies that bind the acetylcholine receptors present on motor end plates of muscles are produced. they block the normal binding of acetylcholine and the resulting signalling.
gradually, the muscles are weakened and complement mediated lysis of cells bearing receptors for these antibodies is caused.

symptoms- drooping eyelids, inability to retract corners of the mouth giving the appearence of snarling.

If not treated, then it can lead to severe impairment of eating and movement problems.

SYSTEMIC AUTOIMMUNE DISEASES:

In this case, response is directed towards a broad range of target antigens and involves a number of organs and tissues.

these diseases cause general defect in immune regulation and result in hyperactive t cells and B cells.

Tissue damage is widespread both due to CMI responses and auto-antibodies and immune complexes.

systemic autoimmune diseases can be exemplified through:

1) systemic lupus erythematosus,

2) multiple sclerosis

3)rheumatoid arthritis

SYSTEMIC LUPUS ERYTHMATOSUS -

More common in women, SLE is characterized by fever, rashes, weakness, arthritis, pleurisy and kidney dysfunction.

Affected individuals produce auto-antibodies to a variety of antigens such as DNA, histone, RBC, platelets, leukocytes and clotting factors. interaction of these antibodies with their respective auto-antibodies leads to variety of symptoms.

e.g. auto-antibodies against RBC and platelets lead to hemolytic anaemia and thrombocytopenia.

immune complexes of auto-antibodies and nuclear antigens are deposited along the wall of small blood vessels leading to type 3 hypersensitivity reaction. these complexes activate the complement system and generate membrane attack complexes which damage blood vessels resulting in vasculitis and glomerulonephritis.

besides, elevated level of complement proteins like C3a and C5a takes place. C5a induces increased expression of CR3 on neutrophiles  due to which neutrophiles aggregate and attach to the vascular endothelium. this results in neutropenia and vasculatis leading to severe tissue damage

NOTE: neutropenia is the decrease in the number of neutrophiles and vasculitis is development of various occlusions of the blood vessels.

DIAGNOSIS:antinuclear antibodies are checked for their presence. indirect immunofluoroscent staining with serum from SLE patients produces various characeristics staining patterns.

MULTIPLE SCLEROSIS:

In this case, the cerebrospinal fluid of the patients contain auto-reactive T cells which infiltrate the brain tissue and works to cause inflammation of myelin sheath which insulates nerve fibres. such a breakdown of myelin sheath leads to numerous neurologic dysfunctions.

It is the most common cause of neurologic disability and symptoms may be mild like numbness in limbs to severe like paralysis and loss of vision.

RHEUMATOID ARTHRITIS:

In this case,patients produce a group of auto-antibodies called rheumatoid factors that are reactive with determinants in the Fc region of  IgG . the classic rheumatoid factor is and IgM antibody. so, IgM-IgG complexes are formed and deposited in the joints. 

These immune complexes activate the complement cascade resulting in a type 3 hypersensitivity reaction which leads to chronic inflammation of the joints which is the major symptom though, respiratory, cardiovascular and hematologic systems are also frequently affected.