Autoimmune diseases

Autoimmune diseases

Autoimmune diseases result when the body's immune system turns against itself and mistakenly attacks healthy cells.  An autoimmune disease is a pathological state due to an abnormal immune response of the body to substances and tissues that are normally present in the body.  Structural or functional damage is produced by the action of immunologically competent cells or antibody directed against the normal components of the body

Autoimmunity is the presence of self-reactive immune response (e.g., auto-antibodies, self-reactive T-cells), with or without damage or pathology resulting from it.

For a disease to be regarded as an autoimmune disease it needs to follow Witebsky's postulates

·         Direct evidence from transfer of disease-causing antibody or disease-causing T lymphocyte

·         Indirect evidence based on reproduction of the autoimmune disease in experimental animals

·         Circumstantial evidence from clinical clues

Features of autoimmune diseases

·         Increased levels of immunoglobulin

·         Presence of auto antibodies

·         Deposition of antibodies or their derivatives at site of disease

·         Accumulation of lymphocytes and plasma cells at the site of disease

·         Benefit from immunosuppressive therapy

·         Occurrence of more than one type of auto immune lesions

·         Genetic predisposition

·         Chronic and generally irreversible

·         More incidence among females

Human autoimmune diseases can be divided into organ specific and systemic diseases. The organ-specific diseases involve an autoimmune response directed primarily against a single organ or gland. The systemic diseases are directed against a broad spectrum of tissues and have manifestations in a variety of organs.  Sometimes the damage to self-cells or organs is caused by antibodies; in other cases, T cells are the culprit.

Organ-Specific Autoimmune Diseases: Here the immune response is directed to a target antigen unique to a single organ, so that the manifestations are limited to that organ. The cells of the target organs may be damaged directly by humoral or cell-mediated mechanisms. In some cases, the antibodies may overstimulate or block the normal function of the target organ.

Systemic Autoimmune Diseases: Here, the response is directed toward a broad range of target antigens and involves a number of organs and tissues. These diseases reflect a general defect in immune regulation that results in hyperactive T cells and B cells. Tissue damage is widespread, from cell mediated immune responses and auto-antibodies or by accumulation of immune complexes.

Organ-Specific Autoimmune Diseases

Disease	Self-antigen	Immune response
Goodpasture’s syndrome	Renal and lung basement membranes	Auto-antibodies
Graves’ disease	Thyroid-stimulating hormone receptor	Auto-antibody (stimulating)
Hashimoto’s thyroiditis	Thyroid proteins and cells	TDTH cells, auto-antibodies
Idiopathic thrombocytopenia purpura	Platelet membrane proteins	Auto-antibodies
Insulin-dependent diabetes mellitus	Pancreatic beta cells	TDTH cells, auto-antibodies
Myasthenia gravis	Acetylcholine receptors	Auto-antibody (blocking)
Myocardial infarction	Heart	Auto-antibodies
Pernicious anemia	Gastric parietal cells; intrinsic factor	Auto-antibody
Poststreptococcal glomerulonephritis	Kidney	Antigen-antibody complexes
Spontaneous infertility	Sperm	Auto-antibodies
Addison’s disease	Adrenal cells	Auto-antibodies
Autoimmune hemolytic anemia	RBC membrane proteins	Auto-antibodies

 

Systemic Autoimmune Diseases

Disease	Self-antigen	Immune response
Ankylosing spondylitis	Vertebrae	Immune complexes
Multiple sclerosis	Brain or white matter	TH1 cells and TC cells, auto-antibodies
Rheumatoid arthritis	Connective tissue, IgG	Auto-antibodies, immune complexes
Scleroderma	Nuclei, heart, lungs, gastrointestinal tract, kidney	Auto-antibodies
Sjogren’s syndrome	Salivary gland, liver, kidney, thyroid	Auto-antibodies
Systemic lupus erythematosus (SLE)	DNA, nuclear protein, RBC and platelet membranes	Auto-antibodies, immune complexes

 

Mechanisms for Induction of Autoimmunity

A variety of mechanisms have been proposed and it is likely that autoimmunity does not develop from a single event but rather from a number of different events.

In addition, susceptibility to many autoimmune diseases differs between the two sexes.

1.      Release of Sequestered Antigens

The induction of self-tolerance in T cells results from exposure of immature thymocytes to self-antigens and the subsequent clonal deletion of self-reactive clones. Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developing T cells in the thymus, will not induce self-tolerance. Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation.

For example, sperm arise late in development and are sequestered from the circulation. When some sperm antigens are released into the circulation they can induce auto-antibody formation in men. Similarly, the release of lens protein after eye damage or of heart-muscle antigens after myocardial infarction has been shown to lead to the formation of auto-antibodies.

2.      Molecular Mimicry or cross reacting antigens

A pathogen may express a region of protein that resembles a particular self-component in conformation or primary sequence.  Such molecular mimicry appears in a wide variety of organisms.  Molecular mimicry has been suggested as one mechanism of autoimmunity.  One of the best example is post-rabies encephalitis, which develop in some individuals who had received the rabies vaccine if the preparations of the vaccine included antigens derived from the rabbit brain cells. In a vaccinated person, these rabbit brain-cell antigens could induce formation of antibodies and activated T cells, which could cross-react with the recipient’s own brain cells, leading to encephalitis.

Cross-reacting antibodies are also thought to be the cause of heart damage in rheumatic fever, which can sometimes develop after a Streptococcus infection. In this case, the antibodies are to streptococcal antigens, but they cross-react with the heart muscle.

3.      Inappropriate Expression of Class II MHC Molecules

The pancreatic beta cells of individuals with insulin-dependent diabetes mellitus (IDDM) express high levels of both class I and class II MHC molecules, whereas healthy beta cells express lower levels of class I and do not express class II at all.

Similarly, thyroid acinar cells from those with Graves’ disease have been shown to express class II MHC molecules on their membranes.

4.      Polyclonal B-Cell Activation

A number of viruses and bacteria can induce nonspecific polyclonal B-cell activation. Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus (EBV) are examples.  If B cells reactive to self-antigens are activated by this mechanism, auto-antibodies can appear. For instance, during infectious mononucleosis, which is caused by EBV, a variety of auto-antibodies are produced, including autoantibodies reactive to T and B cells, rheumatoid factors, and antinuclear antibodies.

5.      Antigenic alteration or formation of neo antigens

This may be due to any physical, chemical or biological influence.  Physical influence includes radiation, photosensitization or cold which may modify the antigen to be immunogenic in the individual while chemical agents include drugs.  Antigenic change due tomicrobial infection, mutation, etc comes under biological alteration.

6.      Defects in the idiotype-anti idiyotype network

Autoimmune Diseases Mediated by Direct Cellular Damage or by Stimulating or Blocking Auto-Antibodies.  Autoimmune diseases involving direct cellular damage occur when lymphocytes or antibodies bind to cell-membrane antigens and cause cellular lysis and/or an inflammatory response in the affected organ. Gradually, the function of the organ declines.  Examples of this type of autoimmune disease are Hashimoto’s Thyroiditis, Goodpasture’s Syndrome. 

In some autoimmune diseases, antibodies act as agonists, binding to hormone receptors in stead of the normal ligand and stimulating inappropriate activity. This usually leads to an overproduction of mediators or an increase in cell growth.  Conversely, auto-antibodies may act as antagonists, binding hormone receptors but blocking receptor function. This generally causes impaired secretion of mediators and gradual atrophy of the affected organ.  Examples are Graves’ Disease and Myasthenia Gravis.

Autoimmune diseases are classified into four types

        I.            Hemocytolytic autoimmune diseases

     II.            Localized or organ specific autoimmune diseases

  III.            Systemic autoimmune diseases

  IV.            Transitory autoimmune diseases

I. Hemocytolytic autoimmune diseases

1.      Autoimmune hemolytic anemia: An individual with autoimmune hemolytic anemia will be having auto-antibody to RBC antigens.  This results in complement mediated lysis or antibody-mediated opsonization and phagocytosis of the red blood cells.

2.      Auto immune thrombocytopenia: antibodies formed against platelets. This condition can be seen in idiopathic thrombocytopenic purpura. Symptoms include epistaxis (bleeding from the nose), bleeding gums, poor clotting, hematuria etc.

3.      Autoimmune leucopenia: antibodies are formed against leucocytes and results in decreased leucocyte count

II. Localized or organ specific autoimmune diseases

1.      Hashimoto’s Thyroiditis (lymphadenoid goitre)

In Hashimoto’s thyroiditis, an individual produces auto-antibodies and sensitized TH1 cells specific against thyroid antigens. There will be intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers, causes a goiter, or visible enlargement of the thyroid gland.

Antibodies are formed to thyroid proteins, such as thyroglobulin and thyroid peroxidase and binding of the auto-antibodies to these proteins interferes with iodine uptake and leads to decreased production of thyroid hormones (hypothyroidism).

2.      Pernicious anemia

This is caused by auto-antibodies to intrinsic factor, a membrane-bound intestinal protein on gastric parietal cells. Binding of the auto-antibody to intrinsic factor blocks the intrinsic factor–mediated absorption of vitamin B12. In the absence of sufficient vitamin B12, hematopoiesis decreases and the number of mature red blood cells decrease.  Pernicious anemia is treated with injections of vitamin B12.

3.      Goodpasture’s Syndrome

In Goodpasture’s syndrome, auto-antibodies specific for basement-membrane antigens bind to the basement membranes of the kidney glomeruli and the alveoli of the lungs. Subsequent complement activation leads to direct cellular damage and inflammatory response. This leads to progressive kidney damage and pulmonary hemorrhage. Death may ensue within several months of the onset of symptoms. 

4.      Insulin-Dependent Diabetes Mellitus

IDDM is caused by an autoimmune attack on the pancreas against insulin-producing cells (beta cells) that are located in the islets of Langerhans. The autoimmune attack through CTL, autoantibodies, lytic enzymes from macrophages, destroys beta cells, resulting in decreased production of insulin and consequently increased levels of blood glucose.

The most common therapy for diabetes is daily administration of insulin.

5.      Graves’ Disease or Thyrotoxicosis

Thyroid-stimulating hormone (TSH), produced by the pituitary gland regulate the production of thyroid hormones. Binding of TSH to a receptor on thyroid cells stimulates the synthesis of two thyroid hormones, thyroxine and triiodothyronine.

A patient with Graves’ disease produces auto-antibodies that bind the receptor for TSH and mimic the normal action of TSH, resulting in production of the thyroid hormones. Unlike TSH, however, the autoantibodies are not regulated, and consequently they overstimulate the thyroid and are called long-acting thyroid-stimulating (LATS) antibodies.

6.      Myasthenia Gravis

Here, the patient produces auto-antibodies that bind the acetylcholine receptors on the muscles, blocking the normal binding of acetylcholine.  This also induces complement mediated lysis of the cells. So there will be progressive weakening of the skeletal muscles. The early signs of this disease include drooping eyelids and inability to retract the corners of the mouth, which gives the appearance of snarling.  Further it lead to severe impairment of eating as well as problems with movement.

7.      Addison’s disease

Affected organ is adrenal glands.  There will be lymphocytic infilteration of adrenal gland and circulating antibody against zona glomerulosa.  Also called adrenal insufficiency / hypocortisolism. Symptoms include weight loss, muscle weakness, darkness of skin.

8.      Autoimmune diseases of eye

Phacoanaphylaxis is intraoccular inflammation after cataract surgery which is due to formation of antibody against lens proteins

Sympathetic ophthalmia is inflammation of eye following Perforating injuries of eye. 

9.      Auto immune diseases of nervous system

Rabies vaccinanation sometimes leads to injury of nervous system. This is due to formation of antibodies against sheep nervous tissue, which cross reacts with human nervous tissue.

10.  Autoimmune diseases of skin

Mainly three types, 1. Pemphigus vulgaris 2. Bullous pemphigoid 3. Dermatitis herpatiformis.

Pemphigus vulgaris: It is characterized by blister formation on skin & mucosa. This disease is due to formation of Antibodies against intercellular cement substance.

Bullous pemphigoid: This disease is due to formation of Antibodies against dermal epithelia junction. Symptoms are eczema, rashes, hemorrhagic blisters, increased skin pigmentation & inflammation.

Dermatitis herpetiformis:  It is a rare auto immune disease of skin characterized by papules & vesicles.  Antibody not known

11.  Autoimmune orchitis

This disease is followed by mumps orchitis.  There will be lymphocytic infiltration of testes and circulating antibody against sperm and germinal cells.  The autoimmune reaction results in infertility. 

III. Systemic Autoimmune Diseases

Here, the autoimmune response is directed toward a broad range of target antigens and involves a number of organs and tissues. Tissue damage is from cell mediated immune responses and from direct cellular damage caused by auto-antibodies or by accumulation of immune complexes.

1.      Systemic Lupus Erythematosus

One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus (SLE), which typically appears in women between 20 and 40 years of age. SLE is characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction. a rash on the cheeks and nose, which is called a “butterfly rash” will be seen.  There will be autoantibodies to several tissue antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors. 

Auto-antibody specific for RBCs and platelets lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively.

Immune complexes of auto-antibodies with various nuclear antigens cause a type III hypersensitive reaction in blood vessels resulting in vasculitis and glomerulonephritis.

Laboratory diagnosis of SLE is through detection of antinuclear antibodies, which are directed against double stranded or single-stranded DNA, nucleoprotein, histones, and nucleolar RNA.

An LE cell is generally observed.  This is a neutrophil or macrophage that has a large pale homogenous body known as LE body.  LE body is immunologically damaged nucleus of a leucocyte. 

2.      Multiple Sclerosis

Multiple sclerosis (MS) is a neurologic disability.  The symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision.  Most people with MS are diagnosed between the ages of 20 and 40. Individuals with this disease produce autoreactive T cells that cause inflammatory lesions along the myelin sheath of nerve fibers. The cerebrospinal fluid of patients contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflammatory lesions, destroying the myelin. Breakdown in the myelin sheath leads to numerous neurologic dysfunctions.

3.      Rheumatoid Arthritis

Rheumatoid arthritis often affects women from 40 to 60 years old. The major symptom is chronic inflammation of the joints, although the hematologic, cardiovascular, and respiratory systems are also frequently affected. Individuals with rheumatoid arthritis produce a group of auto-antibodies called rheumatoid factors (RF).  This is generally an IgM antibody.  These are reactive with the Fc region of IgG.  IgM-IgG complexes are formed and deposited in the joints. These immune complexes can activate the complement cascade, resulting in a type III hypersensitive reaction, which leads to chronic inflammation of the joints.

4.      Scleroderma

This is also known as systemic sclerosis.  It is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) and may also affects internal organs.

Limited scleroderma - mainly affect the hands, arms and face. It is also called CREST syndrome as an acronym of the following manifestations

·         Calcinosis (the deposition of calcium nodules in skin)

·         Raynaud's phenomenon (vasoconstriction in hand)

·         Esophageal dysfunction (difficulty swallowing)

·         Sclerodactyly (skin thickening on fingers)

·         Telangiectasias (dilated capillaries on the face, hands and mucous membranes).

Diffuse scleroderma is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys, esophagus, heart and/or lungs.

5.      Ankylosing spondylitis

This is a type of arthritis with long term inflammation of the joints of the spine and where the spine joins the pelvis. Occasionally other joints such as the shoulders or hips are involved. Eye and bowel problems may also occur.

6.      Polyarteritis nodosa

There will be necrotizing angitis of medium sized arteries resulting in coronary thrombosis, cerebral hemorrhage and gastrointestinal bleeding. 

7.      Sjogren's syndrome

This is a long-term autoimmune disease in which the moisture-producing glands of the body are affected.  This cause dry mouth and dry eyes, dry skin, a chronic cough, vaginal dryness, numbness in the arms and legs, muscle and joint pains, etc. 

IV. Transitory autoimmune diseases

This includes anemia, thrombocytopenia and nephritis that follow microbial infections or drug therapy. This is a transient disease and undergo spontaneous cure when the infection subsides or the drug is withdrawn