_AUTOIMMUNE DISEASES
Autoimmune
diseases occur due to autoimmune responses of
an individual to self-antigens. Self-tolerance prevents autoimmune disease.
Aetiology
Aetiology of autoimmune diseases is multifactorial, involving both genetic and environmental factors.
1. Genetic Factors in Autoimmunity
There is association between MHC genes and several autoimmune diseases. HLA molecule is strongly associated with certain autoimmune diseases, such as ankylosing spondylitis and Reiter's syndrome with HLA B27, rheumatoid arthritis with HLA-DR1, HLA-DR4 or both, systemic lupus erythematosus with HLA-DO locus, insulin dependent diabetes mellitus with HLA-DR3 or HLA-DR4 alleles or both. Genetic factors determine the nature and frequency of autoimmune diseases.
2. Environmental Factors- Microbial Agents in Autoimmunity
Certain microbes have been implicated in triggering autoimmunity. Certain examples are sited below.
Pathogenesis.
Breakdown of central tolerance most likely does not take part in the pathogenesis of autoimmunity. Failure of peripheral tolerance takes part in the pathogenesis of autoimmunity.
1. Molecular Mimicry
Antigens of certain bacteria and viruses mimic (resembles) self-antigens. These are called cross-reacting antigens. Such antigens of microbes may cause immune response by activation of autoreactive T cells or B cells. The antibody or sensitized T cell reacts with the cross-reacting self-antigen and may produce tissue damaging reactions. Examples :
(a) Rheumatic fever. M protein of Streptococcus pyogenes and glycoproteins of heart. Antibodies against M proteins cross-react with glycoproteins of heart, joints and other tissues leading to rheumatic heart disease.
(b) Type I insulin-dependent diabetes mellitus due to cross-reactions between certain coxsackievirus B4 and islet cell antigen glutamic acid decarboxylase. Mumps, measles, rubella, cytomegalovirus and infections mononucleosis have been implicated.
(c) Haemolytic anaemia following Mycoplasma pneumoniae infection.
(d) Reiter syndrome occurs following Shigella, Salmonella, Yersinia, Campylobacter or Chlamydia infection.
(e) Guillain-Barre syndrome following viral or Campylo-bacter infections.
(f) Multiple sclerosis following viral infection.
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Aetiology
Aetiology of autoimmune diseases is multifactorial, involving both genetic and environmental factors.
1. Genetic Factors in Autoimmunity
There is association between MHC genes and several autoimmune diseases. HLA molecule is strongly associated with certain autoimmune diseases, such as ankylosing spondylitis and Reiter's syndrome with HLA B27, rheumatoid arthritis with HLA-DR1, HLA-DR4 or both, systemic lupus erythematosus with HLA-DO locus, insulin dependent diabetes mellitus with HLA-DR3 or HLA-DR4 alleles or both. Genetic factors determine the nature and frequency of autoimmune diseases.
2. Environmental Factors- Microbial Agents in Autoimmunity
Certain microbes have been implicated in triggering autoimmunity. Certain examples are sited below.
Pathogenesis.
Breakdown of central tolerance most likely does not take part in the pathogenesis of autoimmunity. Failure of peripheral tolerance takes part in the pathogenesis of autoimmunity.
1. Molecular Mimicry
Antigens of certain bacteria and viruses mimic (resembles) self-antigens. These are called cross-reacting antigens. Such antigens of microbes may cause immune response by activation of autoreactive T cells or B cells. The antibody or sensitized T cell reacts with the cross-reacting self-antigen and may produce tissue damaging reactions. Examples :
(a) Rheumatic fever. M protein of Streptococcus pyogenes and glycoproteins of heart. Antibodies against M proteins cross-react with glycoproteins of heart, joints and other tissues leading to rheumatic heart disease.
(b) Type I insulin-dependent diabetes mellitus due to cross-reactions between certain coxsackievirus B4 and islet cell antigen glutamic acid decarboxylase. Mumps, measles, rubella, cytomegalovirus and infections mononucleosis have been implicated.
(c) Haemolytic anaemia following Mycoplasma pneumoniae infection.
(d) Reiter syndrome occurs following Shigella, Salmonella, Yersinia, Campylobacter or Chlamydia infection.
(e) Guillain-Barre syndrome following viral or Campylo-bacter infections.
(f) Multiple sclerosis following viral infection.
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2. Release of Sequestered Antigens
Sequestered antigens are those that can not interact with the immune system during development as they are anatomically sequestered and hence the lymphocytes specific for such sequestered antigens are not deleted. These are treated as foreign when introduced into the circulation, and elicit both humoral and cellular responses.
(a) Lens and uveal tract of the eye. The antigens cause post-traumatic uveitis, endophthalmitis.
(b) Spermatozoa- Aspermatogenesis (Sterility).
(c) Central nervous system- Encephalitis.
3. Epitope Spreading
These are epitopes of self-protein that are not readily recognized by the immune system during development and hence the T cells specific for such 'cryptic' self-epitopes are not deleted. It is molecular sequestration of antigens.
The progression and chronicity of the autoimmune response may be maintained by cryptic self-epitopes. Inflammatory response may lead to presentation of cryptic antigens and thus induce epitope spreading. Inflammatory response may be precipitated by microbes.
4. Other Immunological Mechanisms are: Polyclonal lymphocyte activation. (b) Breakdown of T cell clonal anergy, (c) Failure of activation induced apoptosis, (d) Failure of peripheral suppression by T cells.
Autoimmune diseases:
A. Systemic Autoimmune Diseases. Autoimmune diseases involving multiple organs.
1. Systemic lupus erythematosus (SLE)
Autoantibodies are numerous and are against nuclear and other cellular components. Antinuclear antibodies (ANAs) are particularly formed. Antibodies to double-stranded DNA is the hallmark of SLE. Antibodies to double stranded DNA and Smith (Sm) antigen are virtually diagnostic of SLE.
Immune complexes formed by DNA (antigen) and anti-DNA antibody are deposited at different sites, and are responsible for lesions such . as vasculitis, arthritis, glomerulonephritis. Autoantibodies against erythrocytes, neutrophils, and platelets may cause autohaemolytic anaemia, neutropenia and thrombocytopenia respectively by complement mediated cytotoxicity (type II hypersensitivity reaction).
2. Acute Rheumatic Fever- S. pyogenes infections precede the development of rheumatic fever. Antibodies directed against the M proteins of Streptococcus pyogenes cross-react with tissue glycoproteins in the heart, joint and other tissues.
3. Rheumatoid arthritis
Autoantibodies to the Fc portion of IgG are formed. Autoantibodies are called rheumatoid factor (RF) and are mostly IgM antibodies.
4. Other Systemic Disorders. Reiter's syndrome, Sjogren's syndrome, Systemic sclerosis (Scleroderma), Inflammatory myopathies, Polyarteritis nodosa.
Sequestered antigens are those that can not interact with the immune system during development as they are anatomically sequestered and hence the lymphocytes specific for such sequestered antigens are not deleted. These are treated as foreign when introduced into the circulation, and elicit both humoral and cellular responses.
(a) Lens and uveal tract of the eye. The antigens cause post-traumatic uveitis, endophthalmitis.
(b) Spermatozoa- Aspermatogenesis (Sterility).
(c) Central nervous system- Encephalitis.
3. Epitope Spreading
These are epitopes of self-protein that are not readily recognized by the immune system during development and hence the T cells specific for such 'cryptic' self-epitopes are not deleted. It is molecular sequestration of antigens.
The progression and chronicity of the autoimmune response may be maintained by cryptic self-epitopes. Inflammatory response may lead to presentation of cryptic antigens and thus induce epitope spreading. Inflammatory response may be precipitated by microbes.
4. Other Immunological Mechanisms are: Polyclonal lymphocyte activation. (b) Breakdown of T cell clonal anergy, (c) Failure of activation induced apoptosis, (d) Failure of peripheral suppression by T cells.
Autoimmune diseases:
A. Systemic Autoimmune Diseases. Autoimmune diseases involving multiple organs.
1. Systemic lupus erythematosus (SLE)
Autoantibodies are numerous and are against nuclear and other cellular components. Antinuclear antibodies (ANAs) are particularly formed. Antibodies to double-stranded DNA is the hallmark of SLE. Antibodies to double stranded DNA and Smith (Sm) antigen are virtually diagnostic of SLE.
Immune complexes formed by DNA (antigen) and anti-DNA antibody are deposited at different sites, and are responsible for lesions such . as vasculitis, arthritis, glomerulonephritis. Autoantibodies against erythrocytes, neutrophils, and platelets may cause autohaemolytic anaemia, neutropenia and thrombocytopenia respectively by complement mediated cytotoxicity (type II hypersensitivity reaction).
2. Acute Rheumatic Fever- S. pyogenes infections precede the development of rheumatic fever. Antibodies directed against the M proteins of Streptococcus pyogenes cross-react with tissue glycoproteins in the heart, joint and other tissues.
3. Rheumatoid arthritis
Autoantibodies to the Fc portion of IgG are formed. Autoantibodies are called rheumatoid factor (RF) and are mostly IgM antibodies.
4. Other Systemic Disorders. Reiter's syndrome, Sjogren's syndrome, Systemic sclerosis (Scleroderma), Inflammatory myopathies, Polyarteritis nodosa.
_ B. Single organ or Cell-type Autoimmune Diseases
I. Blood Diseases
1. Autoimmune haemolytic anaemia. See chapter 26.
2. Pernicious anaemia. Autoantibodies to intrinsic factor and parietal cell. Autoimmune atrophic gastritis occur.
3. Agranulocytosis. Antibodies are directed against neutrophils.
4. Idiopathic thrombocytopenic purpura (ITP). Autoantibodies are directed against platelets.
II. Endocrine Disorders
1. Insulin dependent diabetes mellitus (IDDM) or Type I diabetes mellitus. Autoreactive T cells destroy the islet cells of the pancreas. Autoantibodies are directed against intracellular islet cell antigens such as glutamic acid decarboxylase.
2. Insulin-resistant diabetes. Antibodies to insulin receptors interfere with insulin binding.
3. Graves' disease. It occurs due to autoantibodies to the TSH receptor. Autoantibodies to the TSH receptor or thyroid-stimulating immunoglobulin (TSI) is relatively specific for Graves' disease.
4. Hashimoto's thyroiditis. Primarily by defect in T cells. Autoantibodies are directed against the following thyroid antigens : (a) Thyroglobulin, (b) Thyroid peroxidase, (c) TSH receptor, and (d) Iodine transporter. Complement-dependent cytotoxicity and ADCC may contribute to destruction of thyroid tissue.
III. Other Single Organ Disorders
1. Myasthenia gravis. Antibodies to acetylcholine receptor of neuromuscular junction are found in serum.
2. Autoimmune orchitis after vasectomy probably results from immune response against antigen of spermatozoa normally sequestered in the testis.
3. Goodpasture syndrome. Antibodies are formed against collagen in basement membrane of kidneys and lungs.
4. Guillain-Barre syndrome. Antibodies against myelin protein are found.
5. Autoimmune hepatitis. Antinuclear, anti m itochondrial and anti-smooth muscle antibodies are found in serum.
6. Primary biliary cirrhosis. Antimitochondrial antibodies are present in serum.
7. Ulcerative colitis.
8. Membranous glomerulonephritis. Antibodies to a renal autoantigen cause idiopathic membranous glornerLilonephritis.
9. Autoimmune encephalomyelitis.
NOTE : Autoantibodies may be found in the serum of normal individuals, particularly in old people.
I. Blood Diseases
1. Autoimmune haemolytic anaemia. See chapter 26.
2. Pernicious anaemia. Autoantibodies to intrinsic factor and parietal cell. Autoimmune atrophic gastritis occur.
3. Agranulocytosis. Antibodies are directed against neutrophils.
4. Idiopathic thrombocytopenic purpura (ITP). Autoantibodies are directed against platelets.
II. Endocrine Disorders
1. Insulin dependent diabetes mellitus (IDDM) or Type I diabetes mellitus. Autoreactive T cells destroy the islet cells of the pancreas. Autoantibodies are directed against intracellular islet cell antigens such as glutamic acid decarboxylase.
2. Insulin-resistant diabetes. Antibodies to insulin receptors interfere with insulin binding.
3. Graves' disease. It occurs due to autoantibodies to the TSH receptor. Autoantibodies to the TSH receptor or thyroid-stimulating immunoglobulin (TSI) is relatively specific for Graves' disease.
4. Hashimoto's thyroiditis. Primarily by defect in T cells. Autoantibodies are directed against the following thyroid antigens : (a) Thyroglobulin, (b) Thyroid peroxidase, (c) TSH receptor, and (d) Iodine transporter. Complement-dependent cytotoxicity and ADCC may contribute to destruction of thyroid tissue.
III. Other Single Organ Disorders
1. Myasthenia gravis. Antibodies to acetylcholine receptor of neuromuscular junction are found in serum.
2. Autoimmune orchitis after vasectomy probably results from immune response against antigen of spermatozoa normally sequestered in the testis.
3. Goodpasture syndrome. Antibodies are formed against collagen in basement membrane of kidneys and lungs.
4. Guillain-Barre syndrome. Antibodies against myelin protein are found.
5. Autoimmune hepatitis. Antinuclear, anti m itochondrial and anti-smooth muscle antibodies are found in serum.
6. Primary biliary cirrhosis. Antimitochondrial antibodies are present in serum.
7. Ulcerative colitis.
8. Membranous glomerulonephritis. Antibodies to a renal autoantigen cause idiopathic membranous glornerLilonephritis.
9. Autoimmune encephalomyelitis.
NOTE : Autoantibodies may be found in the serum of normal individuals, particularly in old people.