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Learning Objectives
Upon completion of these materials the student will be able to: Describe contributive factors to autoimmune diseases Distinguish organ specific and systemic autoimmune diseases with examples of each Describe the effects of SLE on the body List four types of autoantibodies found in lupus and describe pattern seen in IFA testing Discuss the symptoms of rheumatoid arthritis Describe the characteristics of the Abs found in rheumatoid arthritis
Learning Objectives
Differentiate Hashimotos thyroiditis and Graves disease on the basis of lab findings and immune mechanism List the main Abs tested for in Graves and Hashimotos diseases and describe testing procedures Relate genetic susceptibility to the development of insulin dependent diabetes mellitus Explain immunologic mechanism known to cause destruction of cells in insulin-dependent diabetes mellitus Discuss immunologic findings in multiple sclerosis, myasthenia gravis and Goodpastures syndrome
Introduction
Autoimmune diseases are the result of damage to the body by the presence of autoantibodies or autoreactive cells About 2% of the population are affected by such diseases There is a breakdown of self tolerance in these individuals Self tolerance is brought about by such mechanisms as clonal deletion of relevant effector cells, active regulation by TS cells and regulation through idiotypic networks Majority of T cells that are processed through the thymus do not survive. Self reactive T cells are destroyed Loss of TS cells may encourage the production of autoAbs
Introduction
MHC molecules influence Ag recognition or nonrecognition by determining peptide that can be presented to T cells The expression of class II molecules on host cells may result in presentation of self Ags for which there is no tolerance In several diseases, there are host cells that exhibit class II molecules on their surfaces after inflammatory response Such cells may function as Ag presenting cells for their own cellular proteins
Introduction
Genetic variation in MHC Ag may account for increased susceptibility in certain individuals Idiotypic network may also play a part in autoimmune diseases This refers to situations whereby antibodies are produced against antibodies When an Ab is produced for the first time, the variable region may be seen as foreign by the host The host may then produce antibodies against it The anti-idiotypic Ab may have reactivity against self Ags
Introduction
Anti-idiotypic Abs are found in diseases such as myasthenia gravis, diabetes mellitus, and Graves disease The anti-idiotypic Abs may mimic the original Ab and combine with the receptor for that Ag Defects in natural killer cells, in the secretion of ILs, in phagocytosis and complements may also contribute Hormones especially estrogen have been found to enhance B-cell activation and suppress regulator activities of T cell Environmental conditions such as infectious agents like viruses, bacteria and drugs contribute to autoimmunity
Rheumatoid Arthritis
Rheumatoid arthritis is a systemic autoimmune disorder It involves the synovial membrane of multiple joints Women are more likely to be affected than men and usually strikes between the ages of 20 and 40 Spontaneous remission may be experienced by some patients otherwise the disease may progress and result in deformity and disability RA has been associated with certain of the HLA class II molecules. HLA-DR1 and DR4 occur in 70% of patients with RA
Rheumatoid Arthritis
Clinical Signs: Diagnosis of RA is based on the 1987 criteria established by the American College of Rheumatology Symptoms include morning stiffness around the joints lasting at least 1 hour, swelling of the soft tissue around three or more joints Others include swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints, symetric arthritis, subcutaneous nodules, a positive RF test Also included is a radiographic evidence of erosion of the joints of the hands, the wrist, or both
Rheumatoid Arthritis
Usually begins with nonspecific symptoms such as fever, malaise, weight loss, and transient joint pain Stiffness and joint pain that gradually improves during the day are characteristics exhibited by most patients Joint are involved progressively to larger joints in a symmetric manner from the knees, hips, elbows, shoulders and cervical spine About 25% of patients have nodules over the bones Nodules may also be found in the myocardium, pericardium, heart valve, pleural, lungs, spleen, and larynx
Rheumatoid Arthritis
Immunologic Findings: The main immunologic finding is the presence of RF RF is a 19S Ab directed against the Fc portion of IgG The Ab is not specific for RA as it is found in other diseases such as SLE, scleroderma, Sjgrens syndrome and B cell lymphoproliferative disorders It has been suggested that RF may be anti-idiotypic antibodies involved in the regulation of immune response In RA, polyclonal activation of B cells may occur resulting in overwhelming amount of antibody to IgG
Rheumatoid Arthritis
Other autoAbs associated with RA include ANA, anticollagen Abs, Abs against cytoskeleton filamentous proteins etc. These Abs may cause immune complex formation with the activation of complement which contribute to pathogenesis Joint damage is due to invasion of inflammatory cells such as neutrophils, and macrophages Proliferation of fibroblast, macrophages, mast cells, and stellar cells result in the formation of a pannus, an organized mass of cells that grow into the joint space
Rheumatoid Arthritis
Laboratory Diagnosis of Rheumatoid Arthritis: Diagnosis is based on a combination of clinical manifestations, radiographic findings and lab tests Laboratory screening test for RF using sheep red cells or latex particles are available and simple to perform Quantitative test are also available which involve nephelometry and ELISA techniques RF is found in other diseases such as syphilis, viral infections, leprosy, chronic liver disease, neoplasm and other inflammatory processes
Rheumatoid Arthritis
The RF test is thus not a specific test for RA and about 10% of patient with the disease test negative for RF C-reactive protein and ESR are usually elevated and complements are normal or elevated Treatment: Treatment include palliatives with rest and nonsteroidal anti-inflammatory drugs like salicylates and ibuprofen Slow-acting antirheumatic drugs (SAARDS) may also be used to treat the condition New therapy include the use of monoclonal Abs that target T cells
Hashimotos Thyroiditis
Hashimotos thyroiditis and Graves disease are organ specific autoimmune diseases Both diseases interfere with the thyroid gland function The thyroid gland located in the anterior region of the neck consist of units called follicles Follicles are lined with cuboidal epithelial cells and filled with colloid The primary constituent of colloid is thyroglobulin which is made up of triiodothyronine (T3) thyroxine (T4) TRH acts on the pituitary gland to induce the release of TSH
Hashimotos Thyroiditis
TSH binds to receptors on the cell membrane of the thyroid gland causing break down of thyroglobulin into T3 and T4 AutoAbs may interfere with this process and cause under or overactivity of the thyroid Hashimotos thyroditis is most often seen in women between the ages of 30 and 40 years Patients develop a combination of goiter or enlarged thyroid, hypothyroidism and thyroid autoantibodies An association with HLA antigens DR4 and DR5 has been noted. DQA1 and DQB1 genes seem to confer resistance
Hashimotos Thyroiditis
Immunologic Findings: Lymphocytic infiltration is seen with development of germinal centers that almost replace the normal glandular architecture of the thyroid Cell infiltrates include T and B cells, macrophages and plasma cells Both CD4 and CD8 cells are found thus the disease is characterized by a cellular and a humoral response Autoantibodies are found in up to 80% of cases
Hashimotos Thyroiditis
Laboratory Testing: The autoantibodies present include Abs to thyroglobulin and to thyroid microsomal antigen now known as thyroid peroxidase Some peroxidase Abs inhibit enzyme activity while others may mediate the cytotoxicity due to natural killer cells Abs to thyroglobulin help to produce hypothyroid conditions Other Abs include colloid Ab (CA2) thyrotropin-binding inhibitory immunoglobulin (TBII)
Hashimotos Thyroiditis
Others are thyroid stimulating immunoglobulin (TSI) and thyroid growth-stimulating immunoglobulin (TGSI) Peroxidase Abs can be measured by particle agglutination assays, complement fixation, RIA and Indirect IFA Abs to thyroglobulin can be measured by precipitaion in agar, indirect IFA, passive agglutination, RIA, and EIA Indirect IFA use human or monkey thyroid tissue fixed to a slide Antithyroglobulin Abs are found in about 80% of patients with the disease
Graves Disease
Graves disease is another autoimmune disease that affects the thyroid gland Graves disease produces hyperthyroidism It the most common cause of hyperthyroidism and affects about 0.5% of the population Women are more susceptible than men by a margin of 7:1 and usually present between the ages of 30 and 40. In whites, the disease is associated with the HLA antigen DR3 while in Asians HLA Bw35 and Bw36 occur more frequently
Graves Disease
HLA DQB1 appears to confer resistance to the disease Clinical Signs: Disease is presented as thyrotoxicosis with a diffusely enlarged goiter that is soft instead of rubbery Signs include nervousness, insomnia, depression, weight loss, heat intolerance, sweating, rapid heart beat Other signs include fatigue, cardiac dysrhythmias, restlessness, and exopthalmus
Graves Disease
Immunologic Findings: The thyroid presents with Hyperplasia with a patchy infiltration of lymphocytes Both CD4 and CD8 cells are present and the T cells appear to play a central role in the pathogenesis of the disease The most significant Ab present is thyroid stimulating hormone receptor antibody (TRab) Ag-Ab combination result in the stimulation of the receptor resulting in the release of the thyroid hormones Another group of Abs called thyroid stimulating antibodies or immunoglobulins (TSab or TSI) may have different specificity
Graves Disease
Laboratory Diagnosis: A key finding in Graves disease is elevated levels of total and free T3 and T4 In addition, TSH levels are low due to Ab stimulation of the thyroid Measurement of the thyroid Abs may be undertaken if the above assays are unclear Treatment: Antithyroid medication may be employed. Radioiodine which emits beta particles may be used. Surgery is also an option.
Insulin-Dependent Diabetes
This disease is characterized by insufficient production of insulin due to an autoimmune destruction of the beta cells of the pancreas Peak onset is b/w 10 and 14 years of age Disease may be attributed to genetic and environmental conditions About 95% of white diabetics carry the HLA-DR3 or DR4 genes It appears that true susceptibility genes for IDDM may occur in the HLA-DQ region
Insulin-Dependent Diabetes
Viral infections have been linked with diabetes Mumps virus, rubella virus, CMV, and Coxsakie B4 virus have all been inconclusively linked to diabetes Congenital rubella infection is the only one for which a link has been definitively identified There appears to be similarity between coxsakie viral protein P2-C and the enzyme glutamic acid decarboxylase. Antibodies are formed against glutamic acid decarboxylase in IDDM Molecular mimicry could initiate Ab production against self Ag
Insulin-Dependent Diabetes
Immunopathology: Inflammation of the islets of Langerhans in the pancreas leads to fibrosis and destruction of most of the beta cells CD4 and CD8 B cells and macrophages are all involved in the destructive process of the islet cells Cellular and humoral immunity are involved in this process The subset of T cells that is activated determines whether the response is cellular or humoral
Insulin-Dependent Diabetes
Laboratory Testing: IDDM is usually diagnosed by the presence of hyperglycemia Abs to islet cells may be screened for by indirect IFA with human or rat islet cells Islet cell may be detected in the sera of newly diagnosed diabetic cases Abs to insulin may be detected by ELISA or RIA methods
Insulin-Dependent Diabetes
Treatment: Insulin has been the standard form of treatment New treatment methods center around the use of immunosuppressive agents Agents that have been tried include azathioprine, cyclosporine A and prednisone All these agents have potentially toxic effects
Multiple Sclerosis
Destruction of the myelin sheath results in the formation of lesions known as plaques in the white matter of the brain and spinal cord Genetic and environmental factors predispose one to this disease MS is associated with the inheritance of HLA antigen DRw15 and DRw6 An inflammatory response to bacteria or virus may trigger the autoimmune process Disease is most often seen in those b/w the ages of 20 & 50 and is more common in women
Multiple Sclerosis
90% of patients alternate between remissions and relapses for many years Within the plaques, CD4 cells, plasma cells and macrophages are found along with immunoglobulin Immunoglobulin is increased in the spinal fluid in 60 to 80% of patients They usually produce oligoclonal bands on protein electrophoresis RIA is used to detect the Abs Therapy include use of corticosteroids
Myasthenia Gravis
Symptoms of disease include facial weakness, difficulty in chewing, and swallowing, difficulty breathing Others include inability to maintain support of the trunk, the neck or the head Antibody mediated damage to the acetylcholine receptors in the skeletal muscle leads to muscle weakness May be associated with the presence of other autoimmune diseases such as SLE Appears to be linked with either HLA-B8 or DRw3 antigens
Myasthenia Gravis
80 to 90% of patients have Abs to acetylcholine receptors which may be the main contributor to pathogenesis Combination of the Abs to the receptors blocks the binding of acetylcholine which destroy the receptors Abs can be detected with RIA methods Anticholinesterase agents are employed in therapy
Goodpastures Syndrome
Goodpastures syndrome is a glomerulonephritis due to Abs reacting specifically with Ags in the kidney Necrosis of the glomerulus is triggered by an Ab that reacts with glycoprotein present in the basement membrane of the glomerulus Results in immune complex deposit and complement fixation which causes the damage to the kidney This may eventually produce renal failure