Immunopathology Type 2, Autoimmunity Flashcards
Describe the molecular and cellular details of the immunologic mechanisms by which tissue damage occurs in a Type II (“cytotoxic antibody”) reaction
- Type II: due to actions of antibodies directed against a specific target tissue or cell, it is one of the forms of autoimmunity.
- “Stimulatory hypersensitivity”: if autoantibody is directed against a cell-surface receptor, it may behave as an agonist, mimicking whatever hormone or factor normally works at that receptor. Example: long-acting thyroid stimulator that mimics TSH and causes hyperthyroidism.
- Complement-mediated damage: antibody to Ach receptor at neuromuscular endplate (in myasthenia gravia). This antibody may block transmission from nerve to muscle or increase receptor turnover, but ends up destroying the endplate by complement/phagocyte-mediated mechanisms.
- Tissues can be damaged by lysis (AIHA), phagocytosis (ATP), or by release of phagocytes’ lysosomal enzymes and ROS’s (Goodpasture’s)
Give an example of a Type II mechanism disease of muscle
Myasthenia gravis (muscle): progressive muscle weakness because patients make antibody to myson and to ACh receptor (AChr). Antibody to myosin has no role in pathogenesis (only diagnostically). The antibody to the alpha-unit of the AChr does the damage–complement and neutrophil-mediated. The antibody to myosin may be the result of the release of sequestered myosin antigen (secondary to cell damage).
Give an example of a Type II mechanism disease of kidney
Goodpasture’s Disease (kidney): formation of autoantibodies to lung and kidney basement membrane (non-living connective tissues framework upon which the endothelial cells of capillaries sit). Type IV collagen is the antigen that is shared between the lung and kidney basement membranes (no other organs involved). Patient has persistent glomerulonephritis and pneumonitis with pulmonary hemorrhages. The antibody is directed against the basement membrane, not trapped as clumps, so the staining by IF is sharp and linear (not lumpy-bumpy as in Type III, immune complex conditions)
Give an example of a Type II mechanism disease of heart
- Rheumatic heart disease (heart): heart disease after infection with streptococcal pyrogenes due to a cross reaction between a Group A streptococcus M protein antigen and a structure on the heart’s endothelial lining, probably laminin on heart values, followed by neutrophil-mediated tissue destruction. Rheumatic fever is the same disease with widespread manifestations, including skin and CNS.
- Dressler’s syndrome (heart): persistent cardiac pain, fever, malaise and pericardial ffusion seen after a heart attack or heart surgery. Patients make autoantibody which reacts with the heart pericardial or myocardial antigens –> immune response. Gets better as heart heals, TX with anti-inflammatory.
Give an example of a Type II mechanism disease of red cells
Autoimmune hemolytic anemia (AIHA) (RBCs): may follow a viral infection or be associated with autoimmune syndrome or cancer. Many drugs (PEN, methyldopa, chlorpromaxine, quinidine) can induce AIHA, usually temporarily. In paroxysmal cold hemoglobinuria (PCH) patient experiences hemolysis after exposure to cold.
Give an example of a Type II mechanism disease of platelets
Autoimmune thrombocytopenia purpura (ATP) (platelets): bleeding abnormality due to destruction of platelets by autoantibody. Platelets are opsonized and their destruction (in the spleen) is rapid. Platelets are needed for blood clotting. TX: suppress immune system and/or remove the spleen. ATP is seen in young healthy people weeks after a viral infection or in older people in association with many other autoantibodies
Give an example of a Type II mechanism disease of lung
Goodpasture’s Disease (kidney): formation of autoantibodies to lung and kidney basement membrane (non-living connective tissues framework upon which the endothelial cells of capillaries sit). Type IV collagen is the antigen that is shared between the lung and kidney basement membranes (no other organs involved). Patient has persistent glomerulonephritis and pneumonitis with pulmonary hemorrhages. The antibody is directed against the basement membrane, not trapped as clumps, so the staining by IF is sharp and linear (not lumpy-bumpy as in Type III, immune complex conditions)
Give an example of a Type II mechanism disease of thyroid
- Hashimoto’s thyroiditis (thyroid): inflammatory disease of thyroid where there is B and T cell immunity to various thyroid antigens, including thyroglobulin. The antibodies to thyroid antigens are destructive, not stimulatory. The thyroid is infiltrated with T cells. T cell damage allows antibodies access to normally sequestered antigens makes condition worse. Results in HYPOthyroidism.
- Graves’ disease: hyperthyroidism causes by long-acting thyroid stimulator (LATS), a IgG antibody to the TSH receptor on thyroid cells. LATS binds to the receptors, it mimics TSH and cause cell to secrete thyroid hormones. Normal feedback cannot occur.
Give an example of a Type II mechanism disease of pancreatic islets.
Describe the fluorescent antibody tests which would allow you to make the diagnosis of Goodpasture’s Syndrome, given: patient’s kidney biopsy, normal kidney biopsy, patient’s serum, and fluoresceinated goat antisera to human IgG and complement.
a. Direct Test: take patient kidney (will already have antibody on its glomerular basement membrane)and add the fluorescently labeled goat antisera to human IgG. If patient has Goodpasture’s, you will observe binding alone the glomerulus because there was already antibody on the kidney that enable the goat anti-human antibody to bind.
b. Indirect Test: take a normal kidney biopsy and place on slide, add patient serum, add fluorescently labeled goal antisera to human IgG. If patient has Goodpasture’s the antibody in their serum with bind with basement membrane on normal biopsy and the fluorescent probe will light up the regions. In Goodpasture’s the antibody is directed against the basement membrane, not trapped in clumps, so the staining is sharp and linear, not “lumpy-bumpy” (as in Type III immune complex conditions)
Distinguish between the “lumpy-bumpy” and “linear” immunofluorescent patterns in terms of the most probable immunopathologies they represent
- -Linear immunofluorescent patterns indicate that the antibody is binding to a specific structure, like the basement membrane. The fluorescent antibody will show a clear structure that its coating. This is type II immunopathology, antibody against self.
- -Lumpy-bumpy patters indicate immune complex pathologies, whereby antigen and antibody clump together and precipitate. They do not line any particular structures, they just bind together in large groups. This is type III immunopathology.
Describe how you could tell, using fluorescent antibodies and biopsies of patient’s kidney, if Type II or Type III immunopathology was involved. Name the antibodies you would use and the fluorescent patterns you would see.
Linear immunofluorescent patterns indicate that the antibody is binding to a specific structure, like the basement membrane. The fluorescent antibody will show a clear structure that its coating. This is type II immunopathology, antibody against self.
Lumpy-bumpy patters indicate immune complex pathologies, whereby antigen and antibody clump together and precipitate. They do not line any particular structures, they just bind together in large groups. This is type III immunopathology.
