BL - Immunopathology Type II Autoimmunity Flashcards
Type II Immunopathology definition
Pathology due to IgG, IgM or IgA causing harm to self (autoreactive Abs); a normal self protein becomes and antigen and the immune system mounts an immune response to it
5 examples of Type II disease mechanisms
- Myasthenia gravis
- Rheumatic heart disease
- Dressler’s Syndrome
- Goodpasture disease
- Systemic Lupus Erythematosus
Type II immunopathology in heart
1) ‘Inappropriate’ tachycardia is caused by autoantibodies to the B-adrenergic receptor which are stimulatory (mimicking epinephrine); the effect is reversed by Beta blockers
2) Rheumatic heart disease – defined as a heart disease occurring shortly after streptococcal infection (i.e. ‘strep throat’) – is caused by cross-reaction between strep antigen and laminin on heart valves, followed by neutrophil-mediated tissue destruction
3) Dressler syndrome manifests as persistent cardiac pain, fever, malaise, and pericardial effusion seen after a heart attack; caused by an immune response to pericardial or myocardial antigens and treated with anti-inflammatory agents
Type II immunopathology @ muscles
Myasthenia Gravis, a disease of progressive muscle weakness, is caused by autoantibody against the acetylcholine receptor (AChR) on the neuromuscular end plate; neutrophils release digestive enzymes at the NMJ resulting in synaptic destruction. Myasthenia = “muscle weakness”
Type II immunopathology @ red blood cells
Autoimmune hemolytic anemia (AIHA) – may follow a viral infection or be drug-induced; paroxysmal cold hemoglobinuria (PCH) is a rare form in which patients experience hemolysis after exposure to cold due to autoantibody which only binds to red cells at 15C
-Antibody (IgG or IgM) recognizes RBCs and activates complement via C1q, 1, 4, 2, 3, 5, 6, 7, 8, 9; MAC forms and C9 polymerizes in the membrane, forming a pore that lyses the RBC
Type II immunopathology @ platelets
Autoimmune thrombocytopenic purpura (ATP) – caused by autoreactive antibodies to platelets; platelets become opsonized by complement and their destruction occurs in the spleen; manifests as bleeding abnormalities
Type II immunopathology @ thyroid
1) Hashimoto’s Thyroiditis – caused, in part, by autoantibodies to thyroid antigens; these autoantibodies are destructive, not stimulatory (as in hyperthyroidism); the thyroid is infiltrated by T cells, resulting in hypothyroidism.
2) Long Acting Thyroid Stimulator (LATS) is an IgG auto-antibody to the TSH receptor on thyroid cells found in the blood of most patients with hyperthyroidism; LATS binds the receptor mimicking TSH and causing the cell to release thyroid hormones
Type II immunopathology @ kidney
Goodpasture Syndrome - characterized by production of autoantibodies to Type IV collagen in the basement membrane of lung and kidneys; presents as glomerulonephritis and pneumonitis
Flourescent antibody test in diagnosis of Goodpasture syndrome
- Use Ab from goat against human Ig and tag with fluorescence
- Observe immunoflourescence pattern within glomerulus
- Linear pattern indicates Igs are lining basement membrane of glomerulus
“lumpy-bumpy” vs. “linear” immunoflourescent patterns
- Sharp and linear immunofluorescence represents antibody directed against the basement membrane, as in Type II immunopathology
- Lumpy/bumpy immunofluorescence represents antibody trapped in clumps within the basement membrane, as in Type III immunopathology
Goodpasture vs. SLE-related glomerulonephritis identification
In Type II immunopathology the kidney biopsy will already have his autoantibodies on its glomerular basement membrane; add labeled anti-IgG; it will bind if there is already Ab in this kidney and you will see either a “sharp” pattern of fluorescence (Type II) or a “lumpy/clumpy” pattern (Type III)
Molecular nature of “Rheumatoid Factor”
RF is anti-IgG IgM antibodie. Good biomarker for rheumatoid arthritis
Role of AIRE gene in preventing autoimmunity
- AIRE is a thymic transcription factor that drives the thymic expression of various extra-thymic proteins; developing T cells that are exposed to these proteins in the thymus are deleted via negative selection so that they do not become auto reactive
- In normal thymuses, the CHRNA1 gene, which codes for the AChR, is upregulated by AIRE and expressed in the thymus
- In some families, a certain allele of CHRNA1 does not interact with AIRE and so is not expressed in the thymus; Th clones reactive with the AchR are not deleted by negative selection; Tfh are therefore available to help B cells make antibody to the receptor
- APECED – chronic candidiasis, hypoparathyroidism, or Addison’s disease
Mechanisms of tissue damage in Type II immunopathology
- complement-mediated damage: damaged by lysis, phagocytosis, or by released lysosomal enzymes/reactive oxygen species
- stimulatory hypersensitivity: autoantibody targets cell-surface receptor and acts as agonist
Illicit help model of autoimmunity
- anti-self B cell binds self protein + foreign epitope
- ingests and digests
- foreign epitope presented to Tfh on MHC II
- Tfh secretes IL-4, etc.
- B cell activated and secretes Abs to self
