BL.2.9: Type 3 Immunopathologies, Myeloid neoplasms Flashcards
Arthus reaction and serum sickness are local and general manifestations of immune complex disease; describe the mechanism of tissue damage. Discuss why this is sometimes called ‘innocent bystander injury.’
The intermediate complexes get stuck in the basement membrane. There, they activate complement by binding C1q and initiating the classical complement cascade. C3a and C5a attract neutrophils, which arrive and release a variety of inflammatory factors, including the proteases cathepsin G and elastase; and hydrogen peroxide, which by activating metalloproteinases also contributes to the proteolytic degradation of the basement membrane. C3a and C5a will, as anaphylatoxins, release histamine and other mediators from mast cells, increasing the inflammatory reaction (â–ºand they may cause hives).Therefore, the basement membrane and surrounding tissues are innocent bystanders that get damaged.
Indicate the critical size at which immune complexes get stuck in basement membranes.
Complexes of just the right size: ‘about a million daltons’. They can activate complement but are below the size that is rapidly removed by the RES.
Describe ‘one-shot’ serum sickness. Make a chart showing antigen, antibody and immune complex levels in relation to time and to symptoms.
About 10-14 days after the administration of a large dose of animal serum, fever, malaise, rash and itch, and arthralgia develop. Hives may be observed. Examination will reveal tender lymphadenopathy, and urinalysis may show increased red blood cell casts and protein. Inflammatory markers in the blood will be increased (C-reactive protein, erythrocyte sedimentation rate) and total hemolytic complement decreased.
Discuss the types of tissues in which damage is most likely to occur from deposition of immune complexes.
Simple biophysics says that complexes will be trapped most in capillary beds where there is most filtration of blood; that is, where there is net outflow of fluid. For example, any location that must be kept wet qualifies:
Discuss the immunological mechanism of a typical Type III disease involving exogenous antigen.
- Exposure to a lot of antigen starts withno, or only very small, complexes.2. Complex formation in relative antigen excess, so they are smaller than optimal-proportions complexes; in fact, they may be just the size to get lodged in basement membranes. â–ºThat is the time that symptoms begin.They persist a week or more.3. As antibody production increases, exponentially, a time will come where equivalence between the antibody in circulation and the remaining antigen is achieved, and large complexes form.Then the large complexes are readily cleared by the RES.
Discuss how urticaria could result from interaction of antigen with either IgE or IgG antibody.
Antigen + IgG: Immune complexes form, get stuck in basement membrane of vessels, C3a and C5a as anaphylatoxins, release histamine from mast cells, causing hivesOr, can just be a Type 1, IgE allergic response.
Name 4 different kinds of human immune complex disease or problem and indicate a type of antigen involved in each condition.
Actinomycetes –> Farmer’s lungStrep Pyogenes –> GlomerulonephritisAnimal antibodies –> Serum sicknessHepatitis –> Similar to serum sickness
Discuss the meaning of finding a fluffy white precipitate in a patient’s serum after a day in the refrigerator.Include the name used for such precipitates, the most likely composition, and the interpretation of the phenomenon.
Fluffy white precipitate = cryoglobulinIt means that an immune complex has formedThese are ‘mixed’ cryoglobulins, being antigen + antibody
Define rheumatoid factor and discuss its components.
One of the oldest known autoantibodies is ‘rheumatoid factor,’ RF, often present in the blood of patients with rheumatoid arthritis, and some other conditions. It is an IgM antibody to the patient’s own IgG.
Discuss the pathogenesis of post-streptococcal glomerulonephritis. Describe the diagnosis of this condition by fluorescent antibody technique, and name the pattern of resulting fluorescence.
Symptoms begin 10-14 days after infection (strep throat, scarlet fever, impetigo of skin) and are typical of Type III, with the kidney being the most affected site. Signs and symptoms include nausea and vomiting, fever, malaise, hypertension, reduced urine output, hematuria, joint pain and rash. Serum complement levels are decreased. Diagnosis is by history and renal biopsy. Treatment is symptomatic and supportive, and includes antibiotics. â–ºThe disease is usually self-limiting and recovery can be uneventful with proper care. It is seen nowadays mostly in developing countries, where treatment with antibiotics may be delayed or unavailable, and it can still be fatal.Lumpy bumpy antibodies in basement membrane.
Discuss the pathogenesis of hypersensitivity pneumonitis, for example Farmer’s Lung.
It is caused by exposure to thermophilic Actinomycetes, filamentous bacteria which are found in moldy hay and silage. After chronic exposure by inhalation, the farmer develops serum IgG antibodies. Then one day, perhaps when the hay has been unusually damp and is now drying and aerosolizing spores, she inhales enough antigen that antigen-antibody complexes form in the lungs as the mold proteins diffuse through the alveoli into the capillaries. â–ºComplement and neutrophils cause the symptoms; this is often called an ‘allergic’ disease but it is Type III, not Type I. An acute attack will start 4 to 8 hours after the exposure, with shortness of breath, a dry cough, malaise, fever, and tachycardia. Most episodes are rather more chronic, with similar but milder symptoms, to which arthritis is sometimes added.
Compare and contrast MPN and MDS in terms of the bone marrow, the peripheral blood, potential outcomes, and the utility of cytogenetic findings in each.
Similarities:Both are clonal, neoplastic disorders that can progress to marrow failure or acute leukemia. They can both be traced back to problems with pluri/multipotential stem cells. Both show hypercellular marrow (almost all of the cells in the marrow are hematopoietic). They both progress from chronic (low blast-cell content) to actute (high blast-cell content).Differences:CMPD: increased proliferation of myeloid cells (one or more types). See elevated counts of these types in the peripheral smear and on the CBC.MDS: Perturbed” maturation of one or more types of myeloid precursors
Describe the phases of PV.
Early PV: Mold red blood cell increase, JAK2 mutationPolycythemic phase: arterial and venous thrombosis, hemorrhage, splenomegaly, true increase in hematocritMarrow: hypercellular, decreased iron stores, normochromic/cytic RBC, neut/basophilia, thrombocytosisPost-polycythemic phase: increasing splenomegaly, possible weight loss, night sweats, feverMarrow: fibrosis, osteosclerosis, precursors in sinuses, less precursors in marrow, leukoerythroblastosis
Discuss in general terms the pathogenesis of the myeloproliferative neoplasms (MPN) and how knowledge of the pathogenesis has aided in diagnosis and treatment of MPN.
Activation of intracellular signaling pathways• Tyrosine kinases, activators of signaling pathways, have been implicated• The archetypal tyrosine kinase in this regard; the BCR-ABL1 protein• Abnormal kinases necessary but not sufficient for MPN development• Progression of MPN to AML or marrow fibrosis due to accumulations of genetic perturbations
What is the prognosis of CML
Prognosis of CMLKnowledge of the BCR-ABL1 gene and its tyrosine kinase protein product facilitated the development and use of the targeted therapeutic agent imatinib to treat CML.a. The complete cytogenetic response rate to imatinib (i.e. the Philadelphia chromosome goes away) is 70-90%.b. The 5-yar progression free survival and overall survival rate for imatinib is 80-95%.
