Amyloidosis is defined as the extracellular accumulation at systemic or organ-specific level of insoluble low molecular weight protein fibrils manifesting a beta pleated sheet configuration and a characteristic staining pattern. Several different types of proteins may lead to this phenomenon, and amyloidosis is defined by the biochemical nature of the protein in the deposits and further classified according to whether the deposits are localized or systemic, acquired or inherited, and by the resulting clinical phenotype. Amyloidosis includes subtypes such as light chain, associated with serum amyloid A protein, heritable and familial forms, dialysis-related disease, and organ-specific conditions. The pathogenesis and clinical features of these clinical and pathological entities will be critically discussed in this review article.
Purified from a Mediterranean plant nearly two centuries ago, colchicine has been discovered to inhibit many steps in the inflammatory process. The drug has good oral bioavailability and some enterohepatic recirculation, requiring dose adjustments for kidney disease and avoidance in liver disease. Toxicities are primarily gastrointestinal, hepatic, and hematologic. Colchicine is approved by the U.S. Federal Drug Administration for the treatment and prophylaxis of gout flares but has also been tried with varying success in the treatment of familial Mediterranean fever, primary biliary cirrhosis, psoriasis, Behçet's disease, aphthous stomatitis, linear IgA dermatosis, relapsing polychondritis, Sweet's syndrome, scleroderma, amyloidosis, leukocytoclastic vasculitis, epidermolysis bullosa, and dermatomyositis.
Familial Mediterranean fever (FMF) is the most common of a rare group of disorders collectively termed familial hereditary periodic fever syndromes, also known as autoinflammatory syndromes. FMF is clinically characterized by intermittent bouts of fever with peritonitis and abdominal pain, pleuritis, arthritis, or erysipelas-like rashes. Amyloidosis due to chronic inflammation progressing to renal failure is one of the most serious potential complications of this disease. Individuals with FMF have identifiable genetic defects in the Mediterranean fever (MEFV) gene, which codes for the protein pyrin. Pyrin normally blunts neutrophil-mediated inflammation, likely via interleukin-1 (IL-1) downregulation, but is defective in FMF. Potential treatments include colchicine, with case reports of benefits with catecholamine blockade (prazosin), tumor necrosis factor (TNF) antagonism (etanercept, thalidomide), and IL-1 receptor blockade (anakinra).
Objective: The biologic explanation for fetal receptivity to donor engraftment and subsequent long-term tolerance following transplantation early in gestation is not known. We investigated the role fetal immune ontogeny might play in fetal transplantation tolerance in sheep. Methods: Engraftmentof allogeneic and xenogeneicHSC was determined 60 days following transplantation at different time points in sheep fetal gestation. Parallel analysis of surface differentiation antigen expression on cells from lymphoid organs of timed gestational age fetal sheep was determined by flow cytometry using available reagents. Results: An engraftment window was identified after day 52 gestation lasting until day 71 (term gestation: 145 days). This period was associated with the expression of the leukocyte common antigen CD45 on all cells in the thymus. Double-positive and single-positive CD4 and CD8 cells began appearing in the thymus just prior (day 45 gestation) to the beginning of the engraftment window, while single-positive CD4 or CD8 cells do not begin appearing in peripheral organs until late in the engraftment period, suggesting deletional mechanisms may be operative. In concert, surface IgM-positive cells express CD45 in the thymus at day 45, with a comparable delay in the appearance of IgM/CD45 cells in the periphery until late in the engraftment window. Conclusions: These findings support a central role for the thymus in multilineage immune cell maturation during the period of fetal transplantation receptivity. Further, they suggest that fetal engraftment receptivity is due to gestational age-dependent deletional tolerance.
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