pylori) are induced by decreased naive regulatory T cells, in conjunction with T-helper 1 cells releasing proinflammatory cytokines

pylori) are induced by decreased naive regulatory T cells, in conjunction with T-helper 1 cells releasing proinflammatory cytokines. clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues ( 50 per high-power field, with IgG4/IgG ratio 40%). IgG4-RSD may potentially be rarely associated with (S)-(+)-Flurbiprofen the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies. and gastrointestinal clear cell sarcoma ITGAM in association with IgG4-RSD have been reported in the lung, parotid gland, ureter and small intestine, respectively.140,150,187,188 Further studies are mandated in this field to determine if there is any causal relationship between the malignancies and IgG4-RSD. PROPOSED ETIOPATHOGENESIS OF IgG4-RELATED SCLEROSING DISEASE The pathogenesis of IgG4-related sclerosing disease is still not clearly understood. The disease may represent a hypersensitive/allergic reaction as compared to being an autoimmune disease.189 An association of IgG4-related AIP with gastric ulcer and Helicobacter pylori (H. pylori) infection has been proposed.190-192 It has been theorized by Okazaki, et al.193 that the development of the acronym ‘AIP’ involves a biphasic mechanism in which the initial response to self-antigens such as carbonic anhydrase, lactoferrin, pancreatic secretory trypsin inhibitor and ?-fodrin and molecular mimicry (H. pylori) are induced by decreased naive regulatory T cells, in conjunction with T-helper 1 cells releasing proinflammatory cytokines. Progression is mediated through increased memory regulatory T cell and T-helper 2 cell immune responses resulting in chronic inflammation. The inflammatory infiltrate usually comprises of a mixed population of T and B cells, with increased CD4+, CD25+, FOXP3+ regulatory T cells.31,194,195 T-helper cell 2 cytokines (interleukin-4, interleukin-5, and interleukin-13) and regulatory cytokines (interleukin-10 and transforming growth factor) are upregulated in the involved tissues.194-196 Other proposed hypothesis regarding the pathogenesis include enhanced T-helper type 2 responses to intestinal microflora197 and an immune-mediated pathogenesis based on the ultrastructural finding of electron dense immune complex deposits along the basement membranes of pancreatic acini and renal tubules.32 According to the results of a recent study conducted by screening of pooled IgG from patients with AIP, a specific reactivity with a peptide demonstrating homology with plasminogen-binding protein of and with ubiquitin-protein ligase E3 component n-recognin 2 (an enzyme with high levels of expression in pancreatic acinar cells) was noted in the serum samples from 90% of patients with AIP and 10% of patients with pancreatic cancer. Healthy controls did not show any expression.198 It remains to be seen whether truly plays a role in the development of AIP and IgG4-RSD. DIAGNOSTIC CRITERIA FOR IgG4-RELATED SCLEROSING DISEASE Diagnosis of IgG4-RSD requires not only an increase in the absolute number of IgG4+ cells but also an increased IgG4+/IgG+ ratio for the correct diagnosis. An absolute IgG4+ plasma cell count is not sufficient as a sole index as IgG4+ cells normally comprise approximately 5% of all IgG+ cells, and may be present in significant numbers in any inflammatory lesions with increased plasma cells even though the percentage might remain in the acceptable range. A high IgG4+/IgG+ percentage alone is also not sufficient for a diagnosis because in cases with a few plasma cells, an erroneously high ratio may be calculated owing to the relative proportions of both IgG and IgG4+ plasma cells. We are in agreement (S)-(+)-Flurbiprofen with other investigators with regard to the cut-offs for the absolute number of IgG4+ cells 50/high-power fields (HPF) and ratio of IgG4+/IgG+ cells 40%.31 We also propose selecting areas with the maximum density of IgG4+ plasma cells. At least three HPFs should be counted, (S)-(+)-Flurbiprofen and the average number of IgG4+ plasma cells per HPF should be calculated to give the results. In borderline cases, a descriptive diagnosis with a comment indicating “increased IgG4+ plasma cells” should be rendered along with (S)-(+)-Flurbiprofen a disclaimer for the.