http://repub.eur.nl/res/aut/1728/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/38970/ 2013-02-15T00:00:00Z Rationale: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement ofBcells in the pathogenesis of sarcoidosis. Objectives: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease. Methods: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, andserumimmunoglobulin levels.Vaccinationresponses in patients with sarcoidosis to influenza virus and encapsulated bacteria andmolecular analysis ofimmunoglobulin heavy chain transcriptswere studied for functional analysis of immunoglobulin responses. Measurements and Main Results: Perigranuloma localization of IgAproducing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD271 memory B cells were significantly reduced, and CD272IgA1 B cells were significantly increased; the results are normalized in patients treated with TNF-ablockers.Despitethis,patientshadnormal serumimmunoglobulin levels and normal antigen-specific immunoglobulin responses. IgAand IgGtranscripts, however, showed highfrequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses. Conclusions: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD272IgA1 B cells could be a marker for treatment with TNF-a blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis. Copyright http://repub.eur.nl/res/pub/9864/ 2002-01-01T00:00:00Z Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24. http://repub.eur.nl/res/pub/20017/ 1999-09-22T00:00:00Z Type·1 diabetes mellitus is an autoimmune disease. The clinical manifestation is the end-point of a subclinical process that destroys the insulin producing B·cells in the islets of Langerhans (prediabetes). Prediabetes may last months to years and theoretically gives the unique opportunity for prevention of the disease. This requires the availability of an effective therapy and the possibility to reliably identify individuals who are eligible for such a therapy. In order to develop intervention strategies, studies on the pathogenesis of Type-1 diabetes are required. At the clinical manifestation of the disease B-cell autoimmunity has been present for years. As a consequence disease-initiating events will have disappeared and the immune response and pathophysiology of the B-cells may have changed due to the ongoing destruction process. Thus, studies of the prediabetic phase are a prerequisite. The identification of those who are at high risk to develop the disease is therefore an important key to further studies on the pathogenesis of Type-1 diabetes. In addition, clinical trials of potential prevention strategies require the development of reliable techniques to identify such individuals. Using a combination of genetic markers and autoantibodies against B-cell antigens, prediction is possible in first·degree relatives of patients with Type-1 diabetes. For relatives baring high genetic risk markers and being positive for more than one B-cell autoantibody the risk to proceed to diabetes exceeds 60%. However, the majority of new cases of Type-1 diabetes occur in the general population and it is not clear whether prediction in the general population is as efficient as in first degree relatives. This thesis aims to: • Decipher the natural course of B-cell autoantibodies and their relation to disease progression in established diabetes and prediabetes • Improve knowledge on the applicability of antibodies for the prediction of Type-1 diabetes in the general population • Improve the performance of screening by technical evaluation of assays to detect GAD· and IA2·antibodies in serum http://repub.eur.nl/res/pub/9205/ 1999-01-01T00:00:00Z