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Gošeova bolest je oboljenje lizozoma kod kojeg je korelacija između genotipa i fenotipske ekspresije bolesti slaba te se samim tim ni težina bolesti ne može pouzdano predvideti. Citopatološke promene u ovoj bolesti nisu izazvane samo nakupljanjem nerazgrađenog glikolipida, već i aktivacijom makrofaga, a koncentracije različitih citokina, važnih za proces inflamacije, su povišene u serumu ovih bolesnika. Takođe, nekoliko studija u literaturi navode dokaze o povećanoj incidenciji hematoloških komplikacija u bolesnika sa Gošeovom bolešću, uključujući monoklonsku i poliklonsku gamapatiju i hematološke malignitete, a posebno multipli mijelom. U kohorti naših bolesnika u Srbiji je ranije već opisana visoka incidencija rearanžmana gena za teški lanac imunoglobulina, što sugeriše da se aktivacija imunskog sistema može javiti relativno rano tokom bolesti. Predmet rada istraživanja ove studije je bila analiza uticaja klonskog rearanžmana gena za teški lanac imunoglobulina i/ili prisustva pojedinih alela gena koji kodiraju molekule važne u inflamaciji (TNFα, IL-10 i IL-6) na težinu kliničke slike obolelih od Gošeove bolesti. Materijal i metod: U ovu kohortnu studiju su bili uključeni pacijenti oboleli od Gošeove bolesti u Srbiji koji su u periodu od 2008 – 2016. godine lečeni na Klinici za hematologiju i Klinici za endokrinologiju, dijabetes i bolesti metabolizma Kliničkog centra Srbije, u Beogradu, kao i Klinici za hematologiju Kliničkog centra u Nišu. Kriterijumi za isključenje iz studije su bili: odbijanje pacijenta da učestvuje u studiji, smrt pacijenta ili emigracija u druge države. Kontrolna grupa za poređenje učestalosti ispitivanih polimorfnih genotipova za citokinske gene je bila selektovana iz baze DNK uzoraka Laboratorije za imunologiju Instituta za Mikrobiologiju i imunologiju. Svaki od ispitanika je detaljno obavešten o cilju studije i potpisao je dobrovoljan pristanak za učestvovanje u njoj. Iz uzoraka pune venske krvi je vršena izolacija DNK, a detekcija i anali, Gaucher disease is a lysosomal storage disease showing weak genotype-phenotype correlation, with poorly predictable disease severity. Cytopathological alterations are caused not only by the accumulation of the undegraded glycolipid substrate, but also by macrophage activation, displaying serum elevation of various cytokines with important influence to inflammation. Several studies in the literature showed increased incidence of hematological complications in Gaucher patients, including monoclonal and polyclonal gammopathies as well as hematological malignancies, especially multiple myeloma. We had already described a high incidence of immunoglobulin heavy chain gene rearrangements in a cohort of Serbian patients, suggesting that an early occurrence of immune system activation is possible early in the disease course. The object of this study was the analysis of clonal rearrangements of IGH genes and frequencies of alleles of cytokine genes important for inflammation (TNFα, IL-10 and IL-6) as well as their influence on disease severity in Gaucher patients. Material and methods: the cohort study included patients with Gaucher disease treated in Serbia since 2008 – 2016, at the Clinic of hematology and Clinic for endocrinology, diabetes and metabolic diseases of Clinical center of Serbia in Belgrade, as well as Clinic of hematology, Clinical Center of Niš. Exclusion criteria were: patient refusal to participate in the study, death of a patient and / or emmigration of a patient. Control group for frequency analysis of polymorphic genotypes of cytokine genes was selected out of the database of DNA samples acquired from Laboratory of immunology, Institute of microbiology and immunology. Every subject was thoroughly informed of the aim of the study and signed the informed consent in order to participate in it voluntarily. Venous blood samples were taken with subsequent DNA isolation permitting detection and analysis of cytokine gene polymorphisms (TNF, IL10 and IL6) using t

Uvod: Nekoliko studija u literaturi navode dokaze o povećanoj incidenci hematoloških komplikacija u bolesnika sa Gošeovom bolešću, uključujući monoklonsku i poliklonsku gamapatiju i hematološke malignitete, a posebno multipli mijelom. Metode: Određivana je serumska koncentracija imunoglobulina kao i rearanžman gena za teški lanac imunoglobulina - IGH, PCR analizom. Klonalni PCR produkti su direktno sekvencirani i analizirani koristeći adekvatne alate i baze podataka. Monoklonski proteini seruma su detektovani i identifikovani metodom elektroforeze. Rezultati: Među 27 bolesnika, klonalni IGH rearanžman je otkriven kod osmoro, od kojih je petoro imalo i monot klonski protein u serumu. Hipergamaglobulinemija je otkrivena u 9/27 bolesnika. Podaci o praćenju za 17 bolesnika su pokazali da je klonalni rearanžman ostao isti u četiri bolesnika, dok je u jednog bolesnika iščezao tokom perioda praćenja. Preostalih 12/17 bolesnika nisu imali klonalni IGH rearanžman niti su ga stekli nakon perioda praćenja. Zaključak: Iako klonska ekspanzija može da nastane relativno rano u toku Gošeove bolesti, barem sudeći prema rearanžmanu IGH gena, detektovani klonovi mogu biti tranzitorni. Pažljivo kliničko praćenje ovih bolesnika je obavezno, uključujući i nadzor nad limfoidnim neoplazmama, posebno multiplim mijelomom., Background: Several studies support the evidence of increased incidence of hematological complications in Gaucher disease including monoclonal and polyclonal gammopathies and blood malignancies, especially multiple myeloma. Methods: Serum concentrations of immunoglobulins and PCR analysis of the IGH gene rearrangements were performed. The clonal PCR products were directly sequenced and analyzed with the appropriate database and tools. Serum monoclonal proteins were detected and identified by electrophoresis. Results: Among 27 Gaucher patients, clonal IGH rearrangement was discovered in eight, with 5/8 having also serum monoclonal protein. Elevated immunoglobulins were detected in 9/27 patients. Follow-up data for 17 patients showed that the clonal rearrangement remained the same in four of them, however, in one patient it disappeared after the follow-up period. The remaining 12/17 patients were without previous IGH clonal rearrangement and remained so after the follow-up. Conclusions: Although clonal expansion may occur relatively early in the disease course, at least judging by the IGH gene rearrangements in Gaucher patients, the detected clones may be transient. A careful clinical follow-up in these patients is mandatory, including monitoring for lymphoid neoplasms, especially multiple myeloma.

Introduction: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. Materials and methods: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. Results: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. Conclusion: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease.