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    Hematopoietic Stem Cell Transplantation in Patients with Heterozygous STAT1 Gain-of-Function Mutation
    (SPRINGER/PLENUM PUBLISHERS, 2019-01-01) Kiykim, Ayca; Charbonnier, Louis Marie; Akcay, Arzu; Karakoc-Aydiner, Elif; Ozen, Ahmet; Ozturk, Gulyuz; Chatila, Talal A.; Baris, Safa
    PurposeHuman signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT.MethodsData on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-)- and interleukin 17 (IL-17)-expressing CD4(+) T cells and analysis of IFN--induced STAT1 phosphorylation in patient 1 (P1)'s T cells.ResultsP1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN- production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4(+) T cells of P1 were normalized following transplantation.ConclusionHSCT could be an alternative and curative therapeutic option for selected STAT1 GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.
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    Gut immune homeostasis: the immunomodulatory role of Bacillus clausii, from basic to clinical evidence
    (TAYLOR \& FRANCIS LTD, 2022-01-01) Wong-Chew, Rosa Maria; de Castro, Jo-Anne A.; Morelli, Lorenzo; Perez, Marcos; Ozen, Metehan
    Introduction The gut microbiota affects the development of the gut immune system in early life. Perturbations to microbiota structure and composition during this period can have long-term consequences on the health of the individual, through its effects on the immune system. Research in the last few decades has shown that probiotic administration can reverse these effects in strain- and environment-specific ways. Bacillus clausii (B. clausii) has been in use for many decades as a safe and efficacious probiotic, but its mode of action has not yet been completely elucidated. Areas covered In this review, we discuss how the gut immune system works, the factors that affect its functioning, and the plethora of research highlighting its role in various diseases. We also discuss the known modes of action of Bacillus probiotics, and highlight the preclinical and clinical evidence that reveal how B. clausii acts to bolster gut defense. Expert opinion We anticipate that the treatment and/or prevention of dysbiosis will be central to managing human health and disease in the future. Discovering the pathophysiology of autoimmune diseases, infections, allergies, and some cancers will aid our understanding of the key role played by microbial communities in these diseases.