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Pyruvate kinase deficiency (PKD) is the rare glycolytic enzyme defect causing hemolytic anemia. Treatments are mainly red cell transfusion and/or splenectomy, leading to iron overload. Allogeneic bone marrow transplantation (BMT) is alternatively curative treatment for severe PKD. The intensity of conditioning is often controversial because of higher risk of graft failure and organ damage. Here, we present a transfusion-dependent PKD patient undergoing BMT from an HLA-identical sibling using intensively immunosuppressive conditioning regimen. This report suggests that BMT using immunosuppressive conditioning regimen may be a feasible and effective treatment for patients with severe PKD with iron overload. We suggest the timing of the transplantation at an earlier age in severe PKD predicted from gene mutation is preferred before cumulative damage of transfusion. [ABSTRACT FROM AUTHOR]

Gain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease. However, the molecular basis for the gain of STAT1 function remains largely unclear. Here, we investigated the structural features of STAT1 GOF residues to better understand the impact of these pathogenic mutations. We constructed STAT1 alanine mutants of the α3 helix residues of the coiled-coil domain, which are frequently found in CMC pathogenic mutations, and measured their transcriptional activities. Most of the identified GOF residues were located inside the coiled-coil domain stem structure or at the protein surface of the anti-parallel dimer interface. Unlike those, Arg-274 was adjacent to the DNA-binding domain. In addition, Arg-274 was found to functionally interact with Gln-441 in the DNA-binding domain. Because Gln-441 is located at the anti-parallel dimer contact site, Gln-441 reorientation by Arg-274 mutation probably impedes formation of the dimer. Further, the statistical analysis of RNA-seq data with STAT1-deficient epithelial cells and primaryTcells from aCMCpatient revealed that theR274Q mutation affected gene expression levels of 66 and 76 non-overlapping RefSeq genes, respectively. Because their transcription levels were only slightly modulated by wild-type STAT1, we concluded that the R274Q mutation increased transcriptional activity but did not change dramatically the repertoire ofSTAT1 targets. Hence, we provide a novel mechanism of STAT1 GOF triggered by a CMC pathogenic mutation. [ABSTRACT FROM AUTHOR]

Filamentous fungi were detected in the blood culture of a one-year-old boy after autologous peripheral blood stem cell transplantation. The patient was suspected to have aspergillosis and received micafungin. Fungi were isolated on potato dextrose agar medium and incubated at 37°C for 2-5days. Grayish, cottony colonies formed. A slide culture showed a spherical sporangium at the tips of the sporangiophores .The fungus could have been a zygomycete. The zygomycete was isolated from three blood cultures. The antifungal drug was changed from micafungin to liposomal amphotericin B, which resulted in an improvement in the patient&s symptoms. Growth was observed at 37°C, but not 42°C in a growth temperature test. Gene sequence analysis identified the fungus as Mucor velutinosus. To the best of our knowledge, this is the first time M. velutinosus has been detected in Japan, and this case is very rare. Zygomycetes are known to be pathogens that cause fungal infections in immunodeficient patients such as those with leukemia. They are difficult to identify by culture and are identified at autopsy in many cases. Therefore, culture examinations should be performed for immunodeficient patients with the consideration of zygomycetes. [ABSTRACT FROM AUTHOR]

B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common y chain (yc)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Ra) in normal, but not STAT3-deficient, CD40L-stimulated naive B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21 R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naive B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21Rdue to impaired responsiveness to IL-21. [ABSTRACT FROM AUTHOR]