Baylor Institute for Immunology Research

Jiang, Y., Y. Zhu, W. Qiu, Y. J. Liu, G. Cheng, Z. J. Liu and S. Ouyang (2016). “Structural and functional analyses of human ddx41 dead domain.” Protein Cell: 2016 Dec [Epub ahead of print].

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DEAD-box proteins, which are named after the strictly conserved amino acid sequence Asp-Glu-Ala-Asp, were first identified as a distinct family in the late 1980s when alignments based on eight homologues of the yeast eIF4A highlighted the presence of several conserved motifs (Linder et al., 1989). DEAD-box proteins are widely distributed in different life forms, ranging from bacteria to human and constitute the largest RNA helicase family (Jiang et al.,2016). They are involved in many aspects of RNA metabolism, such as splicing, mRNA export, transcriptional and translational regulation, ribosome biogenesis and RNA decay (Rocak and Linder, 2004). The core of DEAD-box proteins is organized into two major domains. Domain 1 (DEAD domain) consists of motifs Q, I (Walker A, P-loop), II (Walker B, DEAD-box), Ia, GG, Ib and III, whereas domain 2 (Helicase domain) consists of motifs IV, V and VI. Different motifs are involved in nucleotide binding (Q, I and II), RNA binding (Ia, Ib, IV and V) and ATP hydrolysis (III and possibly VI). Compared with the two conserved domains, the N- and C-terminal regions are variable and divergent. Their functions are not fully characterized, but they are thought to confer their own specificity on different proteins (Hogbom et al., 2007).

Askar, M., R. Sobecks, T. Wang, M. Haagenson, N. Majhail, A. Madbouly, D. Thomas, A. Zhang, K. Fleischhauer, K. Hsu, M. Verneris, S. J. Lee, S. R. Spellman and M. Fernandez-Vina (2016). “Mhc class i chain-related gene a (mica) donor-recipient mismatches and mica-129 polymorphism in unrelated donor hematopoietic cell transplantations has no impact on outcomes in acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome: A center for international blood and marrow transplant research study.” Biol Blood Marrow Transplant: 2016 Dec. [Epub ahead of print].

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Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

Chen, Y. B., T. Wang, M. T. Hemmer, C. Brady, D. R. Couriel, A. Alousi, J. Pidala, A. Urbano-Ispizua, S. W. Choi, T. Nishihori, T. Teshima, Y. Inamoto, B. Wirk, D. I. Marks, H. Abdel-Azim, L. Lehmann, L. Yu, M. Bitan, M. S. Cairo, M. Qayed, R. Salit, R. P. Gale, R. Martino, S. Jaglowski, A. Bajel, B. Savani, H. Frangoul, I. D. Lewis, J. Storek, M. Askar, M. A. Kharfan-Dabaja, M. Aljurf, O. Ringden, R. Reshef, R. F. Olsson, S. Hashmi, S. Seo, T. R. Spitzer, M. L. MacMillan, A. Lazaryan, S. R. Spellman, M. Arora and C. S. Cutler (2016). “Gvhd after umbilical cord blood transplantation for acute leukemia: An analysis of risk factors and effect on outcomes.” Bone Marrow Transplant: 2016 Dec [Epub ahead of print].

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Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Aiken, T., A. Garber, D. Thomas, N. Hamon, R. Lopez, R. Konjeti, A. McCullough, N. Zein, J. Fung, M. Askar and B. V. John (2016). “Donor ifnl4 genotype is associated with early post-transplant fibrosis in recipients with hepatitis c.” PLoS One 11(11).

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BACKGROUND AND AIMS: Early post-transplant hepatic fibrosis is associated with poor outcomes and may be influenced by donor/recipient genetic factors. The rs368234815 IFNL4 polymorphism is related to the previously described IL28B polymorphism, which predicts etiology-independent hepatic fibrosis. The aim of this study was to identify the impact of donor and/or recipient IFNL4 genotype on early fibrosis among patients transplanted for hepatitis C (HCV). METHODS: Clinical data were collected for 302 consecutive patients transplanted for HCV. 116 patients who had available liver biopsies and donor/recipient DNA were included. 28% of these patients with stage 2 fibrosis or greater were compared to patients without significant post-transplant fibrosis with respect to clinical features as well as donor/recipient IFNL4 genotype. RESULTS: The IFNL4 TT/TT genotype was found in 26.0% of recipients and 38.6% of donors. Patients who developed early post-transplant fibrosis had a 3.45 adjusted odds of having donor IFNL4 TT/TT genotype (p = 0.012). Donor IFNL4 TT/TT genotype also predicted decreased overall survival compared to non-TT/TT genotypes (p = 0.016). CONCLUSIONS: Donor IFNL4 TT/TT genotype, a favorable predictor of spontaneous HCV clearance pre-transplant, is associated with increased early post-transplant fibrosis and decreased survival.

Bao, M., Y. Wang, Y. Liu, P. Shi, H. Lu, W. Sha, L. Weng, S. Hanabuchi, J. Qin, J. Plumas, L. Chaperot, Z. Zhang and Y. J. Liu (2016). “Nfatc3 promotes irf7 transcriptional activity in plasmacy–toid dendritic cells.” J Exp Med 213(11): 2383-2398.

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Plasmacytoid dendritic cells (pDCs) rapidly produce large amounts of type 1 interferon (IFN) after Toll-like receptor 7 and 9 engagements. This specialized function of type 1 IFN production is directly linked to the constitutive expression of IRF7, the master transcription factor for type 1 IFN production. However, the IRF7 regulatory network in pDCs remains largely unknown. In this study, we identify that the transcription factor NFATC3 specifically binds to IRF7 and enhances IRF7-mediated IFN production. Furthermore, knockout of NFATC3 greatly reduced the CpG DNA-induced nuclear translocation of IRF7, which resulted in impaired type 1 IFN production in vitro and in vivo. In addition, we found that NFATC3 and IRF7 both bound to type 1 IFN promoters and that the NFAT binding site in IFN promoters was required for IRF7-mediated IFN expression. Collectively, our study shows that the transcription factor NFATC3 binds to IRF7 and functions synergistically to enhance IRF7-mediated IFN expression in pDCs.