We describe the results of the first genome-wide association study (GWAS) of post-traumatic stress disorder (PTSD) performed using trauma-exposed white non-Hispanic participants from a cohort of ...veterans and their intimate partners (295 cases and 196 controls). Several single-nucleotide polymorphisms (SNPs) yielded evidence of association. One SNP (rs8042149), located in the retinoid-related orphan receptor alpha gene (RORA), reached genome-wide significance. Nominally significant associations were observed for other RORA SNPs in two African-American replication samples-one from the veteran cohort (43 cases and 41 controls) and another independent cohort (100 cases and 421 controls). However, only the associated SNP from the veteran African-American replication sample survived gene-level multiple-testing correction. RORA has been implicated in prior GWAS studies of psychiatric disorders and is known to have an important role in neuroprotection and other behaviorally relevant processes. This study represents an important step toward identifying the genetic underpinnings of PTSD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Foxp3-expressing regulatory T cells (Tregs) are central regulators of immune homeostasis and tolerance. As it has been suggested that proper Treg function is compromised under inflammatory ...conditions, seeking for a pathway that enhances or stabilizes Treg function is a subject of considerable interest. We report that interleukin (IL)-27, an IL-12 family cytokine known to have both pro- and anti-inflammatory roles in T cells, plays a pivotal role in enhancing Treg function to control T cell-induced colitis, a model for inflammatory bowel disease (IBD) in humans. Unlike wild-type (WT) Tregs capable of inhibiting colitogenic T-cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T-cell responses. Tregs stimulated with IL-27 expressed substantially improved suppressive function in vitro and in vivo. IL-27 stimulation of Tregs induced expression of Lag3, a surface molecule implicated in negatively regulating immune responses. Lag3 expression in Tregs was critical to mediate Treg function in suppressing colitogenic responses. Human Tregs also displayed enhanced suppressive function and Lag3 expression following IL-27 stimulation. Collectively, these results highlight a novel function for the IL-27/Lag3 axis in modulating Treg regulation of inflammatory responses in the intestine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antibody‐mediated allograft rejection is an increasingly recognized problem in clinical transplantation. However, the primary location of donor‐specific alloantibody (DSA)‐producing cells after ...transplantation have not been identified. The purpose of this study was to test the contribution of allospecific antibody‐secreting cells (ASCs) from different anatomical compartments in a mouse transplantation model. Fully MHC‐mismatched heart allografts were transplanted into three groups of recipients: nonsensitized wild type, alloantigen‐sensitized wild‐type and CCR5−/− mice that have exaggerated alloantibody responses. We found that previous sensitization to donor alloantigens resulted in the development of antidonor alloantibody (alloAb) with accelerated kinetics. Nevertheless, the numbers of alloantibody‐secreting cells and the serum titers of antidonor IgG alloantibody were equivalent in sensitized and nonsensitized recipients 6 weeks after transplantation. Regardless of recipient sensitization status, the spleen contained higher numbers of donor‐reactive ASCs than bone marrow at days 7–21 after transplantation. Furthermore, individual spleen ASCs produced more antidonor IgG alloantibody than bone marrow ASCs. Taken together, our results indicate that the spleen rather than bone marrow is the major source of donor‐reactive alloAb early after transplantation in both sensitized and nonsensitized recipients.
This study identifies spleen rather than bone marrow as a primary location of donor‐specific alloantibody‐producing cells in a mouse model of cardiac transplantation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A new undergraduate organic laboratory experiment has been developed for amide bond formation between biorenewable 2-furoic acid and either of two substituted piperazines to prepare medicinally ...relevant amide products using a procedure with industrial significance. The reactions proceeded smoothly under ambient conditions using the combination of N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) in a minimal volume of acetonitrile with a direct crystallization upon addition of water. Students successfully collected their product by filtration and then characterized it by NMR (1H, 13C, COSY, DEPT-135, HSQC), IR, MS, and melting point. Students also explored the reaction mechanism and compared green chemistry aspects of their procedure with literature routes. A virtual version of the experiment was adapted for remote instruction.
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IJS, KILJ, NUK, PNG, UL, UM
The presence of CD28− memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA‐4Ig induction therapy. In vitro analyses have ...indicated poor alloantigen‐induced CD28− memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28− memory CD8 T cell proliferation. Addition of IL‐15, but not IL‐2 or IL‐7, to co‐cultures of CD28− or CD28+ memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28− and enhanced CD28+ memory T cell proliferation. Proliferating CD28− memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28+ memory CD8 T cells. CTLA‐4Ig inhibited alloantigen‐induced proliferation of CD28+ memory CD8 T cell proliferation but had no effect on alloantigen plus IL‐15‐induced proliferation of either CD28− or CD28+ memory CD8 T cells. These results indicate the ability of IL‐15, a cytokine produced by renal epithelial during inflammation, to provoke CD28− memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA‐4Ig‐mediated costimulation blockade.
IL‐15 induces the activation of alloreactive CD28‐ memory CD8 T cells and confers resistance of alloreactive CD28+ memory CD8 T cells to CTLA‐4Ig‐mediated inhibition.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Building on studies showing that ischemia–reperfusion‐(I/R)‐injury is complement dependent, we tested links among complement activation, transplantation‐associated I/R injury, and murine cardiac ...allograft rejection. We transplanted BALB/c hearts subjected to 8‐h cold ischemic storage (CIS) into cytotoxic T‐lymphocyte associated protein 4 (CTLA4)Ig‐treated wild‐type (WT) or c3−/− B6 recipients. Whereas allografts subjected to 8‐h CIS rejected in WT recipients with a median survival time (MST) of 37 days, identically treated hearts survived >60 days in c3−/− mice (p < 0.05, n = 4–6/group). Mechanistic studies showed recipient C3 deficiency prevented induction of intragraft and serum chemokines/cytokines and blunted the priming, expansion, and graft infiltration of interferon‐γ–producing, donor‐reactive T cells. MST of hearts subjected to 8‐h CIS was >60 days in mannose binding lectin (mbl1−/−mbl2−/−) recipients and 42 days in factor B (cfb−/−) recipients (n = 4–6/group, p < 0.05, mbl1−/−mbl2−/− vs. cfb−/−), implicating the MBL (not alternative) pathway. To pharmacologically target MBL‐initiated complement activation, we transplanted BALB/c hearts subjected to 8‐h CIS into CTLA4Ig‐treated WT B6 recipients with or without C1 inhibitor (C1‐INH). Remarkably, peritransplantation administration of C1‐INH prolonged graft survival (MST >60 days, p < 0.05 vs. controls, n = 6) and prevented CI‐induced increases in donor‐reactive, IFNγ‐producing spleen cells (p < 0.05). These new findings link donor I/R injury to T cell–mediated rejection through MBL‐initiated, complement activation and support testing C1‐INH administration to prevent CTLA4Ig‐resistant rejection of deceased donor allografts in human transplant patients.
Recipient complement deficiency or peritransplant administration of a C1‐inhibitor blocks inflammation and T cell activation induced by prolonged donor cold storage and overcomes abatacept‐resistant murine heart transplant rejection.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This review relates the basic functions of platelets to specific aspects of organ allograft rejection. Platelet activation can occur in the donor or recipient before transplantation as well as during ...antibody‐ and cell‐mediated rejection. Biopsies taken during organ procurement from cadaver donors have documented that activated platelets are attached to vascular endothelial cells or leukocytes. In addition, many patients waiting for transplants have activated platelets due to the diseases that lead to organ failure or as a result of interventions used to support patients before and during transplantation. The contribution of platelets to hyperacute rejection of both allografts and xenografts is well recognized. Intravascular aggregates of platelets can also be prominent in experimental and clinical transplants that undergo acute antibody or cell‐mediated rejection. In acute rejection, platelets can recruit mononuclear cells by secretion of chemokines. After contact, monocytes, macrophages and T cells interact with platelets through receptor/ligand pairs, including P‐selectin/PSGL‐1 and CD40/CD154. There is a potential for therapy to inhibit platelet mediated immune stimulation, but it is counterbalanced by the need to maintain coagulation in the perioperative period.
Platelets have many potential effects on innate immune responses in the donor and recipient before transplantation as well as on adaptive immunity during antibody‐ and cell‐mediated rejection.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The pathogenic role of macrophages in antibody‐mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein‐1 (MCP‐1/CCL2) is a potent chemotactic factor for monocytes and macrophages. ...The current studies used a murine model of AMR to investigate the role of graft‐derived CCL2 in AMR and how macrophages may participate in antibody‐mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC‐mismatched WT A/J allografts with high donor‐reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor‐reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor‐reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2−/− versus WT allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL‐1β and IL‐12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2‐deficient allografts on Day 7. The results indicate that allograft‐derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.
This study investigating the role of macrophage functions in antibody‐mediated rejection of heart allografts in a mouse model indicates that the absence of allograft CCL2 expression markedly reduces antidonor antibodyinduced allograft inflammation including the infiltration of classically activated macrophages.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Murine CCR5−/− recipients produce high titers of antibody to complete MHC‐mismatched heart and renal allografts. To study mechanisms of class I MHC antibody‐mediated allograft injury, we tested the ...rejection of heart allografts transgenically expressing a single class I MHC disparity in wild‐type C57BL/6 (H‐2b) and B6.CCR5−/− recipients. Donor‐specific antibody titers in CCR5−/− recipients were 30‐fold higher than in wild‐type recipients. B6.Kd allografts survived longer than 60 days in wild‐type recipients whereas CCR5−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils and macrophages, and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8−/−/CCR5−/−, but not μMT−/−/CCR5−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts recovered at day 10 from CCR5−/− and CD8−/−/CCR5−/− recipients and from RAG‐1−/− allograft recipients injected with anti‐Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of antidonor class I MHC antibody can mediate allograft rejection, that donor‐reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity.
Anti–class I antibodies induce graft expression of perforin, CCL5 and myeloperoxidase during antibody‐mediated rejection of single class I MHC‐disparate allografts in a mouse model.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele ...associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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