Evidence implicating histidyl-tRNA synthetase (Jo-1) in the pathogenesis of the anti-synthetase syndrome includes established genetic associations linking the reproducible phenotype of muscle inflammation and interstitial lung disease with autoantibodies recognizing Jo-1. To better address the role of Jo-1-directed B and T cell responses in the context of different genetic backgrounds, we employed Jo-1 protein immunization of C57BL/6 and NOD congenic mice. Detailed analysis of early antibody responses following inoculation with human or murine Jo-1 demonstrates remarkable species-specifity, with limited cross recognition of Jo-1 from the opposite species. Complementing these results, immunization with purified peptides derived from murine Jo-1 generates B and T cells targeting species-specific epitopes contained within the amino terminal 120 amino acids of murine Jo-1. The eventual spreading of B cell epitopes that uniformly occurs 8 weeks post immunization with murine Jo-1 provides additional evidence of an immune response mediated by autoreactive, Jo-1-specific T cells. Corresponding to this self-reactivity, mice immunized with murine Jo-1 develop a striking combination of muscle and lung inflammation that replicates features of the human antisynthetase syndrome.
Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte‐derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand‐1 (PD‐L1):CD86 ratios, high IL‐10/no IL‐12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5–10 × 106 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD‐L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and “cross‐dressing” of host DCs in blood and lymph nodes. PD‐L1 co‐localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T‐bethiEomeshi memory CD8+ T cells decreased, whereas regulatory (CD25hiCD127−Foxp3+): T‐bethiEomeshi CD8+ T cell ratios increased. Thus, donor‐derived DCreg infusion may induce systemic changes in host antigen‐presenting cells and T cells potentially conducive to modulated anti‐donor immune reactivity at the time of transplant.
Conclusion. Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.
Alloimmune responses driven by donor-specific antibodies (DSAs) can lead to antibodymediated rejection (ABMR) in organ transplantation. Yet, the cellular states underlying alloreactive B cell responses and the molecular components controlling them remain unclear. Using high dimensional profiling of B cells in a cohort of 96 kidney transplant recipients, we identified expanded numbers of CD27 + CD21activated memory (AM) B cells that expressed the transcription factor T-bet in patients who developed DSAs and progressed to ABMR. Notably, AM cells were less frequent in DSA+ABMR-patients and at baseline levels in DSApatients. RNA-seq analysis of AM cells in patients undergoing ABMR revealed these cells to be poised for plasma cell differentiation and to express restricted IGHV sequences reflective of clonal expansion. In addition to T-bet, AM cells manifested elevated expression of IRF4 and Blimp1, and upon co-culture with autologous T follicular helper cells, differentiated into DSAproducing plasma cells in an IL-21 dependent manner. The frequency of AM cells was correlated with the timing and severity of ABMR manifestations. Importantly, T-bet + AM cells were detected within kidney allografts along with their restricted IGHV sequences. This study delineates a pivotal role for AM cells in promoting humoral responses and ABMR in organ transplantation and highlights them as important therapeutic targets.
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