Aggor et al. report that a gut-specific bacterium can promote oral immunity to Candida albicans. Image credit: Rachel Bailey.
Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ regulatory T (Treg) cells and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
Erica G. Schmitt, Kelsey A. Toth, Samuel I. Risma, Ana Kolicheski, Nermina Saucier, Rafael J. Feliciano Berríos, Zev J. Greenberg, Jennifer W. Leiding, Jack J. Bleesing, Akaluck Thatayatikom, Laura G. Schuettpelz, John R. Edwards, Tiphanie P. Vogel, Megan A. Cooper
People living with HIV-1 (PLWH) exhibit more rapid antibody decline following routine immunization and elevated baseline chronic inflammation than people without HIV-1 (PWOH), indicating potential for diminished humoral immunity during SARS-CoV-2 infection. Conflicting reports have emerged on the ability of PLWH to maintain humoral protection against SARS-CoV-2 co-infection during convalescence. It is unknown if peak COVID-19 severity, along with HIV-1 infection status, associates with the quality and quantity of humoral immunity following recovery. Using a cross-sectional observational cohort from the USA and Peru, adults were enrolled 1-10 weeks post-SARS-CoV-2 infection diagnosis or symptom resolution. Serum antibodies were analyzed for SARS-CoV-2-specific response rates, binding magnitudes, ACE2 receptor blocking and antibody dependent cellular phagocytosis (ADCP). Overall, (1) PLWH exhibited a trend towards decreased magnitude of SARS-CoV-2-specific antibodies, despite modestly increased overall response rates when compared to PWOH, (2) PLWH recovered from symptomatic outpatient COVID-19 had comparatively diminished immune responses, and (3) PLWH lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when comparing asymptomatic to symptomatic outpatient disease.
Daniel J. Schuster, Shelly Karuna, Caroline Brackett, Martina S. Wesley, Shuying S. Li, Nathan Eisel, DeAnna Tenney, Sir'Tauria Hilliard, Nicole L. Yates, Jack R. Heptinstall, LaTonya D. Williams, Xiaoying Shen, Robert Rolfe, Robinson Cabello, Lu Zhang, Sheetal Sawant, Jiani Hu, April Kaur Randhawa, Ollivier Hyrien, John A. Hural, Lawrence Corey, Ian Frank, Georgia D. Tomaras, Kelly E. Seaton
Pancreatitis, the inflammatory disorder of the pancreas, has no specific therapy. Genetic, biochemical and animal model studies revealed that trypsin plays a central role in the onset and progression of pancreatitis. Here, we performed biochemical and preclinical mouse experiments to offer proof of concept that orally administered dabigatran etexilate can inhibit pancreatic trypsins and shows therapeutic efficacy in trypsin-dependent pancreatitis. We found that dabigatran competitively inhibited all human and mouse trypsin isoforms (Ki range 10-79 nM) and dabigatran plasma concentrations in mice given oral dabigatran etexilate well exceeded the Ki of trypsin inhibition. In the T7K24R trypsinogen mutant mouse model, a single oral gavage of dabigatran etexilate was effective against cerulein-induced progressive pancreatitis with a high degree of histological normalization. In contrast, spontaneous pancreatitis in T7D23A mice, which carry a more aggressive trypsinogen mutation, was not ameliorated by dabigatran etexilate, given either as daily gavages or by mixing it with solid chow. Taken together, our observations confirmed that benzamidine derivatives such as dabigatran are potent trypsin inhibitors and show therapeutic activity against trypsin-dependent pancreatitis in T7K24R mice. Lack of efficacy in T7D23A mice is likely related to the more severe pathology and insufficient drug concentrations in the pancreas.
Zsófia G. Pesei, Zsanett Jancsó, Alexandra Demcsák, Balázs Csaba Németh, Sandor Vajda, Miklós Sahin-Tóth
Since the introduction of new generation pertussis vaccines, resurgence of pertussis is observed in many developed countries. Former whole-cell pertussis vaccines (wP) are able to protect against disease and transmission but have been replaced in several industrialized countries because of their reactogenicity and adverse effects. Current acellular pertussis vaccines (aP), made of purified proteins of Bordetella pertussis, are efficient at preventing disease but fail to induce long-term protection from infection. While the systemic and mucosal T cell immunity induced by the two types of vaccines has been well described, much less is known concerning B cell responses. Taking advantage of an inducible AID fate-mapping mouse model, we compared effector and memory B cells induced by the two classes of vaccines and showed that a stronger and broader memory B cell and plasma cell response is achieved by a wP prime. We also observed that homologous or heterologous vaccine combinations that include at least one wP administration, even as a booster dose, are sufficient to induce this broad effector response, thus highlighting its dominant imprint on the B cell profile. Finally, we describe the settlement of memory B cell populations in the lung following subcutaneous wP prime vaccination.
Viviana Valeri, Akhésa Sochon, Clara Cousu, Pascal Chappert, Damiana Lecoeuche, Pascal Blanc, Jean-Claude Weill, Claude-Agnès Reynaud
We previously reported that Smad Anchor for Receptor Activation (SARA) plays a critical role in maintaining epithelial cell phenotype. Here, we show that SARA suppresses myofibroblast precursor transdifferentiation in a mouse model of scleroderma. Mice overexpressing SARA specifically in PDGFRβ+ pericytes and pan-leukocytes (SARATg) developed significantly less skin fibrosis in response to bleomycin injection compared to wild-type littermates (SARAWT).Single cell RNASeq analysis of skin PDGFRβ+ cells implicated pericyte subsets assuming myofibroblast characteristics under fibrotic stimuli, and SARA overexpression blocked the transition. In addition, a cluster that expresses molecules associated with Th2 cells and macrophage activation was enriched in SARAWT, but not in SARATg mouse, after bleomycin treatment. Th2- specific Il-31 expression was increased in skin of the bleomycin-treated SARAWT mice, and scleroderma patients. Receptor-ligand analyses indicated that lymphocytes mediate pericyte transdifferentiation in SARAWT mice, while with SARA overexpression the myofibroblast activity of pericytes was suppressed. Together, these data suggest a novel crosstalk between myofibroblast precursors and immune cells in the pathogenesis of SSc, for which SARA plays a critical role.
Katia Corano-Scheri, Xiaoyan Liang, Vidhi Dalal, I. Caroline Le Poole, John Varga, Tomoko Hayashida
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