Immunology
Abstract
Idiopathic CD4 lymphocytopenia (ICL) is a clinically heterogeneous immunodeficiency disorder defined by low numbers of circulating CD4+ T cells and increased susceptibility to opportunistic infections. CD8+ T cells, NK, and/or B cells may also be deficient in some patients. To delineate possible pathogenic cellular mechanisms in ICL, we compared immune system development and function in NOD-RAGKO-γcKO (NRG) mice transplanted with hematopoietic stem cells from patients with ICL or healthy controls. CD34+ hematopoietic stem cells from healthy controls and patients with ICL reconstituted NRG mice equally well. In contrast, PBMC transfers into NRG mice identified 2 ICL engraftment phenotypes, reconstituting and nonreconstituting (NR), based on the absence or presence of donor lymphopenia. For patients in the NR group, the distribution of lymphocyte subsets was similar in the peripheral blood of both the patient and the corresponding humanized mice. The NR-ICL group could be further divided into individuals whose CD3+ T cells had defects in proliferation or survival. Thus, ICL cellular pathogenesis might be classified by humanized mouse models into 3 distinct subtypes: (a) T cell extrinsic, (b) T cell intrinsic affecting proliferation, and (c) T cell intrinsic affecting survival. Humanized mouse models of ICL help to delineate etiology and ultimately to guide development of individualized therapeutic strategies.
Authors
Ainhoa Perez-Diez, Xiangdong Liu, Virginia Sheikh, Gregg Roby, David F. Stroncek, Irini Sereti
Abstract
Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti–Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.
Authors
Keven M. Robinson, Krishnaveni Ramanan, Joshua M. Tobin, Kara L. Nickolich, Matthew J. Pilewski, Nicole L. Kallewaard, Bret R. Sellman, Taylor S. Cohen, John F. Alcorn
Abstract
Advances in genomic medicine have elucidated an increasing number of genetic etiologies for patients with common variable immunodeficiency (CVID). However, there is heterogeneity in clinical and immunophenotypic presentations and a limited understanding of the underlying pathophysiology of many cases. The primary defects in CVID may extend beyond the adaptive immune system, and the combined defect in both the myeloid and lymphoid compartments suggests the mechanism may involve bone marrow output and earlier progenitors. Using the methylation profile of the human androgen receptor (AR) gene as a surrogate epigenetic marker for bone marrow clonality, we examined the hematopoietic compartments of patients with CVID. Our data show that clonal hematopoiesis is common among patients with adult-onset CVID who do not have associated noninfectious complications. Nonblood tissues did not show a skewed AR methylation status, supporting a model of an acquired clonal hematopoietic event. Attenuation of memory B cell differentiation into long-lived plasma cells (CD20–CD27+CD38+CD138+) was associated with marked changes in the postdifferentiation methylation profile, demonstrating the functional consequence of clonal hematopoiesis on humoral immunity in these patients. This study sheds light on a potential etiology of a subset of patients with CVID, and the findings suggest that it is a stage of an acquired lymphocyte maturation disorder.
Authors
Gabriel K. Wong, Sara Barmettler, James M. Heather, David Millar, Sarah A. Penny, Aarnoud Huissoon, Alex Richter, Mark Cobbold
Abstract
Immune homeostasis in the gut associated lymphoid tissues (GALT) is critical to prevent the development of inadvertent pathologies. B cells as the producers of antibodies and cytokines plays an important role in maintaining the GALT homeostasis. However, the mechanism by which B cells specifically direct their responses towards non-self-antigens and become ignorant to self-antigens in the GALT is not known. Therefore, we developed a novel mouse model by expressing Duck Egg Lysozyme (DEL) in gut epithelial cells in presence of HEL reactive B cells. Notably, we observed a transient activation and rapid deletion of self-reactive B cells in Peyers Patches and Mesenteric lymph nodes upon self-antigen exposure. The survival of self-reactive B cells upon exposure to their self-antigen was partially rescued by blocking receptor editing but could be completely rescued by stronger survival signal like ectopic expression of BCL2. Importantly, rescuing the self-reactive B cells promoted production of auto-antibodies and gut inflammation. Mechanistically, we identify a specific activation of TGFβ signaling in self-reactive B cells in the gut and a critical role of this pathway in maintaining peripheral tolerance. Collectively, our studies describe functional consequences and fate of self-reactive B cells in GALT and provide novel mechanistic insights governing self-tolerance of B cells in the gut.
Authors
Ashima Shukla, Cindi Chen, Julia Jellusova, Charlotte R. Leung, Elaine Kao, Numana Bhat, Wai W. Lin, John R. Apgar, Robert C. Rickert
Abstract
Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosphotyrosine phosphatase, non-receptor type (PTPN) 22 in effector CD8+ T cells enhances the efficacy of ACT for tumor clearance in mice. In the current work, we demonstrate that, upon ACT, PTPN22-deficient effector CD8+ T cells afford greater protection against tumors expressing very low affinity antigen, but do not survive long-term in vivo. Persistence of CD8+ T cells following tumor clearance is improved by ACT of memory phenotype cells that have a distinct metabolic phenotype as compared to effector T cells. Importantly, PTPN22-deficient T cells have comparable capacity to form long-lived memory cells in vivo but enhanced anti-tumor activity in vivo and effector responses ex vivo. These findings provide key insight into the regulation of effector and memory T cell responses in vivo, and indicate that PTPN22 is a rationale target to improve ACT for cancer.
Authors
Rebecca J. Brownlie, David Wright, Rose Zamoyska, Robert J. Salmond
Abstract
Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55ß conditioned resistance to cytokine withdrawal-induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55ß was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CTCF binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.
Authors
Iris K. Madera-Salcedo, Beatriz E. Sánchez-Hernández, Yevgeniya Svyryd, Marcela Esquivel-Velázquez, Noé Rodríguez-Rodríguez, María Isabel Trejo-Zambrano, H. Benjamín García-González, Gabriela Hernández-Molina, Osvaldo M. Mutchinick, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín
Abstract
BACKGROUND. Autologous stem-cell transplantation (ASCT) is the standard treatment for R/R B-NHL, while chimeric antigen receptor T (CAR-T) therapy targeting CD19 emerges as an alternative strategy. Here we report a comparative analysis of the two strategies in a single center. METHODS. We performed a prospective single-arm study of CAR-T therapy in 29 patients with R/R B-NHL and compared the outcomes with contemporaneous 27 patients who received ASCT. NHL was diagnosed by histopathological assessments, and the safety and efficacy were compared. RESULTS. The CAR-T group exhibited better rates of CR (48.0% vs. 20.8%, P=0.046) and one-year OS (74.4% vs. 44.5%, P=0.044) compared with the ASCT group. Subpopulation analysis showed that patients with IPI scores ≥ 3 achieved significantly higher ORR and CR rates in the CAR-T group than in the ASCT group (ORR: 72.0% vs. 10.0%, P=0.002; CR: 38.9% vs 0% P=0.030, respectively). The most common severe adverse events in the CAR-T group were cytokine release syndrome, neurotoxicity and infection compared with cytopenia, gastrointestinal toxicity and infection in the ASCT group. Additionally, the incidence of non-hematologic severe adverse events (SAEs) was markedly lower in the CAR-T group than in the ASCT group (20.7% vs. 48.1% P=0.030). CONCLUSION. CAR-T therapy exhibited superior clinical outcomes in safety and efficacy over ASCT in patients with R/R B-NHL, suggesting CAR-T may be a recommended alternative to ASCT.
Authors
Caixia Li, Ying Zhang, Changfeng Zhang, Jia Chen, Xiaoyan Lou, Xiaochen Chen, Liqing Kang, Nan Xu, Minghao Li, Jingwen Tan, Xiuli Sun, Jin Zhou, Zhen Yang, Xiangping Zong, Pu Wang, Ting Xu, Changju Qu, Haiwen Huang, Zhengming Jin, Lei Yu, Depei Wu
Abstract
Solid organ transplantation can treat end-stage organ failure, but the half-life of transplanted organs colonized with commensals is much shorter than that of sterile organs. Whether organ colonization plays a role in this shorter half-life is not known. We have previously shown that an intact whole-body microbiota can accelerate the kinetics of solid organ allograft rejection in untreated colonized mice when compared to germ-free (GF) or to antibiotic-pre-treated colonized mice, by enhancing the capacity of antigen presenting cells (APCs) to activate graft-reactive T cells. However, the contribution of intestinal versus skin microbiota to these effects was unknown. Here, we demonstrate that colonizing the skin of GF mice with a single commensal, Staphylococcus epidermidis (S. epi), while preventing intestinal colonization with oral vancomycin, was sufficient to accelerate skin graft rejection. Notably, unlike the mechanism by which whole-body microbiota accelerates skin graft rejection, cutaneous S. epi did not enhance the priming of alloreactive T cells in the skin-draining lymph nodes (LNs). Rather, cutaneous S. epi augmented the ability of skin APCs to drive the differentiation of alloreactive T cells. This study reveals that the extra-intestinal donor microbiota can affect transplant outcome and may contribute to the shorter half-life of colonized organs.
Authors
Yuk Man Lei, Martin Sepulveda, Luqiu Chen, Ying Wang, Isabella Pirozzolo, Betty Theriault, Anita S. Chong, Yasmine Belkaid, Maria-Luisa Alegre
Abstract
Rheumatoid arthritis is linked with altered host immune responses and severe joint destruction. Recent evidence suggests that loss of gut homeostasis and barrier breach by pathobionts, including Porphyromonas gingivalis, may influence disease severity. The mechanism(s) leading to altered gut homeostasis and barrier breakdown in inflammatory arthritis are poorly understood. In the present study, we found a significant reduction in intestinal concentrations of several proresolving mediators during inflammatory arthritis, including downregulation of the gut-protective mediator resolvin D5n-3 DPA (RvD5n-3 DPA). This was linked with increased metabolism of RvD5n-3 DPA to its inactive 17-oxo metabolite. We also found downregulation of IL-10 expression in the gut of arthritic mice that was coupled with a reduction in IL-10 and IL-10 receptor (IL-10R) in lamina propria macrophages. These changes were linked with a decrease in the number of mucus-producing goblet cells and tight junction molecule expression in the intestinal epithelium of arthritic mice when compared with naive mice. P. gingivalis inoculation further downregulated intestinal RvD5n-3 DPA and Il-10 levels and the expression of gut tight junction proteins. RvD5n-3 DPA, but not its metabolite 17-oxo-RvD5n-3 DPA, increased the expression of both IL-10 and IL-10R in macrophages via the upregulation of the aryl hydrocarbon receptor agonist l-kynurenine. Administration of RvD5n-3 DPA to arthritic P. gingivalis–inoculated mice increased intestinal Il-10 expression, restored gut barrier function, and reduced joint inflammation. Together, these findings uncover mechanisms in the pathogenesis of rheumatoid arthritis, where disruption of the gut RvD5n-3 DPA–IL-10 axis weakens the gut barrier, which becomes permissive to the pathogenic actions of the pathobiont P. gingivalis.
Authors
Magdalena B. Flak, Romain A. Colas, Estefanía Muñoz-Atienza, Michael A. Curtis, Jesmond Dalli, Costantino Pitzalis
Abstract
Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell–mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.
Authors
Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar
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