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关键词： Microchimerism   HLA   Autoimmune disease  

摘要： Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.

关键词： MHC polymorphism   Evolution   Bioinformatics   Primates   Selective sweep  

摘要： T cells recognize peptides displayed on the surface of cells on MHC molecules. Genetic variation in MHC genes alters their peptide-binding repertoire and thus influences the potential immune response generated against pathogens. Both gorillas and chimpanzees show reduced diversity at their MHC class I A (MHC-A) locus compared to humans, which has been suggested to be the result of a pathogen-mediated selective sweep. More specifically, gorillas lack A3 lineage alleles while chimpanzees seem to have lost the A2 lineage. While previous studies showed this using phylogenetic analysis, here, we take an in silico functional approach and use the peptide-MHC binding prediction software NetMHCpan to examine the peptide-binding repertoires of common human, chimpanzee, and gorilla MHC-A molecules. We find that both gorillas and chimpanzees lack the A02 peptide binding specificity (supertype) despite gorillas being expected to have this specificity since they kept the A2 lineage. Additionally, we show that human MHC molecules with the A02 specificity bind fewer virus-derived peptides than other MHC molecules. We also do not find differential presentation of self-peptides by the A02 supertype, making the purpose of maintaining this specificity in high frequencies in the human population unclear. Taken together, we hypothesize that poor presentation of viral peptides by A02 supertype MHC molecules could have resulted in a selective sweep in chimpanzees and/or gorillas, though we could not identify a specific virus that may have caused this sweep.

关键词： Kidney Transplantation   HLA   Fairness   Kidney Exchange Programs (KEP)   Multi-Agent Kidney Exchange (MKEP)  

摘要： This paper presents a comprehensive review of the last two decades of research on Kidney Exchange Programs (KEPs), systematically categorizing and classifying key contributions to provide readers with a structured understanding of advancements in the field. The review highlights the evolution of KEP methodologies and lays the foundation for our contribution. We propose three mathematical models aimed at improving both the quantity and quality of kidney transplants. Model 1 maximizes the number of transplants by focusing on compatibility based on blood type and PRA, without additional constraints. Model 2 introduces a minimum Human Leukocyte Antigen (HLA) compatibility threshold to enhance transplant quality, though this leads to fewer matches. Model 3 extends the problem to a Multi-Agent Kidney Exchange Program (MKEP), pooling incompatible donor-recipient pairs across multiple agents, resulting in a higher number of successful transplants while ensuring fairness across agents. Sensitivity analyses demonstrate tradeoffs between transplant quantity and quality, with Model 3 striking the optimal balance by leveraging multi-agent collaboration to improve both the number and quality of transplants. These findings underscore the potential benefits of more integrated kidney exchange systems. (c) 2025 by the authors;licensee Growing Science, Canada

关键词： Peptides   Artificial neural networks   HLA-I alleles   IFN-gamma   CD107a  

摘要： Toxoplasma gondii infects approximately 30% of the population, and there is currently no approved vaccine. Identifying immunogenic peptides with high affinity to different HLA molecules is a promising vaccine strategy. This study used an in silico approach using artificial neural networks to identify T. gondii peptides restricted to HLA-A*02, HLA-A*24, and HLA-B*35 alleles. Proteomes from seven T. gondii strains and transcriptomic data of overexpressed genes from T. gondii-RH in human PBMC were also used. Parasite protein sequences were analyzed with R 'Epitope Prediction' library. Peptide candidates were evaluated in the artificial neural networks based on the probabilities of output neurons (p > 0.5). The IFN-gamma responses in PBMC from T. gondii seronegative and seropositive individuals were evaluated by ELISpot. Peptides with higher IFN-gamma induction were evaluated to identify cytotoxic response in CD8+ T cells (CD107a). In silico analysis identified 36 peptides from T. gondii proteins with predicted affinity to HLA-A*02, A*24, and B*35 alleles. Experiments with PBMCs revealed that a peptide restricted to HLA-A02 (P1: FLFAWITYV) induced a significant increase in IFN-gamma-producing cells (p = 0.004). For HLA-A24, a peptide (P8: VFAFAFAFFLI) also induced a significant IFN-gamma response (p = 0.004), while for the HLA-B*35 allele, the P6 peptide (YPIAPSFAM) induced a response that differed significantly from the control (p = 0.05). These peptides induced also a significant percentage of central memory CD8 + T cells expressing the degranulation marker CD107a (p < 0.05). Finally, we identified three T. gondii peptides that induced IFN-gamma response, and a cytotoxic response measured by CD107a expression on CD45RAneg-CD8 cells. These peptides could be considered part of a multi-epitope vaccine against toxoplasmosis in humans.

关键词： Anti-cytokine autoantibodies   Phenocopy   Secondary immunodeficiency   Wound healing  

关键词： Chikungunya virus   Chikungunya fever   Cytokine storm   Signatures   Proinflammatory response  

摘要： Introduction The present study aimed at evaluating the systemic profile and network connectivity of immune mediators during acute chikungunya fever (CHIKF) according to days of symptoms onset and ageing. Methods A total of 161 volunteers (76 CHIKF patients and 85 non-infected healthy controls) were enrolled. Results and discussion Data demonstrated that a massive and polyfunctional storm of serum immune mediators was observed in CHIKF. Distinct patterns of mediators were observed according to days of symptoms onset. Most chemokines and proinflammatory cytokines were increased early at D0-1, with some increased throughout the kinetics timeline, while others presented a waning profile towards D4-12. Rhythmic signatures further underscored these findings. Increased levels IL-17 appeared as a hallmark of intense arthralgia, while CCL5&IL-5 and TNF-alpha&IL-10 duets are age-tunning features in CHIKF. Differential connectivity of networks was observed with ageing, with a progressive increase in the overall connectivity from < 8 yo towards 51-89 yo. Of note, subsets of immune mediators (IL-17, IL-2 and IL-5) displayed hotspots of hyperconnectivity in elderly as compared to younger patients. Conclusion Together, the overall scenario reveals unique patterns of soluble immune mediators during acute CHIKF infection with an oscillating symphony according to days of symptoms and ageing, which brings insight to future tailor-made therapeutic interventions.

关键词： Major histocompatibility complex   SXY module   RFX5 gene   Whole exome sequencing  

摘要： The major histocompatibility complex (MHC) encompasses a group of genes critical for immune system regulation. In humans, these molecules are referred to as human leukocyte antigens (HLA) due to their initial discovery in human leukocytes. Class I molecules present antigens to CD8 + T cells, while Class II molecules present to CD4 + T cells. Here we report a patient who had a background of parental consanguinity and a family history suggestive of immunodeficiency. He presented with clinical symptoms including fever, septic arthritis, recurrent moniliasis. Preliminary diagnostic tests revealed hypogammaglobulinemia and CD4 lymphopenia. Further immunological assessment indicated extremely low expression levels of HLA molecules: HLA ABC at 5% and HLA DR at 0%. Genetic analysis showed a mutation in the regulatory factor X5 (RFX5) gene, leading to a combined immunodeficiency diagnosis. Consequently, hematopoietic stem cell transplantation (HSCT) was planned. Regulatory factor X5plays a pivotal role in immune function by transactivating genes critical for the expression of MHC Class I and Class II molecules, as well as beta- 2-microglobulin (B2M). MHC Class I transcription is controlled indirectly by RFX5, and the RFX5 gene mutation in the patient likely caused the markedly reduced expression of HLA ABC in addition to HLA DR. Combined HLA-ABC and HLA-DR expression analyses via flow cytometry may serve as a valuable diagnostic tool for identifying RFX5-related immunodeficiency at an early stage, facilitating timely genetic testing and appropriate clinical management.

关键词： Spinal cord injury   Collagen hydrogel   bFGF   IL-10   Microspheres  

摘要： Traumatic spinal cord injury (TSCI) is a severe event within the central nervous system, leading to the impairment of sensory and motor abilities at the injury site in the spinal cord. Current therapeutic approaches offer limited efficacy in improving recovery, underscoring the need to explore alternative treatments. In the present study, we examined the sustained co-delivery of basic fibroblast growth factor (bFGF) and interleukin-10 (IL-10), encapsulated in microspheres and incorporated into a collagen-based hydrogel, for its effects on the healing of TSCI in an animal model. Seventy-five male Sprague Dawley rats were randomly divided into five groups: control, TSCI, hydrogel, microspheres, and hydrogel loaded with microspheres (Hyd + Micro). Tissue samples were collected from the injury site for further evaluation. Compared to the TSCI group, treatment groups demonstrated notably higher numerical densities of neurons and greater motor neuron health, as well as increased levels of vascular endothelial growth factor (VEGF) and antioxidative factors (catalase [CAT], glutathione [GSH], and superoxide dismutase [SOD]), and improved neurological function scores (electromyography [EMG], Basso-Beattie-Bresnahan (BBB) test, and narrow beam-walking test [NBT]). These changes were most pronounced in the Hyd + Micro group. The treatment also led to a significant decrease in the counts of apoptotic and glial cells, alongside reduced levels of malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1 beta and TNF-alpha), with the most notable enhancements seen in the Hyd + Micro group. These findings indicate that the co-delivery of bFGF and IL-10 encapsulated in microspheres within a collagen-based hydrogel provides enhanced neuroprotective effects in TSCI animal models.

关键词： Allergic rhinitis   Follicular regulatory T cells   Type 2 follicular helper T   Interleukin-35  

摘要： BackgroundAllergic rhinitis (AR) represents a persistent inflammatory condition affecting the upper respiratory tract, characterized by abnormal initiation of the immunoglobulin E (IgE)-mediated cascade. Follicular helper T (Tfh) cells and regulatory T (Tfr) cells are pivotal in orchestrating the development of IgE production in AR patients. IL-35, an anti-inflammatory cytokine, secreted by various cellular *** investigate the interplay and underlying mechanisms between interleukin-35 (IL-35) and Tfr/Tfh2 cells in the context of *** animal models employing BALB/c mice and IL-35-deficient mice underwent sensitization and challenge procedures utilizing ovalbumin (OVA) as the antigen in vivo. IL-35 was administered intranasally prior to OVA challenges. Nasal histopathological examination, PBMC isolation, Tfr/Tfh2 cell staining, Tfr/Tfh2 sorting and culture, and qPCR analysis as well as enzyme-linked immunosorbent assay (ELISA) were conducted for exploring the effect of IL-35 on Tfr/Tfh2 *** of IL-35 suppressed OVA-elicited allergic inflammation in murine models. IL-35 treatment led to an elevation in the proportion of peripheral blood Tfr cells and a decrease in Tfh2 cells. IL-35 also downregulated IL-4 and IL-21 protein expression by Tfh2 cells and upregulated IL-10 and transforming growth factor-beta (TGF-beta) production by Tfr cells. The anti-ICOS treatment abrogated the effect of IL-35 on Tfh2 and Tfr *** study provided novel insights into the mechanisms of IL-35 action and its promoting effects on Tfh2 and inhibiting effects on Tfr cells by targeting key transcription factors, contributing to the understanding of the pathogenesis and treatment of AR.

关键词： Type one diabetes mellitus   HLA-DQA1   HLA-DQB1   CTLA-4  

摘要： Background Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the selective destruction of pancreatic beta cells, leading to insulin deficiency. Both genetic and environmental factors contribute to disease susceptibility. Among genetic factors, human leukocyte antigen (HLA) class II molecules, particulary DQA1 and DQB1 haplotypes, have been associated with T1D risk. This study aimed to identify haplotypes that increase susceptibility to or provide protection against T1D in Jordanian population. Methods A total of 200 healthy individuals and 200 T1D patients were included in the study. Genomic DNA was extracted from blood samples and HLA-DQA1, HLA-DQB1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) gene regions were amplified by PCR. The PCR products were then subjected to restriction enzyme digestion and analyzed through agarose gel electrophoresis to determine different haplotypes. Results Among the analyzed haplotypes, HLA-DQA1*01:01 was found to be significantly associated with increased susceptibility to T1D. In contrast, HLA-DQA1*02:01 and HLA-DQB1*05:01 appeared to provide protective effects against T1D. No significant differences were observed for other haplotypes between the control and patient groups. Additionally, no significant difference has been observed in terms of CTLA-4 polymorphisms. Conclusion These findings suggest that HLA-DQA1*01:01 may serve as a genetic marker for T1D susceptibility, while HLA-DQA1*02:01 and HLA-DQB1*05:01 may confer protectionin the Jordanian population. Identifying these genetic risk factors could contribute to early disease prevention strategies and advanced research into additional genetic markers associated with T1D.