The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual’s life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA’s real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as “microgenobiota”.

The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles’ extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease.

Background: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by dysregulated mucosal immunity. Despite major advances in therapies, a high proportion of patients do not achieve or sustain remission. Cellular immunotherapies have emerged as a mechanistically distinct therapeutic strategy with potential relevance for refractory disease. In the present paper, the authors aim to evaluate the rationale and current evidence supporting chimeric antigen receptor (CAR)-engineered immune cells and regulatory T (Treg)-cell–based therapies in IBD. Preclinical studies and early translational data support biological plausibility and feasibility of these therapies. However, available human evidence remains limited, with sparse clinical experience and short follow-up. Methods: A systematic review was conducted according to PRISMA guidelines. Search was performed in PubMed and EMBASE databases from inception to February 2026 including terms like “IBD”, “CAR-T”, “CAR-Treg” and “Treg therapy” among others. Eligible studies included preclinical, translational and clinical reports evaluating CAR-engineered immune cells in IBD models. Results: A total of 11 studies met the inclusion criteria after the screening and were included in the review. CAR-Treg technologies build upon advances achieved with conventional CAR-T cells in oncology and enable antigen-specific immune regulation rather than cytotoxicity. Preclinical studies and early translational data support biological plausibility and feasibility. However, available human evidence remains limited, with sparse clinical experience and short follow-up. Major unresolved issues include cellular persistence, phenotypic stability (particularly for Tregs), optimal antigen selection, manufacturing scalability, and long-term safety. Conclusions: Cellular immunotherapies represent a promising but still investigational therapeutic paradigm in IBD. Robust clinical trials with standardized endpoints and long-term safety monitoring are needed before their clinical adoption.

Background: Tofacitinib is a Janus kinase inhibitor used to treat inflammatory diseases, including rheumatoid arthritis and ulcerative colitis (UC). Previous studies have reported an increased risk of thromboembolic events in patients with rheumatoid arthritis treated with tofacitinib. Therefore, evaluating whether these effects are also present in other inflammatory diseases such as UC is important. Methods: In this exploratory study, we evaluated the impact of tofacitinib on platelet function and coagulation profiles in patients with active UC receiving tofacitinib (n=10), compared with patients treated with anti-TNF agents (n=10) and healthy controls (HC; n=10). Patients were assessed at baseline and after 14 weeks of treatment. Platelet aggregation was assessed by lumiaggregometry, while platelet activation was evaluated by flow cytometry through PAC-1 binding and surface expression of CD62P and CD63. Coagulation was assessed by rotational thromboelastometry (ROTEM ^® ) using extrinsic (EXTEM) and intrinsic (INTEM) pathway activation assays. Longitudinal analyses evaluated the effects of time, treatment, and their interaction. Results: Tofacitinib did not significantly affect platelet aggregation or the expression of platelet activation markers compared with either anti-TNF-treated patients or HC. Regarding thrombus dynamics, a significant difference was observed only in the INTEM assay when comparing the tofacitinib and anti-TNF groups, showing longer clot formation times in tofacitinib-treated patients; however, neither group differed from HC. Conclusions: In this study, tofacitinib treatment was not associated with increased platelet aggregation, platelet activation, or enhanced coagulation in patients with UC.