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Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case–control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population ( p  = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p  < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group ( p  < 0.001) and RIF-Group ( p  = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL ( p  = 0.009) and RIF ( p  = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal–fetal KIR-HLA-C mismatch in patients.

[This corrects the article DOI: 10.3389/fimmu.2024.1451552.].

The prevalence of gluten-related disorders, mainly celiac disease (CD) and non-celiac gluten sensitivity (NCGS), varies between 0.6% and 13% in the general population. There is controversial evidence regarding the association of both CD and NCGS with extra-digestive manifestations, including recurrent reproductive failure (RRF), which may have clinical implications. To study the prevalence of HLA susceptibility alleles for CD/NCGS in a cohort of female patients with RRF from a single reference center and to evaluate the effect of a gluten-free diet on reproductive success. A retrospective study was conducted on 173 patients with RRF, consecutively attended at the Reproductive Immunology Unit of San Carlos University Clinical Hospital in Madrid. We collected and analyzed the clinical, analytical, and immunological profiles of RRF patients who presented HLA alleles associated with CD and NCGS (HLA DQ2.2, DQ2.5, DQ8, and DQ7.5). We observed a significantly higher prevalence of HLA alleles associated with CD and NCGS in our RRF cohort compared to the prevalence in the general population (69% vs. 35%-40%, p<0.0001). Only 2.3% of patients met the criteria for a CD diagnosis. In our RRF cohort, HLA-genetic susceptibility for CD/NCGS (HLA-risk group) was associated with a significantly higher rate of hypothyroidism compared to patients without these alleles (HLA-negative group) (48.7% vs. 26.92%, p=0.03). Patients with HLA-genetic susceptibility for CD/NCGS and thyroid disease had a significantly higher success rate in the subsequent pregnancy after management (55% vs. 30%, p=0.002). Two factors were found to be significant in this group: a gluten-free diet (p=0.019) and the use of levothyroxine (p=0.042). In our cohort of RRF patients, we observed a significantly higher prevalence of HLA susceptibility genes for CD/NCGS compared to the general population, also associated with a higher incidence of thyroid alterations. A gluten-free diet and the use of levothyroxine in cases of thyroid pathology had significant beneficial effects on pregnancy outcomes. We suggest that HLA typing for CD/NCGS and a gluten-free diet, in the presence of risk alleles, can improve pregnancy outcomes in RRF patients.

Gamma delta (γδ) T cells are a unique subset of T lymphocytes with distinctive features that make them highly promising candidates for cancer therapy. Their MHC-independent recognition of tumor antigens, ability to mediate direct cytotoxicity, and role in modulating the tumor microenvironment position them as versatile agents in cancer immunotherapy. This review integrates and synthesizes the existing data on γδ T cells, with an emphasis on the development and optimization of in vitro expansion protocols. Critical aspects are detailed such as activation strategies, co-culture systems, cytokine use, and other parameters to ensure robust cell proliferation and functionality, which may be valuable for those developing or optimizing clinical practices. Finally, we discuss current advancements in γδ T cell research, clinical experience, and highlight areas needing further exploration. Considering these data, we hypothesize and propose potential new applications such as engineering γδ T cells for enhanced resistance to immune checkpoint pathways or for localized cytokine delivery within the tumor microenvironment, which could broaden their therapeutic impact in the treatment of cancer and beyond.

Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.