Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates

Background: Homozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization. Methods: We measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls. Results: We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization. Conclusions: This study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.

Large-Scale Structure-Based Screening of Potential T Cell Cross-Reactivities Involving Peptide-Targets From BCG Vaccine and SARS-CoV-2

Although not being the first viral pandemic to affect humankind, we are now for the first time faced with a pandemic caused by a coronavirus. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been responsible for the COVID-19 pandemic, which caused more than 4.5 million deaths worldwide. Despite unprecedented efforts, with vaccines being developed in a record time, SARS-CoV-2 continues to spread worldwide with new variants arising in different countries. Such persistent spread is in part enabled by public resistance to vaccination in some countries, and limited access to vaccines in other countries. The limited vaccination coverage, the continued risk for resistant variants, and the existence of natural reservoirs for coronaviruses, highlight the importance of developing additional therapeutic strategies against SARS-CoV-2 and other coronaviruses. At the beginning of the pandemic it was suggested that countries with Bacillus Calmette-Guérin (BCG) vaccination programs could be associated with a reduced number and/or severity of COVID-19 cases. Preliminary studies have provided evidence for this relationship and further investigation is being conducted in ongoing clinical trials. The protection against SARS-CoV-2 induced by BCG vaccination may be mediated by cross-reactive T cell lymphocytes, which recognize peptides displayed by class I Human Leukocyte Antigens (HLA-I) on the surface of infected cells. In order to identify potential targets of T cell cross-reactivity, we implemented an in silico strategy combining sequence-based and structure-based methods to screen over 13,5 million possible cross-reactive peptide pairs from BCG and SARS-CoV-2. Our study produced (i) a list of immunogenic BCG-derived peptides that may prime T cell cross-reactivity against SARS-CoV-2, (ii) a large dataset of modeled peptide-HLA structures for the screened targets, and (iii) new computational methods for structure-based screenings that can be used by others in future studies. Our study expands the list of BCG peptides potentially involved in T cell cross-reactivity with SARS-CoV-2-derived peptides, and identifies multiple high-density “neighborhoods” of cross-reactive peptides which could be driving heterologous immunity induced by BCG vaccination, therefore providing insights for future vaccine development efforts.

Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review

Although autoimmunity contributes to rheumatoid arthritis (RA), several lines of evidence challenge the dogma that it is mainly an autoimmune disorder. As RA-associated human leukocyte antigens shape microbiomes and increase the risk of dysbiosis in mucosae, RA might rather be induced by epigenetic changes in long-lived synovial presenting cells, stressed by excessive translocations into joints of bacteria from the poorly cultivable gut, lung, or oral microbiota (in the same way as more pathogenic bacteria can lead to “reactive arthritis”). This narrative review (i) lists evidence supporting this scenario, including the identification of DNA from oral and gut microbiota in the RA synovium (but in also healthy synovia), and the possibility of translocation through blood, from mucosae to joints, of microbiota, either directly from the oral cavity or from the gut, following an increase of gut permeability worsened by migration within the gut of oral bacteria such as Porphyromonas gingivalis; (ii) suggests other methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls, namely, longitudinal studies of oral, gut, blood, and synovial microbiota combined with transcriptomic analyses of immune cells in individual patients at risk of RA, and in overt RA, before, during, and following flares of RA.

Endothelial-immune crosstalk contributes to vasculopathy in non-alcoholic fatty liver disease

The top cause of mortality in patients with non-alcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, the mechanisms of NAFLD-associated vasculopathy remain understudied. We developed blood outgrowth endothelial cell (BOEC) models from NAFLD and healthy subjects. NAFLD BOECs exhibited global transcriptional upregulation of chemokine hallmarks and human leukocyte antigens. In mouse models of diet-induced NAFLD, we further confirmed enhanced endothelial expressions of CXCL12 in the aortas and liver vasculatures. To elucidate endothelial-immune crosstalk, we performed immunoprofiling by single-cell analysis, uncovering T cell intensification and potentially T-helper type 1 inflammation in NAFLD patients. Functionally, interference of the CXCL12-CXCR4 axis by small molecule AMD3100 selectively modulated the chemotaxis of patient-derived CD4+ T cells and natural killer cells towards NAFLD BOECs, restoring endothelial barrier integrity. Clinically, we detected three folds more circulating damaged endothelial cells in NAFLD patients than healthy controls. Our work provides insights for modulation of interactions with effector immune subsets to mitigate endothelial injury in NAFLD.

Effect of MHC Linked 7-Gene Signature on Delayed Hepatocellular Carcinoma Recurrence

Dysregulated immune response significantly affects hepatocellular carcinoma’s (HCC) prognosis. Human Leukocyte Antigens are key in devising immune responses against HCC. Here, we investigated how HLAs modulate HCC development at the transcriptomic level. RNA-seq data of 576 patients from two independent cohorts was retrieved. The clinicopathological relevance of all HLA genes was investigated using Fisher-Exact, correlation, and Kaplan–Meier and cox regression survival tests. Clustering of ~800 immune-related genes against HLAs was completed using a ward-agglomerative method. Networks were generated using 40 HLA associated unique genes and hub genes were investigated. HLAs including HLA-DMA, HLA-DMB, HLA-DOA and HLA-DRB6 were associated with delayed recurrence in both discovery (204 HCC cases) and validation (372 HCC cases) cohorts. Clustering analyses revealed 40 genes associated with these four HLAs in both cohorts. A set of seven genes (NCF4, TYROBP, LCP2, ZAP70, PTPRC, FYN and WAS) was found co-expressed at gene–gene interaction level in both cohorts. Furthermore, survival analysis revealed seven HLA-linked genes as predictors of delayed recurrence. Multivariate analysis also predicted that mean expression of 7-gene is an independent predictor of delayed recurrence in both cohorts. We conclude that the expression of 7-gene signature may lead to improved patient prognosis. Further studies are required for consideration in clinical practice.