Homozygous HLA-DQB1*06:02 combined with T-cell receptor alpha polymorphism results in narcolepsy onset - A familial case report.

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.

Human leukocyte antigen epitope mismatch loads and the development of de novo donor-specific antibodies in cardiothoracic organ transplantation.

De novo donor-specific human leucocyte antigen (HLA) antibodies (dnDSA) are associated with increased risk of rejection and mortality in solid organ transplantation. Such dnDSA is produced in some recipients upon allorecognition of mismatched HLA post-transplant. HLA matching is not currently considered in the allocation of deceased donor hearts and lungs and pre-transplant immunological risk stratification is based entirely on the mean fluorescence intensity (MFI) of circulating donor-directed HLA antibodies. HLA epitope-based matching tools predict B-cell or T-cell HLA epitopes that are present in the donor's HLA but absent in the recipient's HLA. We hypothesized that patients with higher epitope mismatch loads would be at increased risk of dnDSA development. We retrospectively analysed 73 heart and/or lung transplant recipients who were tested for DSA between 2015 and 2020. HLAMatchmaker, PIRCHE-II and HLA epitope mismatch algorithm (HLA-EMMA) were used to calculate eplet mismatch (EpMM) loads, T-cell epitope mismatch (TEpMM) loads and solvent accessible amino acid mismatch (SAMM) loads, respectively. Multivariate analyses showed that HLA-EMMA was the only tool with a significant association between the total score for all HLA loci and dnDSA production [odds ratio (OR) 1.021, 95% confidence interval (CI) 1.003-1.042, p = .0225] though this increased risk was marginal. The majority of dnDSA were directed against HLA-DQ and patients with higher HLA-DQ TEpMM loads (OR = 1.008, CI = 1.002-1.014, p = .007), and HLA-DR+DQ SAMM loads (OR = 1.035, CI = 1.010-1.064, p = .0077) were most at risk of producing dnDSA. We also showed that patients with a risk epitope within the HLA molecule encoded for by HLA-DQA1*05 + HLA-DQB1*02/03:01 were significantly more likely to produce dnDSA. The use of HLA epitope-based matching tools could be used for cardiothoracic transplant risk stratification to enable early intervention and monitoring of patients at increased risk of producing dnDSA.

Systematic review of associations between HLA and renal function.

INTRODUCTION: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations. METHODS: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study. RESULTS: A total of 95 HLA types and 14 three-locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. DISCUSSION: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.