The major histocompatibility (MHC) locus, also known as the Human Leukocyte Antigen (HLA) genes, is located on the short arm of chromosome 6, and contains three regions (Class I, Class II and Class III). This 5 Mbp locus is one of the most variable regions of the human genome, yet it also encodes a set of highly conserved and important proteins related to immunological response. Genetic variations in this region are responsible for more diseases than in the entire rest of the human genome. However, information on local structural features of the DNA is largely ignored. With recent advances in long-read sequencing technology, it is now becoming possible to sequence the entire 5 Mbp MHC locus, producing complete diploid haplotypes of the whole region. Here, we describe structural maps based on the complete sequences from six different homozygous HLA cell lines. We find long-range structural variability in the different sequences for DNA stacking energy, position preference and curvature, variation in repeats, as well as more local changes in regions forming open chromatin structures, likely to influence gene expression levels. These structural maps can be useful in visualizing large scale structural variation across HLA types, in particular when this can be complemented with epigenetic signals.

The major histocompatibility complex (MHC) with its highly polymorphic HLA genes represents one of the most intensely studied genomic regions in the genome. MHC proteins play a key role in antigen-specific immunity and are associated with a wide range of complex diseases. Despite decades of research and many advances in the field, the characterization and interpretation of its genetic and genomic variability remain challenging. Here an overview is provided of the MHC, the nature of its exceptional variability, and the complex evolutionary processes assumed to drive this variability. Highlighted are also recent advances in the field that promise to improve our understanding of the variability in the MHC and in antigen-specific immunity more generally.

Skin, the largest organ of body, is a highly immunogenic tissue with a diverse collection of immune cells. Highly polymorphic human leukocyte antigen (HLA) molecules have a central role in coordinating immune responses as recognition molecules. Nevertheless, HLA gene expression patterns among diverse cell types within a specific organ, like the skin, have yet to be thoroughly investigated, with stromal cells attracting much less attention than immune cells. To illustrate HLA expression profiles across different cell types in the skin, we performed single-cell RNA sequencing (scRNA-seq) analyses on skin datasets, covering adult and fetal skin, and hair follicles as the skin appendages. We revealed the variation in HLA expression between different skin populations by examining normal adult skin datasets. Moreover, we evaluated the potential immunogenicity of multiple skin populations based on the expression of classical HLA class I genes, which were well represented in all cell types. Furthermore, we generated scRNA-seq data of developing skin from fetuses of 15 post conception weeks (PCW), 17 PCW, and 22 PCW, delineating the dynamic expression of HLA genes with cell type-dependent variation among various cell types during development. Notably, the pseudotime trajectory analysis unraveled the significant variance in HLA genes during the evolution of vascular endothelial cells. Moreover, we uncovered the immune-privileged properties of hair follicles at single-cell resolution. Our study presents a comprehensive single-cell transcriptomic landscape of HLA genes in the skin, which provides new insights into variation in HLA molecules and offers a clue for allogeneic skin transplantation.

暂无摘要。

The etiological complexity of multiple sclerosis, an immune-mediated, neurodegenerative disease with multifactorial etiology is still elusive because of an incomplete understanding of the complex synergy between contributing factors such as genetic susceptibility and aberrant immune response. Recently, the disease phenotypes have also been shown to be associated with dysbiosis of the gut microbiome, a dynamic reservoir of billions of microbes, their proteins and metabolites capable of mimicring the autoantigens. Microbial factors could potentially trigger the neuroinflammation and symptoms of MS. In this perspective article, we discussed how microbial molecules resulting from a leaky gut might mimic a host\'s autoantigen, potentially contributing to the disease disequilibrium. It further highlights the importance of targeting the gut microbiome for alternate therapeutic options for the treatment of MS.

Background: Sepsis is a clinical syndrome, due to a dysregulated inflammatory response to infection. Accumulating evidence shows that human leukocyte antigen (HLA) genes play a key role in the immune responses to sepsis. Nevertheless, the effects of HLA genes in sepsis have still not been comprehensively understood. Methods: A systematical search was performed in the Gene Expression Omnibus (GEO) and ArrayExpress databases from inception to 10 September 2021. Random forest (RF) and modified Lasso penalized regression were conducted to identify hub genes in multi-transcriptome data, thus we constructed a prediction model, namely the HLA classifier. ArrayExpress databases, as external validation, were utilized to evaluate its diagnostic, prognostic, and predictive performance. Immune cell infiltration score was calculated via CIBERSORTx tools and single-sample gene set enrichment analysis (ssGSEA). Gene set variation analysis (GSVA) and ssGSEA were conducted to determine the pathways that are significantly enriched in different subgroups. Next, we systematically correlated the HLA classifier with immunological characteristics from multiple perspectives, such as immune-related cell infiltration, pivotal molecular pathways, and cytokine expression. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to validate the expression level of HLA genes in clinical samples. Results: A total of nine datasets comprising 1,251 patients were included. Based on RF and modified Lasso penalized regression in multi-transcriptome datasets, five HLA genes (B2M, HLA-DQA1, HLA-DPA1, TAP1, and TAP2) were identified as hub genes, which were used to construct an HLA classifier. In the discovery cohort, the HLA classifier exhibited superior diagnostic value (AUC = 0.997) and performed better in predicting mortality (AUC = 0.716) than clinical characteristics or endotypes. Encouragingly, similar results were observed in the ArrayExpress databases. In the E-MTAB-7581 dataset, the use of hydrocortisone in the HLA high-risk subgroup (OR: 2.84, 95% CI 1.07-7.57, p = 0.037) was associated with increased risk of mortality, but not in the HLA low-risk subgroup. Additionally, immune infiltration analysis by CIBERSORTx and ssGSEA revealed that B cells, activated dendritic cells, NK cells, T helper cells, and infiltrating lymphocytes (ILs) were significantly richer in HLA low-risk phenotypes, while Tregs and myeloid-derived suppressor cells (MDSCs) were more abundant in HLA high-risk phenotypes. The HLA classifier was significantly negatively correlated with B cells, activated dendritic cells, NK cells, T helper cells, and ILs, yet was significantly positively correlated with Tregs and MDSCs. Subsequently, molecular pathways analysis uncovered that cytokine-cytokine receptor (CCR) interaction, human leukocyte antigen (HLA), and antigen-presenting cell (APC) co-stimulation were significantly enriched in HLA low-risk endotypes, which was significantly negatively correlated with the HLA classifier in multi-transcriptome data. Finally, the expression levels of several cytokines (IL-10, IFNG, TNF) were significantly different between the HLA subgroups, and the ratio of IL-10/TNF was significantly positively correlated with HLA score in multi-transcriptome data. Results of qRT-PCR validated the higher expression level of B2M as well as lower expression level of HLA-DQA1, HLA-DPA1, TAP1, and TAP2 in sepsis samples compared to control sample. Conclusion: Based on five HLA genes, a diagnostic and prognostic model, namely the HLA classifier, was established, which is closely correlated with responses to hydrocortisone and immunosuppression status and might facilitate personalized counseling for specific therapy.

In his 1972 paper \'The apportionment of human diversity\', Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection can alter the apportionment of diversity of specific genes or genomic regions. We examine genetic diversity at the human leucocyte antigen (HLA) loci, located within the major histocompatibility complex (MHC) region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The single-nucleotide polymorphisms (SNPs) within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, displaying low FST values. However, when we analyse haplotypes defined by these SNPs (which define \'HLA alleles\'), we find marked differences in frequencies between geographic regions. These differences are not reflected in the FST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting FST. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We discuss the case of Brazil\'s bone marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry. This article is part of the theme issue \'Celebrating 50 years since Lewontin\'s apportionment of human diversity\'.

Granulomatosis with polyangiitis (GPA) previously known as Wegener\'s granulomatosis (WG) is a rare rheumatic disease affecting subjects of all ages. Prevalence and incidence of this systemic disease greatly varies across different ethnic groups. GPA is the commonest form of ANCA-associated vasculitis (AAV) with PR3 positivity among 85-95% of the cases. Scientific investigations of GPA is warranted because its severity, clinical heterogeneity, fast disease manifestation and end-organ damage. The etiology of GPA is still unknown. Major role of HLA and non-HLA genes with immune functions were identified, however, very limited replication was observed in different ethnic populations. In the present review, we have discussed the updates on the global epidemiology and contribution of HLA and major non-HLA genes/loci in GPA. We have also highlighted the cross disease association of GPA associated genes that may help in better disease management and predictive medicine. We proposed that high-resolution HLA typing and development of genetic risk model would help in early disease diagnosis and understanding the prognosis.

Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-α) and different alpha-synuclein (αSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-α display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor κB (NF-κB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight αSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-α and αSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson\'s disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.

Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer\'s disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer\'s disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I β chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.