Haplotype-Specific Expression Analysis of MHC Class II Genes in Healthy Individuals and Rheumatoid Arthritis Patients

Abstract

HLA-DRB1 alleles have been associated with several autoimmune diseases. For anti-citrullinated protein antibody positive rheumatoid arthritis (RA), HLA-DRB1 shared epitope (SE) alleles are the major genetic risk factors. In order to study the genetic regulation of major histocompatibility complex (MHC) Class II gene expression in immune cells, we investigated transcriptomic profiles of a variety of immune cells from healthy individuals carrying different HLA-DRB1 alleles. Sequencing libraries from peripheral blood mononuclear cells, CD4+ T cells, CD8+ T cells, and CD14+ monocytes of 32 genetically pre-selected healthy female individuals were generated, sequenced and reads were aligned to the standard reference. For the MHC region, reads were mapped to available MHC reference haplotypes and AltHapAlignR was used to estimate gene expression. Using this method, HLA-DRB and HLA-DQ were found to be differentially expressed in different immune cells of healthy individuals as well as in whole blood samples of RA patients carrying HLA-DRB1 SE-positive versus SE-negative alleles. In contrast, no genes outside the MHC region were differentially expressed between individuals carrying HLA-DRB1 SE-positive and SE-negative alleles, thus HLA-DRB1 SE alleles have a strong cis effect on gene expression. Altogether, our findings suggest that immune effects associated with different allelic forms of HLA-DR and HLA-DQ may be associated not only with differences in the structure of these proteins, but also with differences in their expression levels.

Bioinformatics and System Biology Approach to Identify the Influences of COVID-19 on Rheumatoid Arthritis

“…Early data had shown that major histocompatibility complex (MHC) was associated with the risk of RA ( 51 ). This risk effect was related to differences in protein structure and expression ( 52 ). SARS-CoV-2 infection was found to cause downregulation of major histocompatibility complex class I (MHC-I) in vivo and in vitro ( 53 ).…”

A systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmunity

“…How may HLA variants affect T-cell fate? The mechanism could depend for example on characteristics of the peptide repertoires presented in the different MHC II variants 25 , 67 – 69 , by differential interactions between the TCR and the HLA that may affect peptide recognition 70 or by different cell type specific expression levels of the MHC II depending on the HLA variant 71 .…”

HLA allele-specific expression: Methods, disease associations, and relevance in hematopoietic stem cell transplantation

“…The authors showed that when compared to the standard single reference mapping, AltHapAlignR improved the accuracy of HLA expression quantification. Recently, AlthHapAlignR was applied in a study demonstrating allele-specific expression in HLA-DRB1 in patients with rheumatoid arthritis and in healthy controls ( 72 ).…”

“…However, in many cases further studies are needed to confirm whether the expression alone is the predisposing factor and how the regulatory variation affects differential expression in diseases. Elevated HLA expression levels have been associated with inflammatory bowel diseases ( 56 , 76 ), scleroderma patients with interstitial lung disease ( 77 ), ankylosing spondylitis ( 78 ), Graves’ disease ( 79 ), systemic lupus erythematosus ( 80 ), rheumatoid arthritis ( 72 ), and multiple sclerosis ( 81 ). Additionally, in celiac disease and type 1 diabetes, higher expression of DQA1*05 and DQB1*02 alleles was found in patients when compared to healthy controls ( 82 , 83 ).…”