HLA-DQA2 and HLA-DQB2 Genes Are Specifically Expressed in Human Langerhans Cells and Encode a New HLA Class II Molecule

Abstract

The precise role of human epidermal Langerhans cells (LCs) in immune response is highly controversial. While studying the gene expression profile of these cells, we were intrigued to identify the HLA-DQB2 gene as potentially expressed in LCs. Despite a strong evolutionary conservation of their sequences, the concomitant expression of the poorly polymorphic HLA-DQA2/HLA-DQB2 genes, paralogous to the HLA-DQA1/HLA-DQB1 genes, has never been detected in any cell type. We confirmed by RT-PCR that the HLA-DQA2 and -DQB2 genes are both expressed in LCs, but not in monocyte-derived dendritic cells, or in blood CD1c+ or plasmacytoid dendritic cells. The presence of the HLA-DQβ2 chain in LCs could be demonstrated by Western blotting, whereas immunofluorescence revealed its localization in early endosomes. As in the case of other HLA class II molecules, the HLA-DQα2 and -DQβ2 chains formed heterodimers that had to associate with the invariant chain to reach endosomal compartments. HLA-DQα2/β2 heterodimers were expressed at the cell surface, where they could mediate staphylococcal superantigen stimulation of T cells. Interestingly, HLA-DQα2 and HLA-DQβ1 chains formed mixed heterodimers which efficiently left the endoplasmic reticulum. These observations strongly suggest that the poorly polymorphic HLA-DQA2 and -DQB2 genes should be considered to be of immunological importance. The HLA-DQα2/β2 molecules could influence the complexity of the repertoire of Ags presented by LCs.

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

“…This prevents the binding of self-peptide fragments prior to MHC II localisation within the endolysosome. 29 Taken together, these data support and further elucidate details about the role of immune system and endolysosomal processes in FTD and PD.…”

Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases

“…The presence of interactions involving this locus shown in Fig 6A supports the notion that the effects of these genes on disease mechanism are cooperative in nature. We examined the epigenetic states of this segment of MHC class II locus (S5 Fig) and found them to be silent in most tissues, but HLA-DQB2 was weakly transcribed in monocytes (E029) and B cells (E032), which is broadly consistent with the reported expression in Langerhans cells [37]. HLA-DQB2 also contained a small (~0.4 kb) enhancer segment in the pancreas (E098).…”

“…These two genes are paralogs of HLA-DQA1 and HLA-DQB1 , and are mostly silent, except in Langerhans cells [37]. Genetic associations of SNPs in the HLA-DQA2/B2 locus have been observed in many other diseases.…”

What chickens might tell us about the MHC class II system

“…In fact, there are some orphan class II genes in humans and mice. The human gene pairs DQA2/DQB2 and DPA2/DPB2 were long considered to be pseudogenes based on lack of expression and polymorphism, but DQA2/DQB2 is expressed in Langerhans cells [37]. The mouse Eb2 gene is expressed at low levels in cell lines [38,39 ].…”

“…However, there are elaborations on this theme, leading to complications that frustrate broad generalisations. For instance, human DQA and DPA (and mouse Aa) genes are highly polymorphic but DRA (and mouse Ea) are virtually monomorphic [32], most human class II haplotypes have two functional DRB genes that have survived from a larger multigene family [33], humans have DP genes which are missing or pseudogenes in mice and rats [34], mole rats have DP but not DR [35], some ruminants have another isotype DY [36], and there are genes not expressed widely, well or at all, such as human DQA2/DQB2 and DPA2/DPB2, and mouse Eb2 [37,38,39 ].…”