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Immunology. 2018 Nov 7. doi: 10.1111/imm.13018. [Epub ahead of print]

HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis.

Author information

1
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221 005, UP, India.
2
Department of Pathology, The University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
3
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy.
4
Telethon Kids Institute, The University of Western Australia, PO Box 855, West Perth, Western Australia, 6872Australia.

Abstract

Genetic variation at HLA-DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA-DRB1 4-digit alleles. In addition to the traditional role of the membrane-distal region of HLA class II molecules in antigen presentation and CD4 T cell activation, the membrane-proximal region mediates "non-traditional" multi-functional activation, differentiation, or death signals, including in DR-expressing T cells. To understand how HLA-DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+ , CD16+ ) and lymphoid (CD4+ , CD8+ , CD19+ ) cells of VL patients (pre- and post-treatment) compared with endemic healthy controls (EHC). While DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post-treatment groups, expression is enhanced on CD4+ DR+ and CD8+ DR+ T cells consistent with T cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon-γ. In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following interferon-γ stimulation. While rs9271252 genotype did not impact significantly on interferon-γ activated DR expression in myeloid, B or CD8+ T cells, CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis. This article is protected by copyright. All rights reserved.

KEYWORDS:

HLA-DR; MHC Class II expression; Visceral leishmaniasis; lymphoid lineage; myeloid lineage

PMID:
30403401
DOI:
10.1111/imm.13018

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