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

Bhawana Singh, Michaela Fakiola, Medhavi Sudarshan, Joyce Oommen, Siddharth Sankar Singh, Shyam Sundar, Jenefer M. Blackwell

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 four-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). Although 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 (IFN-γ). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN-γ stimulation. The rs9271252 genotype did not impact significantly on IFN-γ-activated DR expression in myeloid, B or CD8+ T cells, but 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.

Original languageEnglish
Pages (from-to)174-186
Number of pages13
JournalImmunology
Volume156
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint Dive into the research topics of 'HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis'. Together they form a unique fingerprint.

Cite this