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

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

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HLA-DRB1 Chains
Visceral Leishmaniasis
HLA-DR Antigens
Myeloid Cells
Lymphocytes
T-Lymphocytes
Interferons
Alleles
Leishmania donovani
Blood Banks
Antigen Presentation
T-Lymphocyte Subsets
Population
Single Nucleotide Polymorphism
B-Lymphocytes
Therapeutics
Genotype
Cell Membrane
Membranes
Genes

Cite this

Singh, Bhawana ; Fakiola, Michaela ; Sudarshan, Medhavi ; Oommen, Joyce ; Singh, Siddharth Sankar ; Sundar, Shyam ; Blackwell, Jenefer M. / HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis. In: Immunology. 2019 ; Vol. 156, No. 2. pp. 174-186.
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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.",
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HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis. / Singh, Bhawana; Fakiola, Michaela; Sudarshan, Medhavi; Oommen, Joyce; Singh, Siddharth Sankar; Sundar, Shyam; Blackwell, Jenefer M.

In: Immunology, Vol. 156, No. 2, 01.02.2019, p. 174-186.

Research output: Contribution to journalArticle

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AU - Singh, Bhawana

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AU - Singh, Siddharth Sankar

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