Genetic variation of FcγRIIa induces higher uptake of Leishmania infantum and modulates cytokine production by adherent mononuclear cells in vitro

Front Immunol. 2024 Feb 22:15:1343602. doi: 10.3389/fimmu.2024.1343602. eCollection 2024.

Abstract

Introduction: Single nucleotide variations (SNVs) are specific genetic variations that commonly occur in a population and often do not manifest phenotypically. However, depending on their location and the type of nucleotide exchanged, an SNV can alter or inhibit the function of the gene in which it occurs. Immunoglobulin G (IgG) receptor genes have exhibited several polymorphisms, including rs1801274, which is found in the FcgRIIa gene. The replacement of A with T results in a Histidine (H) to Arginine (R) substitution, altering the affinity of the IgG receptor for IgG subtypes and C-reactive protein (CRP). In this study, we analyzed rs1801274 and its functional implications concerning L. Infantum uptake and cytokine production.

Methods: We genotyped 201 individuals from an endemic area for visceral leishmaniasis to assess the presence of rs1801274 using Taqman probes for a candidate gene study. Additionally, we included seventy individuals from a non-endemic area for a functional study. Subsequently, we isolated and cultivated one-week adherent mononuclear cells (AMCs) derived from the peripheral blood of participants residing in the non-endemic region in the presence of L. infantum promastigotes, with and without antigen-specific IgG and/or CRP. We analyzed the rate of phagocytosis and the production of nitric oxide (NO), tumor necrosis factor (TNF)-a, interleukin (IL)-10, IL-12 p70, IL-1b, IL- 6, and IL-8 in the culture supernatants.

Results and discussion: In participants from the endemic region, the A/G (H/R isoform) heterozygous genotype was significantly associated with susceptibility to the disease. Furthermore, SNVs induced a change in the phagocytosis rate in an opsonin-dependent manner. Opsonization with IgG increased the production of IL-10, TNF-a, and IL-6 in AMCs with the H/R isoform, followed by a decrease in NO production. The results presented here suggest that the rs1801274 polymorphism is linked to a higher susceptibility to visceral leishmaniasis.

Keywords: AMCs; FcγRIIa (CD32a); infection; leishmaniasis; phagocytosis; polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Variation
  • Humans
  • Immunoglobulin G
  • Interleukin-12
  • Leishmania infantum* / genetics
  • Leishmaniasis, Visceral* / genetics
  • Nucleotides
  • Protein Isoforms
  • Receptors, IgG / genetics
  • Tumor Necrosis Factor-alpha

Substances

  • Fc gamma receptor IIA
  • Receptors, IgG
  • Interleukin-12
  • Tumor Necrosis Factor-alpha
  • Nucleotides
  • Protein Isoforms
  • Immunoglobulin G

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The funding sources were not involved in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit this article for publication.