FcγRIIIA-mediated activation of NK cells by IgG heavy chain complexed with MHC class II molecules.

Abstract:

:Natural killer (NK) cells are a major FcγRIIIA-expressing lymphocyte population that mediate antibody-dependent cellular cytotoxicity. Although NK cells are critical for immunity against viruses and tumors, they are also activated in the joints of patients with rheumatoid arthritis (RA) and may be involved in disease progression. We previously found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins, such as IgG heavy chain (IgGH), to the cell surface via association with their peptide-binding grooves. Furthermore, we found that IgGHs bound to HLA class II molecules encoded by RA susceptibility alleles are specific targets for rheumatoid factor, an auto-antibody involved in RA. Here, we report that IgGHs bound to HLA class II molecules preferentially stimulate FcγRIIIA-expressing but not FcγRI-expressing cells. A significant correlation was observed between the reactivity of FcγRIIIA-expressing cells to IgGH complexed with a specific HLA-DR allele and the odds ratio for HLA-DR allele's association with RA. Moreover, primary human NK cells expressing FcγRIIIA demonstrated IFN-γ production and cytotoxicity against cells expressing IgGH complexed with HLA class II molecules. Our findings suggest that IgGH complexed with HLA class II molecules are involved in the activation of FcγRIIIA-expressing NK cells observed within arthritic joints.

journal_name

Int Immunol

journal_title

International immunology

authors

Shimizu Y,Kohyama M,Yorifuji H,Jin H,Arase N,Suenaga T,Arase H

doi

10.1093/intimm/dxz010

subject

Has Abstract

pub_date

2019-04-26 00:00:00

pages

303-314

issue

5

eissn

0953-8178

issn

1460-2377

pii

5307159

journal_volume

31

pub_type

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