Fc Gamma Riiia-Mediated Activation Of Nk Cells By Igg Heavy Chain Complexed With Mhc Class Ii Molecules

Natural killer (NK) cells are a major Fc gamma RIIIA-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 Fc gamma RIIIA-expressing but not Fc gamma RI-expressing cells. A significant correlation was observed between the reactivity of Fc gamma RIIIA-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 Fc gamma RIIIA demonstrated IFN-gamma 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 Fc gamma RIIIA-expressing NK cells observed within arthritic joints.