Cell-free Fc-γ receptors IIIb, autoantibodies and related immune complexes trigger the production of G-CSF and GM-CSF in nonorgan-specific autoimmune diseases

The FcγIIIb and IIa classes of receptors for the Fc portion of IgG are constitutively expressed in polymorphonuclear neutrophiles (PMN). High levels of cell-free (CF) FcγRIIIb were detected in nonorgan-specific autoimmune diseases, as well as related autoantibodies (Ab) present in 56, 58 and 51% of the patients with primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis, respectively. These autoAb were categorized, based on the results of an indirect immunofluorescence (IIF) test for the detection of anti-membrane-bound FcγRIIIbAb, and an enzyme-linked immunosorbent assay for that of Abs recognizing only CF FcγRIIIb. Those sera positive in the IIF test were not cytotoxic ; rather, they enhanced the survival of PMNs (5 methods). The autoAb-triggered antiapoptotic signal was transduced from FcγRIIIb, either directly or through FcγRIIa and/or CD11b, (the β-chain of the neighboring complement receptor type 3). CF FcγRIIIb produced similar effects, as well as immune complexes made up of CF FcγRIIIb and anti-CF FcγRIIIb auto Abs. Anti-FcγRIIIb autoAb-conditioned supernatant had the capacity to induce the transcription of messenger RNA for G- and GM-CSF, resulting in the synthesis of these antiapoptotic factors. Such a delay in apoptosis was associated with a downregulated expression of Bax, whereas Bcl-2 was unmodified. Differed apoptosis of PMNs should occur in patients with anti-FcγRIIIb autoAbs, particularly in the rheumatoid synovial fluid. Treatment with anti-G- and/or anti-GM-CSF might thus be proposed.