RESUMEN
Abnormalities in expression levels of the IgG inhibitory Fc gamma receptor IIB (FcγRIIB) are associated with the development of immunoglobulin (Ig) G serum autoantibodies and systemic autoimmunity in mice and humans. We used Ig gene cloning from single isolated B cells to examine the checkpoints that regulate development of autoreactive germinal center (GC) B cells and plasma cells in FcγRIIB-deficient mice. We found that loss of FcγRIIB was associated with an increase in poly- and autoreactive IgG(+) GC B cells, including hallmark anti-nuclear antibody-expressing cells that possess characteristic Ig gene features and cells producing kidney-reactive autoantibodies. In the absence of FcγRIIB, autoreactive B cells actively participated in GC reactions and somatic mutations contributed to the generation of highly autoreactive IgG antibodies. In contrast, the frequency of autoreactive IgG(+) B cells was much lower in spleen and bone marrow plasma cells, suggesting the existence of an FcγRIIB-independent checkpoint for autoreactivity between the GC and the plasma cell compartment.
Asunto(s)
Autoanticuerpos/biosíntesis , Linfocitos B/fisiología , Centro Germinal/inmunología , Células Plasmáticas/fisiología , Receptores de IgG/fisiología , Animales , Anticuerpos Antinucleares/análisis , Regiones Determinantes de Complementariedad , Inmunoglobulina G/análisis , Cadenas Pesadas de Inmunoglobulina/química , Riñón/inmunología , Ratones , Ratones Endogámicos C57BL , Nucleosomas/inmunología , Receptores de IgG/deficiencia , Hipermutación Somática de InmunoglobulinaRESUMEN
Nph are crucial for proper host defence. Paradoxically, they also contribute to pathology in various inflammatory diseases. Hence, apo of Nph and subsequent removal from inflamed sites is critical for resolution of inflammation. Apo Nph are recognised and cleared by MPhi, supposedly in a "silent" fashion. MPhi show large heterogeneity, comprising various subsets with different functional and biochemical properties. The contribution of these distinct populations to clearance of apo Nph is as yet unknown. Here, we investigated phagocytosis and subsequent functional responses of in vitro generated pro-inflammatory MPhi1 and anti-inflammatory MPhi2. Although only MPhi2 were capable of efficient Nph phagocytosis, we found that contact with apo Nph excerts immunosuppressive effects on both subsets, skewing them towards an anti-inflammatory state.