B cells respond via germinal centers to produce anti-lipid IgG antibodies in a murine model of lupus

Anti-lipid IgG antibodies are produced in some mycobacterial infections and autoimmune diseases (lupus, anti-phospholipid syndrome). However, few studies have addressed the mechanisms that lead to the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a mouse model of lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membrane of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which are involved in the development of the disease. We used this model of lupus to investigate the in vivo mechanisms that lead to the production of anti-lipid IgG antibodies. B cells are activated, in response to most protein antigens, via germinal centers or extrafollicular reactions. In germinal centers, a T cell-dependent response leads to isotype switch, somatic hypermutation, affinity maturation and memory generation, whereas these events do not usually occur in extrafollicular reactions. In this mouse model of lupus induced by chlorpromazine-stabilized NPA, we found plasma cells producing NPA-specific IgGs in the inguinal lymph nodes, the spleen, and bone marrow of mice. We also found a significant number of germinal center B cells specific for NPA in the inguinal lymph nodes and the spleen, and we demonstrated the presence of NPA in these same germinal centers. In contrast, we found very few extrafollicular reaction B cells specific for NPA. Altogether, our data suggest that, in this murine model of lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.