IgM autoantibodies: Roquin and Bob1ng to a different tune

Abstract

Pathogenic autoantibodies directed against ubiquitous self-antigens such as immunoglobulin-G (IgG) anti-double-stranded DNA (anti-dsDNA) antibodies in systemic lupus erythematosus are produced by plasma cells that have undergone immunoglobulin isotype switching and affinity maturation in the germinal centre (GC).1 These autoantibodies form circulating immune complexes that are often deposited in the skin, kidneys and joints where they activate complement to cause tissue damage. In contrast, IgM (and IgA) natural autoantibodies are produced in the steady-state from birth by plasma cells derived from B1 cells, and are ‘hardwired’ to be polyreactive, low-affinity antibodies with relatively low pathogenic potential.2, 3 Nevertheless, IgM autoantibodies bound to antigen are still capable of activating the classical complement pathway and causing diseases such as autoimmune haemolytic anaemias due to cold agglutinins. In this issue, Corcoran and coworkers4 remind us of this by showing that sanroque mice harbouring mutations in Rc3h1/Roquin1 develop a GC-independent IgM-mediated autoimmune disease when crossed with mice deficient for the transcription factor Obf1/Ocab/Bob1 (Figure 1). These IgM anti-dsDNA antibodies are deposited in the kidneys where they cause glomerulonephritis. This remarkable observation adds to the growing list of insights into the regulation of autoantibody responses in the sanroque ENU-mutant mouse model, which is characterized by excessive follicular T helper (Tfh) cell activity and spontaneous GC development.5 Previous studies using this model have focussed on the role of specific genes and cellular interactions involved in the production of GC-dependent autoantibodies, such as the Bcl6, Sh2d1a, Cd28 and Icos.6, 7 However, the current study neatly turns this on its head by showing that sanroque mice develop an even more severe fatal autoimmunity when Obf1 is also deficient and they are unable to form GCs and secrete IgG autoantibodies. This unexpected finding is all the more intriguing given that Obf1 deficiency by itself does not cause autoimmunity, and can also prevent the GC-dependent development of lupus-like autoimmune diseases in aged Ailos−/− 8 and MRL-lpr mice.9