Rheumatoid factor (RF)-producing B cells (red) are located in the marginal sinus (stained green with anti-MOMA1) bridging channels at the border between the T-zone (stained blue with anti-Thy1) and red pulp. The marginal sinus is demarcated by MOMA1 staining, which is interrupted at the bridging channels. The RF B cells proliferate and mutate at this site.

We assume that somatic hypermutation occurs exclusively in germinal centres, but it seems that autoantibody responses could follow different rules. A new study in Science, by William and co-workers, indicates that autoreactive B cells can proliferate and mutate at an alternative location.

Autoimmune-prone MRL.Faslpr mice that carry a transgenic immunoglobulin heavy chain were used in this study. These mice have an increased and detectable frequency of B cells that are specific for IgG2a. Such anti-IgG antibodies, which are known as rheumatoid factors (RFs), are typical of autoimmune diseases such as systemic lupus erythematosus.

Although these mice spontaneously produce high levels of RFs that are somatically mutated, William et al. detected few, if any, RF+ germinal centres in the mouse spleens. Instead, clusters of rapidly proliferating RF+ B cells were found to form at the T-zone–red-pulp border.

To test whether RF+ B cells undergo antigen-driven mutation and selection at this site, RF+ B cells were microdissected from this site and the immunoglobulin variable (Vκ) genes were sequenced. This analysis showed that the RF+ B cells had indeed accumulated mutations, but where did these mutations arise? It remained possible that RF+ B cells were mutated in rare germinal centres before migrating to the extra-follicular site. However, neighbouring B cells were found to have closely related patterns of mutation, which indicates that they had arisen from a common precursor and mutated in situ.

It is not clear why the RF+ B cells shun the specialized microenvironment of the germinal centre. The authors propose that the abundance of self-antigen might prolong the proliferation of B cells at extrafollicular sites, allowing them to reach a threshold number of cell divisions for the initiation of mutation. It is not known whether there might be normal immune responses that follow similar rules.