The balance between activating and inhibitory signals that are delivered to immune cells sets the threshold for determining whether a response is mounted against a particular antigen and therefore whether tolerance or immunity is the result. One example of an inhibitory receptor that is thought to raise the activation threshold and prevent autoimmune reactions is FcγRIIB, which recognizes the Fc component of IgG — for example, in immune complexes. Indeed, several autoimmune-prone mouse strains, such as BXSB, express reduced levels of FcγRIIB at the cell surface of B cells, owing to a promoter polymorphism. Two recent papers by Jeffrey Ravetch and colleagues have investigated how FcγRIIB maintains tolerance and have shown that increasing its expression can be used to restore tolerance in a mouse model of the autoimmune disease systemic lupus erythematosus (SLE).

The first paper, in Nature Immunology, used an immunoglobulin heavy-chain gene-insertion model to look at the mechanism of action of FcγRIIB. 56R VH knock-in mice express a rearranged immunoglobulin heavy-chain variable region with a high affinity for double-stranded DNA. Such DNA-specific antibodies are commonly found in patients and mice with SLE. On the BALB/c background, the knock-in does not result in the production of DNA-specific antibodies because of pairing with 'silencing light-chain variants that alter the specificity. However, this tolerance resulting from light-chain editing is less efficient in C57BL/6 mice, which do develop circulating DNA-specific IgM. When the C57BL/6.56R mice were crossed with Fcγr2b−/− mice, this non-pathogenic IgM was converted to high titres of IgG that caused renal pathology through immune-complex deposition. The increased frequency of IgG production in the FcγRIIB-deficient C57BL/6.56R mice was shown to result from an increased number of IgG+ cells with a plasma-cell phenotype. The authors suggest that FcγRIIB is therefore a modifier of autoimmunity by regulating plasma-cell generation, rather than a primary initiator of the loss of tolerance, which in this case was the result of strain-specific differences in light-chain editing.

Restoring appropriate levels of expression of FcγRIIB by the B cells of autoimmune-prone mice might therefore restore tolerance. In the Science paper, bone marrow from three autoimmune-prone mouse strains — all of which had a deficiency in FcγRIIB expression — was transduced with a vector expressing FcγRIIB and used to reconstitute irradiated recipients. All of the mice that received Fcγr2b-transduced bone marrow had lower levels of DNA-specific antibodies than mice that received bone marrow transduced with the control parental retrovirus or than wild-type mice, indicating that FcγRIIB is a common regulator of autoimmunity on different genetic backgrounds. The Fcγr2b-transduced recipients also had a lack of immune-complex deposition in the kidneys and an absence of renal disease compared with wild-type mice. This effect is probably due to FcγRIIB expression by B cells, which was increased by 50% after retroviral transduction. Tolerance was re-established despite only 40% of B cells being effectively transduced, indicating that only small changes in the activating–inhibitory balance are sufficient to re-set the threshold for disease induction.