DOI:10.1038/nri2063

Long-lived plasma cells are the key producers of serum immuno-globulin. Following a short migratory phase after their generation in germinal centres, long-lived plasma cells become resident in survival niches in the bone marrow. However, these niches have limited capacity and it is not clear exactly how newly generated plasma cells are able to find space, given that plasma cells for previously encountered antigens must also be maintained in the bone marrow. Ken Smith and colleagues investigated this using a mouse model system.

It has been proposed that plasma cells specific for previously encountered antigens are maintained in the bone-marrow niche because immunization results in the activation of memory B cells in an antigen-non-specific manner (known as bystander activation) and these cells then con-tribute to the long-lived plasma-cell

population maintained in the bone marrow. To address this, Smith and colleagues immunized mice with the hapten nitrophenol coupled to chicken γ-globulin. The number of plasma cells specific for nitrophenol was assessed after 9 weeks. When the mice were then immunized with a cocktail of non-specific antigens and the frequency of nitrophenol-specific plasma cells was analysed at 15 weeks, there were fewer nitrophenol-specific plasma cells present in the bone mar-row than at the 9-week stage. This indicates that bystander activation actually results in decreased numbers of bone-marrow plasma cells.

What could be the explanation for this reduction? Smith and col-leagues focused their attention on FcγRIIb, a low-affinity inhibitory receptor for the Fc portion of IgG, as mice deficient in FcγRIIb have more plasma cells than wild-type mice and crosslinking of FcγRIIb induces apoptosis in naive B cells. FcγRIIb was expressed by splenic plasma cells and long-lived plasma cells, and its expression levels were higher on more fully differentiated cells. Abnormal persistence of bone-marrow plasma cells was observed in mice deficient in FcγRIIb, and overexpression of FcγRIIb in trans-genic mice reversed this persistence. Furthermore, crosslinking of FcγRIIb resulted in antigen-independent apoptosis of plasma cells, includ-ing long-lived plasma cells, which are notoriously difficult to kill.

Bone-marrow plasma cells from mice prone to the autoimmune disease systemic lupus erythematosus (SLE) do not express FcγRIIb and therefore these cells could not be killed by crosslinking of FcγRIIb. Failure of FcγRIIb-mediated apoptosis might therefore contribute to the increased number of plasma cells in mice with SLE.

This study supports a model in which the production of low-affinity antibody shortly after antigenic challenge leads to the formation of immune complexes that can crosslink FcγRIIb on bone-marrow plasma cells, leading to the death of a small number of such cells. Plasmablasts generated in germinal-centre reac-tions would then be able to migrate to the bone marrow and find space in the survival niche.

This work could prove to be thera-peutically useful for the treatment of myelomas. Myelomas are malignan-cies of plasma cells and are difficult to treat, but the authors found that some myelomas express FcγRIIb and crosslinking this receptor leads to cell death by apoptosis.

So, the expression of FcγRIIb may provide a mechanistic explana-tion for the homeostatic control of the numbers of long-lived plasma cells in the bone marrow but still allow space for newly generated plasma cells.

Elaine Bell

ORIGINAL RESEARCH PAPER Xiang, Z. et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nature Immunol. 18 February 2007 (doi:10.1038/ni1440) FURTHER READING Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Rev. Immunol. 6, 741– 750 (2006)

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NATURE REVIEWS | IMMUNOLOGY VOLUME 7 | APRIL 2007

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