B cells in autoimmunity: more than antibodies?

Comment on Dunussi-Joannopoulos et al, page 2235

A mouse B-cell–depleting immunoconjugate described by Dunussi-Joannopoulos and colleagues elucidates the role of B cells and plasma cells in immunity/autoimmunity and the consequences of B-cell depletion therapy.

There is rising evidence that B cells play a central role in maintaining autoimmune inflammation. Recent studies using monoclonal antibodies (eg, B-cell–specific anti-CD20 antibodies) have shown that B-cell depletion is an effective therapeutic option in patients with rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases. However, little is known about the primary therapeutic effect of B-cell depletion or its effects on protective humoral immunity. Although serum autoantibody concentrations decline, the reduction of autoantibodies does not necessarily correlate with therapeutic efficacy. Relapses appear to be linked to the reappearance of B cells or autoantibodies in peripheral blood. Despite B-cell depletion, antibodies providing protective immunity against pathogens persist at lower but still effective serum concentrations. In view of this descriptive puzzle, there is an urgent need for animal models highlighting the roles of B lymphocytes in autoimmune diseases and the consequences of specific B-cell depletion. Until now, the development of such models has been hampered by the lack of an antibody capable of depleting CD20-expressing murine B cells. Dunussi-Joannopoulos and colleagues have now succeeded in developing a mouse B-cell–depleting immunoconjugate consisting of an anti-CD22 monoclonal antibody conjugated to calicheamicin. Like CD20, CD22 is expressed by B cells, but not by their precursors or plasma cells. This team of researchers used the conjugate to investigate B-cell depletion and its consequences in a murine model of autoimmune arthritis and in a model for protective immunity to respiratory syncytial virus (RSV). The CD22 immunoconjugate almost completely depletes B cells from all lymphoid organs. B-cell depletion does not affect antibody secretion by pre-existing antibody-secreting cells, whether protective or autoreactive. This is not surprising since CD22 is expressed by B cells but notbyantibody-secreting cells. The persistence of antibody secretion over extended B-cell–depletion periods of more than 30 days strongly suggests that long-lived plasma cells play a prominent role in protective humoral immunity and autoimmunity.^1,2 

These results underline the remarkable stability and persistence of humoral immunity after B-cell depletion. The role of humoral autoimmunity remains controversial. The relevance of the persistent presence of autoantibodies for the onset and continuation of rheumatic inflammation has been clearly demonstrated in the K/BxN and collagen-induced arthritis mouse models.^3,4  In the present report by Dunussi-Joannopoulos and colleagues, collagen II–specific antibodies apparently persist but cannot elicit arthritis (see figure). However, the reported lack of arthritogenicity of anti-collagen antibodies from B-cell–depleted mice could be due to a lack of affinity maturation or class switch, which may have occurred as a consequence of the anti-CD22–mediated termination of the immune response on day 5 or 10.

Can arthritis be induced in B-cell–depleted mice given serum from intact arthritic mice? The CD22 immunotoxin developed by Dunussi-Joannopoulos and colleagues will be a valuable tool to analyze this and other questions regarding the role of B lymphocytes and plasma cells in immune/autoimmune inflammation and to determine whether this is a case of antibody secretion, antigen presentation, and/or immunoregulation. ▪