Do self-perpetuating B lymphocytes drive human autoimmune disease?

Abstract

Normal immunological memory is thought to be underpinned by T lymphocytes. However, in rheumatoid arthritis there are indications that T-lymphocyte control has been subverted by self-perpetuating B lymphocytes. Potential mechanisms in other autoimmune states are less clear, but a number of observations suggest that misappropriation of immunological memory by B lymphocytes may be a common feature of human autoantibody-associated disease. Put simply, autoantibodies drive their own production. If so, the availability of safe B-lymphocyte-depleting agents provides a potential means for reversal of autoimmunity.

Figure 1

A generalized mechanism for autoantibody-associated disease.

Figure 2

Comparison of IgG1 and IgG3 RF dimers showing the difference in hinge length.

Figure 3

A suggested basis for how the long hinge of IgG3 may inhibit IgG3 RF dimers from bringing the signalling γ-chains of FcγRIIIa into apposition.

Figure 4

The basis of ‘bystander’ T-cell help to RF-specific B lymphocytes.

Figure 5

Physiological RF in normal individuals (a); RF in rheumatoid arthritis (b); and RF in HPW (c).

Figure 6

Relative potency of survival signals for autoantigen-specific and RF-specific B cells. Cross-hatching of elements indicates reduced availability because of competition by other ligands.