Gene targeting has revealed a specific and essential role for protein kinase-Cδ (PKCδ) in the induction of B-cell anergy — the state of functional inactivation that is induced in response to self-antigens. PKCδ -knockout mice have been engineered independently by two groups, who report their findings back-to-back in Nature.

Unravelling the differences between the B-cell-signalling pathways that lead to activation, anergy or death is the key to understanding B-cell tolerance, and it might lead to new therapies for antibody-mediated autoimmune diseases. PKCδ is a member of the novel PKC family, which includes PKCδ, -ɛ, -θ and -η. It is emerging that the different family members have diverse roles in the immune system and are implicated in various cellular processes, such as growth, differentiation and death. PKCδ is known to be expressed highly by B cells and to be involved in B-cell receptor (BCR) signalling, but its physiological role had not been determined.

Both groups report that the spleen and lymph nodes of Pkcδ−/− mice are enlarged, owing to an expansion of the B-cell population; however, B-cell development is normal. An abundance of germinal centres in the spleen and lymph nodes of Pkcδ−/− mice indicates that peripheral B cells are out of control.

What might be driving the aberrant activation of B cells in Pkcδ−/− mice? Both groups show that there is a marked increase in the production of IgG antibodies that are specific for nuclear antigens. Moreover, histological analysis of the kidneys showed pathology that is the result of immune-complex deposition. This indicates that B-cell tolerance to self-antigens is defective in the absence of PKCδ.

Mecklenbräuer and co-workers used the classic hen-egg lysozyme (HEL) transgenic model to disect the tolerance defect. Pkcδ−/− mice were crossed with mice that were doubly transgenic for an HEL-specific BCR, and either a membrane or soluble form of HEL. As expected, HEL-specific B cells were deleted in mice that expressed membrane HEL, and this deletion was unaffected by PKCδ deficiency. However, in mice that expressed soluble HEL, Pkcδ−/− HEL-specific B cells failed to become anergic and, instead, proliferated and differentiated into antibody-producing cells.

This group then examined the responses of Pkcδ−/− mice to antigenic stimulation. They found that PKCδ-sufficient and PKCδ-deficient B cells had similar thresholds for activation in vitro, and the levels of proliferation and kinetics of calcium flux were comparable. The authors conclude that Pkcδ−/− B cells have a specific defect in the induction of anergy, rather than a generalized enhancement of signalling. By contrast, Miyamoto and colleagues found that the proliferation of Pkcδ−/− B cells in vitro in response to various mitogenic stimuli was increased, and their study implicates the increased expression of interleukin-6 — a growth-promoting cytokine — in the absence of PKCδ as a possible mechanism. This apparent discrepancy between the two studies remains to be resolved.