Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance

Abstract

The best studied mechanisms of B cell tolerance are receptor editing, clonal deletion and anergy. All of these mechanisms of B cell tolerance depend on the induction of signaling downstream of the B cell receptor by self-antigens. Another important and distinct mechanism of B cell tolerance involves the repression of antigen receptor signaling rather than its induction, utilizes the Lyn Src-family kinase, the SHP-1 tyrosine phosphatase, inhibitory members of the Siglec family, and a carbohydrate-modifying enzyme that is capable of negatively regulating B cell receptor activation known as sialic acid acetylesterase.

Figure 1

The SIAE (sialic acid acetylesterase)-Siglec pathway for inhibitory signaling. [1] The B cell receptor (BCR) and other membrane glycoproteins can have terminal sialic acid decorated N-glycans that are acetylated on the 9-OH position of α2,6 linked sialic acid by SIAT (sialic acid acetyl transferase). [2] These acetyl moieties can be removed (deacetylation) by SIAE either in a vesicle or at the cell surface. [3] Deacetylation of N-glycan sialic acids allows interaction with Siglecs such as CD22 as well as others. This interaction can result in the recruitment of phosphatases such as SHP-1 to Siglec ITIMs (immunoreceptor tyrosine-based inhibitory motifs) [4] and consequently inhibition of BCR signaling [5].

Figure 2

Possible mechanisms by which the SIAE-Siglec pathway could mediate tolerance at the B cell level. (A) Within the B cell follicles of lymph nodes, inhibitory signals prevent weakly autoreactive B cells from migrating to the T cell zone and receiving T cell help in the form of activating signals. In contrast defective inhibitory signaling via the SIAE-Siglec pathway allows autoreactive B cells to migrate to the T cell zone where they receive T cell help, undergo somatic mutation and secrete high affinity autoantibodies. (B) Within the germinal center, inhibitory signaling prevents autoreactive B cells from being positively selected in the light zone. Attenuation of SIAE-Siglec inhibition increases the probability of selection of low affinity autoreactive B cell clones. (C) Inhibitory signals mediated by the SIAE-Siglec pathway normally prevent B cells from serving as efficient auto-antigen presenting cells however disruption of this pathway allows B cell presentation to autoreactive T cells.

Figure 2

Possible mechanisms by which the SIAE-Siglec pathway could mediate tolerance at the B cell level. (A) Within the B cell follicles of lymph nodes, inhibitory signals prevent weakly autoreactive B cells from migrating to the T cell zone and receiving T cell help in the form of activating signals. In contrast defective inhibitory signaling via the SIAE-Siglec pathway allows autoreactive B cells to migrate to the T cell zone where they receive T cell help, undergo somatic mutation and secrete high affinity autoantibodies. (B) Within the germinal center, inhibitory signaling prevents autoreactive B cells from being positively selected in the light zone. Attenuation of SIAE-Siglec inhibition increases the probability of selection of low affinity autoreactive B cell clones. (C) Inhibitory signals mediated by the SIAE-Siglec pathway normally prevent B cells from serving as efficient auto-antigen presenting cells however disruption of this pathway allows B cell presentation to autoreactive T cells.

Figure 2

Possible mechanisms by which the SIAE-Siglec pathway could mediate tolerance at the B cell level. (A) Within the B cell follicles of lymph nodes, inhibitory signals prevent weakly autoreactive B cells from migrating to the T cell zone and receiving T cell help in the form of activating signals. In contrast defective inhibitory signaling via the SIAE-Siglec pathway allows autoreactive B cells to migrate to the T cell zone where they receive T cell help, undergo somatic mutation and secrete high affinity autoantibodies. (B) Within the germinal center, inhibitory signaling prevents autoreactive B cells from being positively selected in the light zone. Attenuation of SIAE-Siglec inhibition increases the probability of selection of low affinity autoreactive B cell clones. (C) Inhibitory signals mediated by the SIAE-Siglec pathway normally prevent B cells from serving as efficient auto-antigen presenting cells however disruption of this pathway allows B cell presentation to autoreactive T cells.