Haoyuan Liu

Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.

B Cell Antigen Receptor Signal Strength and Peripheral B Cell Development are Regulated by a 9-O-Acetyl Sialic Acid Esterase

We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of α2–6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.

The Recirculating B Cell Pool Contains Two Functionally Distinct, Long-Lived, Posttransitional, Follicular B Cell Populations

Disparate models for the development of peripheral B cells may reflect significant heterogeneity in recirculating long-lived B cells that have not been previously accounted for. We show in this study that the murine recirculating B cell pool contains two distinct, long-lived, posttransitional, follicular B cell populations. Follicular Type I IgMlow B cells require Ag-derived and Btk-dependent signals for their development and make up the majority of cells in the recirculating follicular B cell pool. Follicular type II B cells do not require Btk- or Notch-2-derived signals, make up about a third of the long-lived recirculating B cell pool, and can develop in the absence of Ag. These two follicular populations exhibit differences in basal tyrosine phosphorylation and in BCR-induced proliferation, suggesting that they may represent functionally distinct populations of long-lived recirculating B cells.

Synergism between NF-κB1/p50 and Notch2 during the Development of Marginal Zone B Lymphocytes

NF-κB1 and Notch2 are both required for the development of marginal zone (MZ) B cells. Analysis of B lymphocyte development in mice that are doubly heterozygous at the Notch2 and NF-κB1 loci revealed synergism between Notch2 and NF-κB1 during MZ B cell development. Two known transcriptional targets of the Notch pathway, Hes-5 and Deltex-1, were found to be preferentially expressed in MZ B cells and regulated by NF-κB1. These studies provide in vivo evidence for a genetic interaction between the Notch and NF-κB pathways.

The CD9 Tetraspanin Is Not Required for the Development of Peripheral B Cells or for Humoral Immunity

The CD9 tetraspanin is known to be expressed at high levels on marginal zone (MZ) B cells, B-1 B cells, and plasma cells, and its expression is believed to be dependent on signals derived via Btk. In CD9 null mice, however, the development and survival of MZ B cells, B-1 B cells, and plasma cells all appear to be unaffected, and humoral immune responses to T-dependent and T-independent Ags are similar to those seen in wild-type littermate controls. In wild-type mice, CD9 levels may serve to distinguish between the presumed MZ precursor B cell population in the spleen and other IgD-expressing transitional B cells that express lower levels of CD21 and CD1d. These results suggest that CD9 is dispensable for B cell development and humoral immunity, but that this protein may serve as an additional marker for the presumed MZ precursor population of splenic B cells.