Immune regulation

Homomultimeric complexes of CD22 in B cells revealed by protein–glycan cross-linking. Han, S. et al. Nature Chem. Biol. 1, 93–97 (2005)

CD22 is a B-cell co-receptor that functions as a negative regulator of B-cell-receptor signalling. The activity of CD22 is regulated by other cell-surface glycoproteins expressed by the B cell that bind CD22 and mask its ligand-binding domain; these are known as cis ligands. Han et al. developed a method to identify the cis ligands that regulate CD22 activity in situ. B cells were cultured in the presence of sialic-acid analogues (which become incorporated into the cell-surface glycoproteins) that become crosslinked to any bound molecules after exposure to ultraviolet light. Although glycoproteins such as CD19, CD45 and IgM could bind CD22 in vitro, they were not CD22 cis ligands in situ. Instead, CD22 was found to form homomultimers, indicating that CD22 functions as its own cis ligand.

Immunodeficiency

Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Salzer, U. et al. Nature Genet. 10 Jul 2005 (10.1038/ng1600)

TACI is mutant in common variable immunodeficiency and IgA deficiency. Castigli, E. et al. Nature Genet. 10 Jul 2005 (10.1038/ng1601)

Two studies in the August issue of Nature Genetics present evidence of a role for the tumour-necrosis-factor receptor (TNFR)-family member TACI in two human immunodeficiency syndromes, common variable immunodeficiency (CVID) and IgA deficiency. Salzer et al. identified homozygous and heterozygous mutations in the gene encoding TACI (TNFRSF13B) in 13 individuals with CVID (both sporadic and familial forms). TACI, which is expressed by B cells, has been shown to induce immunogloblin class switching after binding either of its ligands, BAFF and APRIL. Accordingly, individuals with mutations that abrogated binding of APRIL had impaired B-cell proliferation and defective class switching in response to interleukin-10 and APRIL or BAFF. As a result, these individuals had humoral immunodeficiency characterized by low serum IgM level and impaired IgG and IgA production, making them susceptible to recurrent bacterial infections. Lymphoproliferation and signs of autoimmunity were also evident in TACI-deficient individuals — similar to features seen in Tnfrsf13b−/− mice. Castigli et al. identified mutations in the same gene in individuals with either CVID or IgA deficiency. Similarly, in response to ligation with APRIL, they observed defective IgG and IgA secretion by B cells from individuals with CVID or IgA deficiency. But only IgA secretion was defective when these cells were stimulated with BAFF. The common genetic basis of CVID and IgA deficiency has long been suspected, as these disorders have been shown to coexist within families.