CD72 is a Negative Regulator of B Cell Responses to Nuclear Lupus Self-antigens and Development of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by production of autoantibodies to various nuclear antigens and overexpression of genes regulated by IFN-I called IFN signature. Genetic studies on SLE patients and mutational analyses of mouse models demonstrate crucial roles of nucleic acid (NA) sensors in development of SLE. Although NA sensors are involved in induction of anti-microbial immune responses by recognizing microbial NAs, recognition of self NAs by NA sensors induces production of autoantibodies to NAs in B cells and production of IFN-I in plasmacytoid dendritic cells. Among various NA sensors, the endosomal RNA sensor TLR7 plays an essential role in development of SLE at least in mouse models. CD72 is an inhibitory B cell co-receptor containing an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region and a C-type lectin like-domain (CTLD) in the extracellular region. CD72 is known to regulate development of SLE because CD72 polymorphisms associate with SLE in both human and mice and CD72−/− mice develop relatively severe lupus-like disease. CD72 specifically recognizes the RNA-containing endogenous TLR7 ligand Sm/RNP by its extracellular CTLD, and inhibits B cell responses to Sm/RNP by ITIM-mediated signal inhibition. These findings indicate that CD72 inhibits development of SLE by suppressing TLR7-dependent B cell response to self NAs. CD72 is thus involved in discrimination of self-NAs from microbial NAs by specifically suppressing autoimmune responses to self-NAs.

Identification of Eight Novel Alternative Splicing Forms of CD72 and Their Differential Expression in a Mouse Model of SLE / 生物化学与生物物理进展

CD72 is a B cell specific receptor that exists in multiple alternative splicing forms. Eight novel alternative splicing forms of CD72 were identified from the spleenocytes of BALB/C mice. Two very unique intron sequences were found in those alternative splicing forms. One kind of splicing variants retained the intron1 in the mRNA. This intron can be translated into 32 amino acid residues without changing the reading frame of the whole proteins. Another kind of splicing variants used an alternative 3' splice site in intron 3(3'AS) which led to premature termination of its encoded protein. The differential expression of the CD72 splicing variants were compared in BALB/C and NZB/W mice that were at different stage of systematic lupus erythematosis(SLE) disease development. It was found that 1) splicing forms containing 3'AS was rare in all samples examinated; 2) splicing forms containing two ITIM domains and transmembrane domains were more abundant in BALB/C mice than in NZB/W mice, even in some cases the two ITIM domains were separated by the intron 1; 3) a shorter splicing form with both exon2 and exon3 missing was expressed highly in terminally diseased NZB/W mice.These results suggested an important role of CD72 alternative splicing forms in B cell receptor signaling and in SLE.