Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum

BMC Immunology

Takeshi Tsubata¹  Katsushi Tokunaga³  Zen-Ichiro Honda²  Naoyuki Tsuchiya⁴  Takahiro Adachi⁵  Yuki Hitomi³ 

[1] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, 332-0012, Japan;Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan;Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan;Doctoral Program in Life System Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, 305-8575, Japan;Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

关键词: C-type lectin domain;    Exon skipping;    Polymorphism;   

Others  :  1077851
DOI  :  10.1186/1471-2172-13-72

 received in 2012-09-17, accepted in 2012-12-21,  发布年份 2012

【 摘 要 】

Background

CD72 is an inhibitory co-receptor expressed on B cells. We previously demonstrated significant association of the polymorphism of the CD72 gene with susceptibility to human systemic lupus erythematosus (SLE) in individuals carrying a SLE-susceptible FCGR2B genotype (FCGR2B-232Thr/Thr). The human CD72 locus generates a splicing isoform that lacks exon 8 (CD72Δex8) as well as full-length CD72 (CD72fl), and the CD72 polymorphism regulates exon 8 skipping.

Results

Here we demonstrated that individuals carrying the disease-protective CD72 genotype exhibit significantly lower serum immunoglobulin levels than do individuals carrying other CD72 genotypes (P < 0.05). Although expression level of CD72fl in the peripheral blood B cells was similar regardless of CD72 genotype, the protein level of CD72Δex8 was increased in individuals carrying the disease-protective CD72 genotype, suggesting a crucial role of CD72Δex8 in regulation of antibody production. By expressing these human CD72 isoforms in mouse cell lines, we further demonstrated that CD72Δex8 is accumulated in endoplasmic reticulum (ER) and fails to regulate BCR signaling whereas human CD72fl is efficiently transported to the cell surface and inhibits signaling through the B cell antigen receptor (BCR), as is the case for mouse CD72.

Conclusion

Human CD72 polymorphism appears to regulate antibody production as well as susceptibility to SLE by regulating expression of ER-localizing CD72Δex8.

【 授权许可】

   
2012 Hitomi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Nakayama E, von Hoegen I, Parnes JR: Sequence of the Lyb-2 B-cell differentiation antigen defines a gene superfamily of receptors with inverted membrane orientation. Proc Natl Acad Sci USA 1989, 86:1352-1356.
• [2]Von Hoegen I, Nakayama E, Parnes JR: Identification of a human protein homologous to the mouse Lyb-2 B cell differentiation antigen and sequence of the corresponding cDNA. J Immunol 1990, 144:4870-4877.
• [3]Beavil AJ, Edmeades RL, Gould HJ, Sutton BJ: α-Helical coiled-coil stalks in the low-affinity receptor for IgE (FcεRII/CD23) and related C-type lectins. Proc Natl Acad Sci USA 1992, 89:753-757.
• [4]Adachi T, Flaswinkel H, Yakura H, Reth M, Tsubata T: The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol 1998, 160:4662-4665.
• [5]Adachi T, Wakabayashi C, Nakayama T, Yakura H, Tsubata T: CD72 negatively regulates signaling through the antigen receptor of B cells. J Immunol 2000, 164:1223-1229.
• [6]Adachi T, Wienands J, Wakabayashi C, Yakura H, Reth M, Tsubata T: SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. J Biol Chem 2001, 276:26648-26655.
• [7]Hitomi Y, Tsuchiya N, Kawasaki A, Ohashi J, Suzuki T, Kyogoku C, Fukazawa T, Bejrachandra S, Siriboonrit U, Chandanayingyong D, et al.: CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B. Hum Mol Genet 2004, 13:2907-2917.
• [8]Tsuchiya N, Honda Z, Tokunaga K: Role of B cell inhibitory receptor polymorphisms for systemic lupus erythematosus: a negative times a negative makes a positive. J Hum Genet 2006, 51:741-750.
• [9]Wakabayashi C, Adachi T, Wienands J, Tsubata T: A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 2002, 298:2392-2395.
• [10]Yan BC, Adachi T, Tsubata T: ER stress is involved in B cell antigen receptor ligation-induced apoptosis. Biochem Biophys Res Commun 2008, 365:143-148.
• [11]Tokunaga K, Imanishi T, Takahashi K, Juji T: On the origin and dispersal of East Asian populations as viewed from HLA haplotypes. In Prehistoric Mongoloid Dispersals. Edited by Akazawa T, Szathmary EJ. Oxford: Oxford University Press; 1996:187-197.
• [12]Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG, Kallenberg CG, Tokunaga K: Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 2002, 46:1242-1254.
• [13]Delibrias CC, Floettmann JE, Rowe M, Dearon DT: Downregulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes. J Exp Med 1997, 186:1575-1583.
• [14]Schwarting R, Castello R, Moldenhauer G, Pezzutto A, von Hoegen I, Ludwig WD, Parnes JR, Dörken B: Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias. Am J Hematol 1992, 41:151-158.
• [15]Schröder M, Kaufman RJ: The unfolded protein response in nutrient sensing and differentiation. Annu Rev Biochem 2005, 74:739-789.
• [16]Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007, 8:519-529.
• [17]Wong WL, Brostrom MA, Kuznetsov G, Gmitter-Yellen D, Brostrom CO: Inhibition of protein synthesis and early protein processing by thapsigargin in cultured cells. Biochem J 1993, 289:71-79.
• [18]Bertrand R, Solary E, O’Connor P, Kohn KW, Pommier Y: Induction of a common pathway of apoptosis by staurosporine. Exp Cell Res 1994, 211:314-321.
• [19]Smith AJ, Gordon TP, Macardle PJ: Increased expression of the B-cell-regulatory molecule CD72 in primary Sjögren’s syndrome. Tissue Antigens 2004, 63:255-259.
• [20]van Vugt MJ, Reefman E, Zeelenberg I, Boonen G, Leusen JH, van de Winkel JG: The alternatively spliced CD64 transcript FcγRIb2 does not specify a surface-expressed isoform. Eur J Immunol 1999, 29:143-149.
• [21]Jaskolski F, Normand E, Mulle C, Coussen F: Differential trafficking of GluR7 Kainate receptor subunit splice variants. J Biol Chem 2005, 280:22968-22976.
• [22]Zarei MM, Zhu N, Alioua A, Eghbali M, Stefani E, Toro L: A novel MaxiK splice variant exhibits dominant-negative properties for surface expression. J Biol Chem 2001, 276:16232-16239.
• [23]Kono H, Kyogoku C, Suzuki T, Tsuchiya N, Honda H, Yamamoto K, Tokunaga K, Honda Z: FcγRIIb Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 2005, 14:2881-2892.
• [24]Fukuyama H, Nimmerjahn F, Ravetch JV: The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 2005, 6:99-106.
• [25]Deng Y, Tsao BP: Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 2010, 6:683-692.
• [26]Goldstein DB: Common genetic variation and human traits. N Engl J Med 2009, 360:1696-1698.
• [27]Cirulli ET, Goldstein DB: Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 2010, 11:415-425.
• [28]Wang GS, Cooper TA: Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 2007, 8:749-761.