Structural and immunogenomic insights into B-cell receptor activation

MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, 100084, China

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Corresponding author: E-mail address: liulab@tsinghua.edu.cn (Wanli Liu)

摘要

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Abstract: B cells express B-cell receptors (BCRs) which recognize antigen to trigger signaling cascades for B-cell activation and subsequent antibody production. BCR activation has a crucial influence on B-cell fate. How BCR is activated upon encountering antigen remains to be solved, although tremendous progresses have been achieved in the past few years. Here, we summarize the models that have been proposed to explain BCR activation, including the cross-linking model, the conformation-induced oligomerization model, the dissociation activation model, and the conformational change model. Especially, we elucidate the partially resolved structures of antibodies and/or BCRs by far and discusse how these current structural and further immunogenomic messages and more importantly the future studies may shed light on the explanation of BCR activation and the relevant diseases in the case of dysregulation.
- B-cell receptor /
- B-cell activation /
- BCR structure /
- Immunogenomics

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Fig. 1. Schematic presentations of IgM-BCR and IgG-BCR. V represents the variable region and C represents the constant region. The heavy chain consists of 4 or 5 domains while the light chain consists of 2 domains VL and CL.

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Table 1. Genes associated with diseases related to B cells.

Gene	Location	SNP with best P value (risk allele) reference	Major phenotype	Reference
FcγRIIB	1q23.3	rs1050501	FcγRIIB-T232 that resultls in abolishment of receptor function is strongly associated with the susceptibility of SLE	Xu et al. (2016)
PTPN22	1p13.2	rs2476601	A SNP in PTPN22 impaires intracellular BCR signal pathway, resulting in B-cell tolerance deficiency and autoimmunity loss; also has a tightly relationship with IDDM, RA, and VTLG	Arechiga et al., 2009, Kyogoku etal., 2004, Lea and Lee, 2011
IgG1	14q32.33	rs117518546	Mutation enhances phosphorylation of ITT-motif, crucially increasing Grb2's staying time in immune synapses	Chen etal. (2018b)
Btk	Xq22.1	rs128621202	Mutation of Btk results in X-linked agma-proteinemia	Maas and Hendriks (2001)
LYN	8q13	rs7829816	Polymorphism of LYN is related to lupus	Harley et al., 2008, Lu etal., 2009
BLK	8p23	rs7812879/rs2248932	Similar to other PTK family genes, lower expression of B LK significantly affects human disease but not in mice	Han etal. (2009)
BANK1	4q24	rs10516487	Polymorphisms of BANK1 are related to lupus, but there are not casual variants identified	Fan et al., 2011, Kozyrev et al., 2008
TNFAIP3	6q23	rs2230926	TNFAIP3 as a risk gene was found in RA for the first time and was related to kinds of autoimmune diseases, such as celiac disease and T1D	Adrianto et al., 2011, Fan et al., 2011, Musone et al., 2008
TNIP1	5q32	rs10036748	Cooperating with TNFAIP3 to attenuate the NF-κB pathway, highlighting the significance of NF-κB pathway in SLE	Gateva et al., 2009, Harley et al., 2008
MECP2	Xq28	rs1734787	MECP2 polymorphism is related to SLE susceptibility	Alesaeidi et al. (2015)
BCR, B-cell receptor; SNP, single-nucleotide polymorphism; SLE, systemic lupus erythematosus; T1D, Type 1 diabetes; IDDM, insulin dependent diabetes mellitus; RA, rheumatoid arthritis; VTLG, Vitiligo.

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