The role of alternative splicing in autoimmune diseases_West China Medical Journal

Authors：

ZHOU Yu ¹ , CHEN Lu ¹ ,  LIU Xinle ²

1. Laboratory of Transcription and Splicing Regulation, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University / Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P. R. China;
2. Department of Laboratory Medicine, West China Second University Hospital, Sichuan University / Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Xinle, Email: xinleliu699@163.com

Keywords：

Alternative splicing; Autoimmune diseases; Gene expression; Regulation methods

DOI：

10.7507/1002-0179.202002225

Video：

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Abstract Full text Figures/Tables Video References Cited by

Alternative splicing plays an important role in the pathogenesis, diagnosis, treatment and prognosis of autoimmune diseases. Alternative splicing is universal and non-preferred in autoimmune diseases, and exon skipping is the most common type in alternative splicing types. The occurrence and development of autoimmune diseases can be influenced by the 5′ splicing, 3′ splicing, number change of exons, splicing affected by the single nucleotide polymorphism and the variance of gene expression levels. Moreover, different single nucleotide polymorphisms of the same gene can affect the development of various autoimmune diseases. This review summarizes the role of different forms of alternative splicing in various autoimmune diseases, and aims to provide a basis for further study of the conditions in different development stages of autoimmune diseases and the regulatory mechanism of different levels of splicing isoforms.

Citation： ZHOU Yu, CHEN Lu, LIU Xinle. The role of alternative splicing in autoimmune diseases. West China Medical Journal, 2021, 36(8): 1132-1138. doi: 10.7507/1002-0179.202002225 Copy

1.	Karagianni P, Tzioufas AG. Epigenetic perspectives on systemic autoimmune disease. J Autoimmun, 2019, 104: 102315.
2.	Wang ET, Sandberg R, Luo S, et al. Alternative isoform regulation in human tissue transcriptomes. Nature, 2008, 456(7221): 470-476.
3.	Baralle FE, Giudice J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol, 2017, 18(7): 437-451.
4.	Chen L, Ge B, Casale FP, et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell, 2016, 167(5): 1398-1415.
5.	Tress ML, Abascal F, Valencia A. Alternative splicing may not be the key to proteome complexity. Trends Biochem Sci, 2017, 42(2): 98-110.
6.	Ellis JD, Barrios-Rodiles M, Colak R, et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Molecular Cell, 2012, 46(6): 884-892.
7.	Guo HB, Qin H. Association study based on topological constraints of protein-protein interaction networks. Sci Rep, 2020, 10(1): 10797.
8.	Chen L, Tovar-Corona JM, Urrutia AO. Alternative splicing: a potential source of functional innovation in the eukaryotic genome. Int J Evol Biol, 2012, 2012: 596274.
9.	Conesa A, Madrigal P, Tarazona S, et al. A survey of best practices for RNA-seq data analysis. Genome Biol, 2016, 17: 13.
10.	Kahles A, Ong CS, Zhong Y, et al. Spladder: identification, quantification and testing of alternative splicing events from RNA-Seq data. Bioinformatics, 2016, 32(12): 1840-1847.
11.	Chauhan R, Raina V, Nandi SP. Prevalence of autoimmune diseases and its challenges in diagnosis. Crit Rev Immunol, 2019, 39(3): 189-201.
12.	Nishizaki SS, Boyle AP. Mining the unknown: assigning function to noncoding single nucleotide polymorphisms. Trends Genet, 2017, 33(1): 34-45.
13.	Iotchkova V, Ritchie GRS, Geihs M, et al. GARFIELD-GWAS analysis of regulatory or functional information enrichment with LD correction. (2016-11-07)[2020-09-05]. https://www.biorxiv.org/content/10.1101/085738v1.
14.	Newman JRB, Conesa A, Mika M, et al. Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res, 2017, 27(11): 1807-1816.
15.	McKay FC, Swain LI, Schibeci SD, et al. Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun, 2008, 9(1): 1-6.
16.	Galarza-Muñoz G, Briggs FBS, Evsyukova I, et al. Human epistatic interaction controls IL7R splicing and increases multiple sclerosis risk. Cell, 2017, 169(1): 72-84.
17.	Mirshafiey A, Asghari B, Ghalamfarsa G, et al. The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J, 2014, 14(1): e13-e25.
18.	Campagnoni AT, Pribyl TM, Campagnoni CW, et al. Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem, 1993, 268(7): 4930-4938.
19.	Boyle LH, Traherne JA, Plotnek G, et al. Splice variation in the cytoplasmic domains of myelin oligodendrocyte glycoprotein affects its cellular localisation and transport. J Neurochem, 2007, 102(6): 1853-1862.
20.	Hilton AA, Slavin AJ, Hilton DJ, et al. Characterization of cDNA and genomic clones encoding human myelin oligodendrocyte glycoprotein. J Neurochem, 1995, 65(1): 309-318.
21.	Muise AM, Walters T, Wine E, et al. Protein-tyrosine phosphatase sigma is associated with ulcerative colitis. Curr Biol, 2007, 17(14): 1212-1218.
22.	Lainez B, Fernandez-Real JM, Romero X, et al. Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. Int Immunol, 2004, 16(1): 169-177.
23.	Vijayakrishnan L, Slavik JM, Illés Z, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity, 2004, 20(5): 563-575.
24.	Gerold KD, Zheng P, Rainbow DB, et al. The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. Diabetes, 2011, 60(7): 1955-1963.
25.	Kozyrev SV, Abelson AK, Wojcik J, et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet, 2008, 40(2): 211-216.
26.	Hitomi Y, Tsuchiya N, Kawasaki A, 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(23): 2907-2917.
27.	Sun J, Lai H, Shen D, et al. Reduced sB7-H3 expression in the peripheral blood of systemic lupus erythematosus patients. J Immunol Res, 2017, 2017: 5728512.
28.	Chen W, Liu P, Wang Y, et al. Characterization of a soluble B7-H3 (sB7-H3) spliced from the intron and analysis of sB7-H3 in the sera of patients with hepatocellular carcinoma. PLoS One, 2013, 8(10): 1-7.
29.	Zhang G, Hou J, Shi J, et al. Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology, 2008, 123(4): 538-546.
30.	Hirahara S, Katsumata Y, Kawaguchi Y, et al. 277 usefulness of soluble PD-1 in patients with systemic lupus erythematosus. Lupus Sci Med, 2017, 4: A127.
31.	Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene. Cell Immunol, 2005, 235(2): 109-116.
32.	Mamegano K, Kuroki K, Miyashita R, et al. Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis. Genes Immun, 2008, 9(3): 214-223.
33.	Graham RR, Kozyrev SV, Baechler EC, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet, 2006, 38(5): 550-555.
34.	Yang A, Kaghad M, Caput D, et al. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet, 2002, 18(2): 90-95.
35.	Unger P, Ewart M, Wang BY, et al. Expression of p63 in papillary thyroid carcinoma and in Hashimoto’s thyroiditis: a pathobiologic link?. Human Pathology, 2003, 34(8): 764-769.
36.	Feldkamp J, Pascher E, Schott M, et al. Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease. J Clin Endocrinol Metab, 2001, 86(9): 4250-4253.
37.	Cascino I, Fiucci G, Papoff G, et al. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol, 1995, 154(6): 2706-2713.
38.	Gu M, Kakoulidou M, Giscombe R, et al. Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis. Clin Immunol, 2008, 128(3): 374-381.
39.	Sung HH, Castro I, Gonzalez S, et al. MUC1/SEC and MUC1/Y overexpression is associated with inflammation in Sjögren’s syndrome. Oral Dis, 2015, 21(6): 730-738.
40.	Ragusa F, Fallahi P, Elia G, et al. Hashimotos’ thyroiditis: epidemiology, pathogenesis, clinic and therapy. Best Pract Res Clin Endocrinol Metab, 2019, 33(6): 101367.
41.	Akatsu C, Shinagawa K, Numoto N, et al. CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J Exp Med, 2016, 213(12): 2691-2706.
42.	Jenks SA, Cashman KS, Zumaquero E, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity, 2018, 49(4): 725-739.
43.	Hitomi Y, Adachi T, Tsuchiya N, et al. Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum. BMC Immunol, 2012, 13: 72.
44.	Dlamini Z, Mokoena F, Hull R. Abnormalities in alternative splicing in diabetes: therapeutic targets. J Mol Endocrinol, 2017, 59(2): R93-R107.
45.	Gregory SG, Schmidt S, Seth P, et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet, 2007, 39(9): 1083-1091.
46.	Evsyukova I, Bradrick SS, Gregory SG, et al. Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA, 2013, 19(1): 103-115.
47.	Prokunina L, Castillejo-López C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet, 2002, 32(4): 666-669.
48.	Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens, 2003, 62(6): 492-497.
49.	Liu C, Jiang J, Gao L, et al. A Promoter region polymorphism in PDCD-1 gene is associated with risk of rheumatoid arthritis in the Han Chinese population of southeastern China. Int J Genomics, 2014, 2014: 247637.
50.	Szolnoki Z, Kondacs A, Mandi Y, et al. A cytoskeleton motor protein genetic variant may exert a protective effect on the occurrence of multiple sclerosis: the janus face of the kinesin light-chain 1 56836CC genetic variant. Neuromolecular Med, 2007, 9(4): 335-339.
51.	Pérez-Sánchez C, Aguirre MA, Pedraza-Arévalo S, et al. AB0128 alterations of the splicing machinery components in leukocytes from patients with systemic lupus erythematosus influences its development and atherothrombotic profile and drives the therapeutic response. Ann Rheum Dis, 2017, 76(Suppl 2): 1091-1092.
52.	Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A, 2001, 98(24): 13866-13871.
53.	Xerri L, Devilard E, Hassoun J, et al. Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol, 1997, 50(2): 87-91.
54.	Cheng J, Zhou T, Liu C, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science, 1994, 263(5154): 1759-1762.
55.	Compston A, Coles A. Multiple sclerosis. Lancet, 2008, 372(9648): 1502-1517.
56.	Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol, 2015, 15(9): 545-558.
57.	Petry KG, Boullerne AI, Pousset F, et al. Experimental allergic encephalomyelitis animal models for analyzing features of multiple sclerosis. Pathol Biol (Paris), 2000, 48(1): 47-53.
58.	Steinman L. Multiple sclerosis. Presenting an odd autoantigen. Nature, 1995, 375(6534): 739-740.
59.	Castro I, Albornoz N, Aguilera S, et al. Aberrant MUC1 accumulation in salivary glands of Sjögren’s syndrome patients is reversed by TUDCA in vitro. Rheumatology (Oxford), 2020, 59(4): 742-753.

1. Karagianni P, Tzioufas AG. Epigenetic perspectives on systemic autoimmune disease. J Autoimmun, 2019, 104: 102315.
2. Wang ET, Sandberg R, Luo S, et al. Alternative isoform regulation in human tissue transcriptomes. Nature, 2008, 456(7221): 470-476.
3. Baralle FE, Giudice J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol, 2017, 18(7): 437-451.
4. Chen L, Ge B, Casale FP, et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell, 2016, 167(5): 1398-1415.
5. Tress ML, Abascal F, Valencia A. Alternative splicing may not be the key to proteome complexity. Trends Biochem Sci, 2017, 42(2): 98-110.
6. Ellis JD, Barrios-Rodiles M, Colak R, et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Molecular Cell, 2012, 46(6): 884-892.
7. Guo HB, Qin H. Association study based on topological constraints of protein-protein interaction networks. Sci Rep, 2020, 10(1): 10797.
8. Chen L, Tovar-Corona JM, Urrutia AO. Alternative splicing: a potential source of functional innovation in the eukaryotic genome. Int J Evol Biol, 2012, 2012: 596274.
9. Conesa A, Madrigal P, Tarazona S, et al. A survey of best practices for RNA-seq data analysis. Genome Biol, 2016, 17: 13.
10. Kahles A, Ong CS, Zhong Y, et al. Spladder: identification, quantification and testing of alternative splicing events from RNA-Seq data. Bioinformatics, 2016, 32(12): 1840-1847.
11. Chauhan R, Raina V, Nandi SP. Prevalence of autoimmune diseases and its challenges in diagnosis. Crit Rev Immunol, 2019, 39(3): 189-201.
12. Nishizaki SS, Boyle AP. Mining the unknown: assigning function to noncoding single nucleotide polymorphisms. Trends Genet, 2017, 33(1): 34-45.
13. Iotchkova V, Ritchie GRS, Geihs M, et al. GARFIELD-GWAS analysis of regulatory or functional information enrichment with LD correction. (2016-11-07)[2020-09-05]. https://www.biorxiv.org/content/10.1101/085738v1.
14. Newman JRB, Conesa A, Mika M, et al. Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res, 2017, 27(11): 1807-1816.
15. McKay FC, Swain LI, Schibeci SD, et al. Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun, 2008, 9(1): 1-6.
16. Galarza-Muñoz G, Briggs FBS, Evsyukova I, et al. Human epistatic interaction controls IL7R splicing and increases multiple sclerosis risk. Cell, 2017, 169(1): 72-84.
17. Mirshafiey A, Asghari B, Ghalamfarsa G, et al. The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J, 2014, 14(1): e13-e25.
18. Campagnoni AT, Pribyl TM, Campagnoni CW, et al. Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem, 1993, 268(7): 4930-4938.
19. Boyle LH, Traherne JA, Plotnek G, et al. Splice variation in the cytoplasmic domains of myelin oligodendrocyte glycoprotein affects its cellular localisation and transport. J Neurochem, 2007, 102(6): 1853-1862.
20. Hilton AA, Slavin AJ, Hilton DJ, et al. Characterization of cDNA and genomic clones encoding human myelin oligodendrocyte glycoprotein. J Neurochem, 1995, 65(1): 309-318.
21. Muise AM, Walters T, Wine E, et al. Protein-tyrosine phosphatase sigma is associated with ulcerative colitis. Curr Biol, 2007, 17(14): 1212-1218.
22. Lainez B, Fernandez-Real JM, Romero X, et al. Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. Int Immunol, 2004, 16(1): 169-177.
23. Vijayakrishnan L, Slavik JM, Illés Z, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity, 2004, 20(5): 563-575.
24. Gerold KD, Zheng P, Rainbow DB, et al. The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. Diabetes, 2011, 60(7): 1955-1963.
25. Kozyrev SV, Abelson AK, Wojcik J, et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet, 2008, 40(2): 211-216.
26. Hitomi Y, Tsuchiya N, Kawasaki A, 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(23): 2907-2917.
27. Sun J, Lai H, Shen D, et al. Reduced sB7-H3 expression in the peripheral blood of systemic lupus erythematosus patients. J Immunol Res, 2017, 2017: 5728512.
28. Chen W, Liu P, Wang Y, et al. Characterization of a soluble B7-H3 (sB7-H3) spliced from the intron and analysis of sB7-H3 in the sera of patients with hepatocellular carcinoma. PLoS One, 2013, 8(10): 1-7.
29. Zhang G, Hou J, Shi J, et al. Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology, 2008, 123(4): 538-546.
30. Hirahara S, Katsumata Y, Kawaguchi Y, et al. 277 usefulness of soluble PD-1 in patients with systemic lupus erythematosus. Lupus Sci Med, 2017, 4: A127.
31. Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene. Cell Immunol, 2005, 235(2): 109-116.
32. Mamegano K, Kuroki K, Miyashita R, et al. Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis. Genes Immun, 2008, 9(3): 214-223.
33. Graham RR, Kozyrev SV, Baechler EC, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet, 2006, 38(5): 550-555.
34. Yang A, Kaghad M, Caput D, et al. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet, 2002, 18(2): 90-95.
35. Unger P, Ewart M, Wang BY, et al. Expression of p63 in papillary thyroid carcinoma and in Hashimoto’s thyroiditis: a pathobiologic link?. Human Pathology, 2003, 34(8): 764-769.
36. Feldkamp J, Pascher E, Schott M, et al. Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease. J Clin Endocrinol Metab, 2001, 86(9): 4250-4253.
37. Cascino I, Fiucci G, Papoff G, et al. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol, 1995, 154(6): 2706-2713.
38. Gu M, Kakoulidou M, Giscombe R, et al. Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis. Clin Immunol, 2008, 128(3): 374-381.
39. Sung HH, Castro I, Gonzalez S, et al. MUC1/SEC and MUC1/Y overexpression is associated with inflammation in Sjögren’s syndrome. Oral Dis, 2015, 21(6): 730-738.
40. Ragusa F, Fallahi P, Elia G, et al. Hashimotos’ thyroiditis: epidemiology, pathogenesis, clinic and therapy. Best Pract Res Clin Endocrinol Metab, 2019, 33(6): 101367.
41. Akatsu C, Shinagawa K, Numoto N, et al. CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J Exp Med, 2016, 213(12): 2691-2706.
42. Jenks SA, Cashman KS, Zumaquero E, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity, 2018, 49(4): 725-739.
43. Hitomi Y, Adachi T, Tsuchiya N, et al. Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum. BMC Immunol, 2012, 13: 72.
44. Dlamini Z, Mokoena F, Hull R. Abnormalities in alternative splicing in diabetes: therapeutic targets. J Mol Endocrinol, 2017, 59(2): R93-R107.
45. Gregory SG, Schmidt S, Seth P, et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet, 2007, 39(9): 1083-1091.
46. Evsyukova I, Bradrick SS, Gregory SG, et al. Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA, 2013, 19(1): 103-115.
47. Prokunina L, Castillejo-López C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet, 2002, 32(4): 666-669.
48. Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens, 2003, 62(6): 492-497.
49. Liu C, Jiang J, Gao L, et al. A Promoter region polymorphism in PDCD-1 gene is associated with risk of rheumatoid arthritis in the Han Chinese population of southeastern China. Int J Genomics, 2014, 2014: 247637.
50. Szolnoki Z, Kondacs A, Mandi Y, et al. A cytoskeleton motor protein genetic variant may exert a protective effect on the occurrence of multiple sclerosis: the janus face of the kinesin light-chain 1 56836CC genetic variant. Neuromolecular Med, 2007, 9(4): 335-339.
51. Pérez-Sánchez C, Aguirre MA, Pedraza-Arévalo S, et al. AB0128 alterations of the splicing machinery components in leukocytes from patients with systemic lupus erythematosus influences its development and atherothrombotic profile and drives the therapeutic response. Ann Rheum Dis, 2017, 76(Suppl 2): 1091-1092.
52. Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A, 2001, 98(24): 13866-13871.
53. Xerri L, Devilard E, Hassoun J, et al. Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol, 1997, 50(2): 87-91.
54. Cheng J, Zhou T, Liu C, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science, 1994, 263(5154): 1759-1762.
55. Compston A, Coles A. Multiple sclerosis. Lancet, 2008, 372(9648): 1502-1517.
56. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol, 2015, 15(9): 545-558.
57. Petry KG, Boullerne AI, Pousset F, et al. Experimental allergic encephalomyelitis animal models for analyzing features of multiple sclerosis. Pathol Biol (Paris), 2000, 48(1): 47-53.
58. Steinman L. Multiple sclerosis. Presenting an odd autoantigen. Nature, 1995, 375(6534): 739-740.
59. Castro I, Albornoz N, Aguilera S, et al. Aberrant MUC1 accumulation in salivary glands of Sjögren’s syndrome patients is reversed by TUDCA in vitro. Rheumatology (Oxford), 2020, 59(4): 742-753.

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