Skip to main content

Advertisement

SpringerLink
Log in

Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases

  • Review
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

There are more than 80 kinds of autoimmune diseases known at present, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), as well as other disorders. Autoimmune diseases have a characteristic of immune responses directly attacking own tissues, leading to systematic inflammation and subsequent tissue damage. B cells play a vital role in the development of autoimmune diseases and differentiate into plasma cells or memory B cells to secrete high-affinity antibody or provide long-lasting function. Drugs targeting B cells show good therapeutic effects for the treatment of autoimmune diseases, such as rituximab (anti-CD20 antibody). Src family protein kinases (SFKs) are believed to play important roles in a variety of cellular functions such as growth, proliferation, and differentiation of B cell via B cell antigen receptor (BCR). Lck/Yes-related novel protein tyrosine kinase (LYN), BLK (B lymphocyte kinase), and Fyn are three different kinds of SFKs mainly expressed in B cells. LYN has a dual role in the BCR signal. On the one hand, positive signals are beneficial to the development and maturation of B cells. On the other hand, LYN can also inhibit excessively activated B cells. BLK is involved in the proliferation, differentiation, and immune tolerance of B lymphocytes, and further affects the function of B cells, which may lead to autoreactive or regulatory cellular responses, increasing the risk of autoimmune diseases. Fyn may affect the development of autoimmune disorders via the differentiation of B cells in the early stage of B cell development. This article reviews the recent advances of SFKs in B lymphocytes in autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Sharif, K., A. Watad, N.L. Bragazzi, M. Lichtbroun, H. Amital, and Y. Shoenfeld. 2018. Physical activity and autoimmune diseases: get moving and manage the disease. Autoimmunity Reviews 17: 53–72. https://doi.org/10.1016/j.autrev.2017.11.010.

    Article  PubMed  CAS  Google Scholar 

  2. Deng YN, Bellanti JA, Zheng SG. 2019. Essential kinases and transcriptional regulators and their roles in autoimmunity. Biomolecules 9(4). https://doi.org/10.3390/biom9040145.

  3. Yin, H., H. Wu, Y. Chen, J. Zhang, M. Zheng, G. Chen, L. Li, and Q. Lu. 2018. The therapeutic and pathogenic role of autophagy in autoimmune diseases. Frontiers in Immunology 9: 1512. https://doi.org/10.3389/fimmu.2018.01512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Shen, H.H., Y.X. Yang, X. Meng, X.Y. Luo, X.M. Li, Z.W. Shuai, D.Q. Ye, and H.F. Pan. 2018. NLRP3: a promising therapeutic target for autoimmune diseases. Autoimmunity Reviews 17 (7): 694–702. https://doi.org/10.1016/j.autrev.2018.01.020.

    Article  PubMed  CAS  Google Scholar 

  5. Gill, R., M.J. McCabe Jr., and A.J. Rosenspire. 2017. Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells. Toxicology and Applied Pharmacology 330: 22–29. https://doi.org/10.1016/j.taap.2017.06.022.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Takemura, S., P.A. Klimiuk, A. Braun, J.J. Goronzy, and C.M. Weyand. 2001. T cell activation in rheumatoid synovium is B cell dependent. Journal of Immunology 167: 4710–4718. https://doi.org/10.4049/jimmunol.167.8.4710.

    Article  CAS  Google Scholar 

  7. Yao, Y., N. Wang, C.L. Chen, L. Pan, Z.C. Wang, J. Yunis, Z.A. Chen, Y. Zhang, S.T. Hu, X.Y. Xu, R.F. Zhu, D. Yu, and Z. Liu. 2020. CD23 expression on switched memory B cells bridges T-B cell interaction in allergic rhinitis. Allergy. https://doi.org/10.1111/all.14288.10.1111/all.14288.

  8. Bugatti, S., B. Vitolo, R. Caporali, C. Montecucco, and A. Manzo. 2014. B cells in rheumatoid arthritis: from pathogenic players to disease biomarkers. BioMed Research International 2014: 681678–681614. https://doi.org/10.1155/2014/681678.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gauld, S.B., and J.C. Cambier. 2004. Src-family kinases in B-cell development and signaling. Oncogene 23: 8001–8006. https://doi.org/10.1038/sj.onc.1208075.

    Article  PubMed  CAS  Google Scholar 

  10. Shao, W.H., and P.L. Cohen. 2014. The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets. Expert Review of Clinical Immunology 10: 573–582. https://doi.org/10.1586/1744666X.2014.893827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Okada, M. 2012. Regulation of the SRC family kinases by Csk. International Journal of Biological Sciences 8: 1385–1397. https://doi.org/10.7150/ijbs.5141.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Huang, R., P. Fang, and B.K. Kay. 2012. Isolation of monobodies that bind specifically to the SH3 domain of the Fyn tyrosine protein kinase. New Biotechnology 29: 526–533. https://doi.org/10.1016/j.nbt.2011.11.015.

    Article  PubMed  CAS  Google Scholar 

  13. Boggon, T.J., and M.J. Eck. 2004. Structure and regulation of Src family kinases. Oncogene 23: 7918–7927. https://doi.org/10.1038/sj.onc.1208081.

    Article  PubMed  CAS  Google Scholar 

  14. Liossis, S.N., E.E. Solomou, M.A. Dimopoulos, P. Panayiotidis, M.M. Mavrikakis, and P.P. Sfikakis. 2001. B-cell kinase lyn deficiency in patients with systemic lupus erythematosus. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 49: 157–165. https://doi.org/10.2310/6650.2001.34042.

    Article  CAS  Google Scholar 

  15. Pleiman, C., M. Clark, L. Gauen, S. Winitz, K. Coggeshall, G. Johnson, et al. 1993. Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p56lyn which interact with the effector molecules phospholipase C-gamma 2, microtubule-associated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase. Molecular and Cellular Biology 13: 5877–5887. https://doi.org/10.1128/mcb.13.9.5877.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kurosaki, T., and M. Hikida. 2009. Tyrosine kinases and their substrates in B lymphocytes. Immunological Reviews 228: 132–148. https://doi.org/10.1111/j.1600-065X.2008.00748.x.

    Article  PubMed  CAS  Google Scholar 

  17. Chaimowitz, N.S., Y.T. Falanga, J.J. Ryan, and D.H. Conrad. 2013. Fyn kinase is required for optimal humoral responses. PLoS One 8 (4): e60640. https://doi.org/10.1371/journal.pone.0060640.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu, W., A. Doshi, M. Lei, M.J. Eck, and S.C. Harrison. 1999. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Molecular Cell 3: 629–638. https://doi.org/10.1016/s1097-2765(00)80356-1.

    Article  PubMed  CAS  Google Scholar 

  19. Luciano, F., J. Ricci, and P. Auberger. 2001. Cleavage of Fyn and Lyn in their N-terminal unique regions during induction of apoptosis: a new mechanism for Src kinase regulation. Oncogene 20: 4935–4941. https://doi.org/10.1038/sj.onc.1204661.

    Article  PubMed  CAS  Google Scholar 

  20. Jin, L.L., L.E. Wybenga-Groot, J. Tong, P. Taylor, M.D. Minden, S. Trudel, C.J. McGlade, and M.F. Moran. 2015. Tyrosine phosphorylation of the Lyn Src homology 2 (SH2) domain modulates its binding affinity and specificity. Molecular & cellular proteomics : MCP 14: 695–706. https://doi.org/10.1074/mcp.M114.044404.

    Article  PubMed  CAS  Google Scholar 

  21. Volkmann, C., N. Brings, M. Becker, E. Hobeika, J. Yang, and M. Reth. 2016. Molecular requirements of the B-cell antigen receptor for sensing monovalent antigens. The EMBO journal 35: 2371–2381. https://doi.org/10.15252/embj.201694177.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. DeFranco, A.L. 2018. Multilayer control of B cell activation by the B cell antigen receptor: following themes initiated with Bill Paul. Frontiers in Immunology 9: 739. https://doi.org/10.3389/fimmu.2018.00739.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Rawlings, D.J., G. Metzler, M. Wray-Dutra, and S.W. Jackson. 2017. Altered B cell signalling in autoimmunity. Nature Reviews. Immunology 17: 421–436. https://doi.org/10.1038/nri.2017.24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Gauld, S.B., J.M. Dal Porto, and J.C. Cambier. 2002. B cell antigen receptor signaling: roles in cell development and disease. Science 296: 1641–1642. https://doi.org/10.1126/science.1071546.

    Article  PubMed  CAS  Google Scholar 

  25. Packard, T.A., and J.C. Cambier. 2013. B lymphocyte antigen receptor signaling: Initiation, amplification, and regulation. F1000Prime Reports 5: 40. https://doi.org/10.12703/P5-40.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xu, Y., N.D. Huntington, K.W. Harder, H. Nandurkar, M.L. Hibbs, and D.M. Tarlinton. 2012. Phosphatidylinositol-3 kinase activity in B cells is negatively regulated by Lyn tyrosine kinase. Immunology and Cell Biology 90: 903–911. https://doi.org/10.1038/icb.2012.31.

    Article  PubMed  CAS  Google Scholar 

  27. Liubchenko, G.A., H.C. Appleberry, C.C. Striebich, K.E. Franklin, L.A. Derber, V.M. Holers, and T. Lyubchenko. 2013. Rheumatoid arthritis is associated with signaling alterations in naturally occurring autoreactive B-lymphocytes. Journal of Autoimmunity 40: 111–121. https://doi.org/10.1016/j.jaut.2012.09.001.

    Article  PubMed  CAS  Google Scholar 

  28. Fleischer, S.J., C. Daridon, V. Fleischer, P.E. Lipsky, and T. Dorner. 2016. Enhanced tyrosine phosphatase activity underlies dysregulated B cell receptor signaling and promotes survival of human lupus B cells. Arthritis & rheumatology 68: 1210–1221. https://doi.org/10.1002/art.39559.

    Article  CAS  Google Scholar 

  29. Kulathu, Y., C. Zuern, J. Yang, and M. Reth. 2019. Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach. Biological Chemistry 400: 555–563. https://doi.org/10.1515/hsz-2018-0308.

    Article  PubMed  CAS  Google Scholar 

  30. Mkaddem, S.B., A. Murua, H. Flament, D. Titecabeauport, C. Bounaix, L. Danelli, et al. 2017. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nature Communications 8: 246. https://doi.org/10.1038/s41467-017-00294-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Schlessinger, J. 2000. New roles for Src kinases in control of cell survival and angiogenesis. Cell 100: 293–296. https://doi.org/10.1016/s0092-8674(00)80664-9.

    Article  PubMed  CAS  Google Scholar 

  32. Corey, S.J., and S.M. Anderson. 1999. Src-related protein tyrosine kinases in hematopoiesis. Blood 93: 1–14. https://doi.org/10.1007/s002770050472.

    Article  PubMed  CAS  Google Scholar 

  33. Hibbs, M.L., D.M. Tarlinton, J. Armes, D. Grail, G. Hodgson, R. Maglitto, S.A. Stacker, and A.R. Dunn. 1995. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83: 301–311. https://doi.org/10.1016/0092-8674(95)90171-X.

    Article  PubMed  CAS  Google Scholar 

  34. Uhlen, M., L. Fagerberg, B.M. Hallstrom, C. Lindskog, P. Oksvold, A. Mardinoglu, et al. 2015. Proteomics. Tissue-based map of the human proteome. Science 347: 1260419. https://doi.org/10.1126/science.1260419.

    Article  PubMed  CAS  Google Scholar 

  35. Zheng, J., H. Li, D. Xu, and H. Zhu. 2017. Upregulation of tyrosine kinase FYN in human thyroid carcinoma: role in modulating tumor cell proliferation, invasion, and migration. Cancer Biotherapy & Radiopharmaceuticals 32: 320–326. https://doi.org/10.1089/cbr.2017.2218.

    Article  CAS  Google Scholar 

  36. Barua, D., W.S. Hlavacek, and T. Lipniacki. 2012. A computational model for early events in B cell antigen receptor signaling: analysis of the roles of Lyn and Fyn. Journal of Immunology 189: 646–658. https://doi.org/10.4049/jimmunol.1102003.

    Article  CAS  Google Scholar 

  37. Nguyen, P.H., O. Fedorchenko, N. Rosen, M. Koch, R. Barthel, T. Winarski, et al. 2016. LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia. Cancer Cell 30: 610–622. https://doi.org/10.1016/j.ccell.2016.09.007.

    Article  PubMed  CAS  Google Scholar 

  38. Scapini, P., S. Pereira, H. Zhang, and C.A. Lowell. 2009. Multiple roles of Lyn kinase in myeloid cell signaling and function. Immunological reviews 228: 23–40. https://doi.org/10.1111/j.1600-065X.2008.00758.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Melissaropoulos, K., and S.N. Liossis. 2018. Decreased CD22 expression and intracellular signaling aberrations in B cells of patients with systemic sclerosis. Rheumatology International 38: 1225–1234. https://doi.org/10.1007/s00296-018-4076-3.

    Article  PubMed  CAS  Google Scholar 

  40. Nguyen, P.H., E. Niesen, and M. Hallek. 2019. New roles for B cell receptor associated kinases: when the B cell is not the target. Leukemia 33: 576–587. https://doi.org/10.1038/s41375-018-0366-8.

    Article  PubMed  CAS  Google Scholar 

  41. Fujimoto, M., Y. Fujimoto, J.C. Poe, P.J. Jansen, C.A. Lowell, A.L. Defranco, et al. 2000. CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 13: 47–57. https://doi.org/10.1016/s1074-7613(00)00007-8.

    Article  PubMed  CAS  Google Scholar 

  42. Dong, S., and J.C. Byrd. 2016. A new role for Lyn in the CLL microenvironment. Cancer Cell 30: 511–512. https://doi.org/10.1016/j.ccell.2016.09.018.

    Article  PubMed  CAS  Google Scholar 

  43. You, M., G. Dong, F. Li, F. Ma, J. Ren, Y. Xu, H. Yue, R. Tang, D. Ren, and Y. Hou. 2017. Ligation of CD180 inhibits IFN-alpha signaling in a Lyn-PI3K-BTK-dependent manner in B cells. Cellular & Molecular Immunology 14: 192–202. https://doi.org/10.1038/cmi.2015.61.

    Article  CAS  Google Scholar 

  44. Franks, S.E., and J.C. Cambier. 2018. Putting on the brakes: regulatory kinases and phosphatases maintaining B cell anergy. Frontiers in Immunology 9: 665. https://doi.org/10.3389/fimmu.2018.00665.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Xu, Y., K.W. Harder, N.D. Huntington, M.L. Hibbs, and D.M. Tarlinton. 2005. Lyn tyrosine kinase: accentuating the positive and the negative. Immunity 22: 9–18. https://doi.org/10.1016/j.immuni.2004.12.004.

    Article  PubMed  CAS  Google Scholar 

  46. Lamagna, C., Y. Hu, A.L. DeFranco, and C.A. Lowell. 2014. B cell-specific loss of Lyn kinase leads to autoimmunity. Journal of Immunology 192: 919–928. https://doi.org/10.4049/jimmunol.1301979.

    Article  CAS  Google Scholar 

  47. Ono, M., H. Okada, S. Bolland, S. Yanagi, T. Kurosaki, and J.V. Ravetch. 1997. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90: 293–301. https://doi.org/10.1016/s0092-8674(00)80337-2.

    Article  PubMed  CAS  Google Scholar 

  48. Getahun, A., N.A. Beavers, S.R. Larson, M.J. Shlomchik, and J.C. Cambier. 2016. Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. Journal of Experimental Medicine 213: 751–769. https://doi.org/10.1084/jem.20150537.

    Article  CAS  Google Scholar 

  49. Nunes de Miranda, S.M., T. Wilhelm, M. Huber, and C.N. Zorn. 2016. Differential Lyn-dependence of the SHIP1-deficient mast cell phenotype. Cell communication and signaling 14 (1): 12. https://doi.org/10.1186/s12964-016-0135-0.

    Article  PubMed  CAS  Google Scholar 

  50. Simpfendorfer, K.R., L.M. Olsson, N. Manjarrez Orduno, H. Khalili, A.M. Simeone, M.S. Katz, et al. 2012. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Human Molecular Genetics 21: 3918–3925. https://doi.org/10.1093/hmg/dds220.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hernandez-Hansen, V., A.J. Smith, Z. Surviladze, A. Chigaev, T. Mazel, J. Kalesnikoff, C.A. Lowell, G. Krystal, L.A. Sklar, B.S. Wilson, and J.M. Oliver. 2004. Dysregulated fc RI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells. The Journal of Immunology 173: 100–112. https://doi.org/10.4049/jimmunol.173.1.100.

    Article  PubMed  CAS  Google Scholar 

  52. Wennstrom, S., and J. Downward. 1999. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Molecular and Cellular Biology 19: 4279–4288. https://doi.org/10.1128/mcb.19.6.4279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Nishizumi, H., I. Taniuchi, Y. Yamanashi, D. Kitamura, D. Ilic, S. Mori, T. Watanabe, and T. Yamamoto. 1995. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3: 549–560. https://doi.org/10.1016/1074-7613(95)90126-4.

    Article  PubMed  CAS  Google Scholar 

  54. Pore, D., E. Huang, D. Dejanovic, N. Parameswaran, M.B. Cheung, and N. Gupta. 2018. Cutting edge: deletion of Ezrin in B cells of Lyn-deficient mice downregulates lupus pathology. Journal of Immunology 201: 1353–1358. https://doi.org/10.4049/jimmunol.1800168.

    Article  CAS  Google Scholar 

  55. Mayeux, J., B. Skaug, W. Luo, L.M. Russell, S. John, P. Saelee, H. Abbasi, Q.Z. Li, L.A. Garrett-Sinha, and A.B. Satterthwaite. 2015. Genetic interaction between Lyn, Ets1, and Btk in the control of antibody levels. Journal of Immunology 195: 1955–1963. https://doi.org/10.4049/jimmunol.1500165.

    Article  CAS  Google Scholar 

  56. Infantino, S., S.A. Jones, J.A. Walker, M.J. Maxwell, A. Light, K. O'Donnell, et al. 2014. The tyrosine kinase Lyn limits the cytokine responsiveness of plasma cells to restrict their accumulation in mice. Science signaling 7 (338): ra77. https://doi.org/10.1126/scisignal.2005105.

    Article  PubMed  CAS  Google Scholar 

  57. Lamagna, C., P. Scapini, J.A. van Ziffle, A.L. DeFranco, and C.A. Lowell. 2013. Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proceedings of the National Academy of Sciences of the United States of America 110: E3311–E3320. https://doi.org/10.1073/pnas.1300617110.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hua, Z., A.J. Gross, C. Lamagna, N. Ramos-Hernandez, P. Scapini, M. Ji, et al. 2014. Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. Journal of Immunology 192: 875–885. https://doi.org/10.4049/jimmunol.1300683.

    Article  CAS  Google Scholar 

  59. Smith, K.G., D.M. Tarlinton, G.M. Doody, M.L. Hibbs, and D.T. Fearon. 1998. Inhibition of the B cell by CD22: a requirement for Lyn. Journal of Experimental Medicine 187: 807–811. https://doi.org/10.1084/jem.187.5.807.

    Article  CAS  Google Scholar 

  60. Cheng, D., M. Deobagkar-Lele, E. Zvezdova, S. Choi, S. Uehara, D. Baup, S.C. Bennett, K.R. Bull, T.L. Crockford, H. Ferry, C. Warzecha, M. Marcellin, A.G. de Peredo, R. Lesourne, C. Anzilotti, P.E. Love, and R.J. Cornall. 2017. Themis2 lowers the threshold for B cell activation during positive selection. Nature Immunology 18: 205–213. https://doi.org/10.1038/ni.3642.

    Article  PubMed  CAS  Google Scholar 

  61. Janas, M.L., P. Hodgkin, M. Hibbs, and D. Tarlinton. 1999. Genetic evidence for Lyn as a negative regulator of IL-4 signaling. Journal of Immunology 163: 4192–4210. https://doi.org/10.1016/S0162-3109(99)00091-0.

    Article  CAS  Google Scholar 

  62. Sefton, B.M., and J.A. Taddie. 1994. Role of tyrosine kinases in lymphocyte activation. Current Opinion in Immunology 6: 372–379. https://doi.org/10.1016/0952-7915(94)90115-5.

    Article  PubMed  CAS  Google Scholar 

  63. Texido, G., I.H. Su, I. Mecklenbrauker, K. Saijo, S.N. Malek, S. Desiderio, et al. 2000. The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Molecular and Cellular Biology 20: 1227–1233. https://doi.org/10.1128/mcb.20.4.1227-1233.2000.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Harley, J.B., M.E. Alarcón-Riquelme, L.A. Criswell, C.O. Jacob, R.P. Kimberly, K.L. Moser, et al. 2008. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nature Genetics 40 (2): 204–210. https://doi.org/10.1038/ng.81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Castillejo-Lopez, C., A.M. Delgado-Vega, J. Wojcik, S.V. Kozyrev, E. Thavathiru, Y.Y. Wu, et al. 2012. Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Annals of the Rheumatic Diseases 71: 136–142. https://doi.org/10.1136/annrheumdis-2011-200085.

    Article  PubMed  CAS  Google Scholar 

  66. Kim, J.E., J.H. Kim, Y. Lee, H. Yang, Y.S. Heo, A.M. Bode, et al. 2016. Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase. Oncotarget 7: 14616–14627. https://doi.org/10.18632/oncotarget.7524.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zhang, H., L. Wang, Y. Huang, C. Zhuang, G. Zhao, R. Liu, and Y. Wang. 2012. Influence of BLK polymorphisms on the risk of rheumatoid arthritis. Molecular Biology Reports 39: 9965–9970. https://doi.org/10.1007/s11033-012-1865-8.

    Article  PubMed  CAS  Google Scholar 

  68. Chen, Y., Q. Wu, Y. Shao, J. Zhang, M. Guan, J. Wan, B. Yu, and W. Zhang. 2012. Identify the association between polymorphisms of BLK and systemic lupus erythematosus through unlabelled probe-based high-resolution melting analysis. International Journal of Immunogenetics 39: 321–327. https://doi.org/10.1111/j.1744-313X.2012.01094.x.

    Article  PubMed  CAS  Google Scholar 

  69. Jiang, S.H., V. Athanasopoulos, J.I. Ellyard, A. Chuah, J. Cappello, A. Cook, S.B. Prabhu, J. Cardenas, J. Gu, M. Stanley, J.A. Roco, I. Papa, M. Yabas, G.D. Walters, G. Burgio, K. McKeon, J.M. Byers, C. Burrin, A. Enders, L.A. Miosge, P.F. Canete, M. Jelusic, V. Tasic, A.C. Lungu, S.I. Alexander, A.R. Kitching, D.A. Fulcher, N. Shen, T. Arsov, P.A. Gatenby, J.J. Babon, D.F. Mallon, C. de Lucas Collantes, E.A. Stone, P. Wu, M.A. Field, T.D. Andrews, E. Cho, V. Pascual, M.C. Cook, and C.G. Vinuesa. 2019. Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nature Communications 10: 2201. https://doi.org/10.1038/s41467-019-10242-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Freudenberg, J., H.S. Lee, B.G. Han, H.D. Shin, Y.M. Kang, Y.K. Sung, S.C. Shim, C.B. Choi, A.T. Lee, P.K. Gregersen, and S.C. Bae. 2011. Genome-wide association study of rheumatoid arthritis in Koreans: population-specific loci as well as overlap with European susceptibility loci. Arthritis and Rheumatism 63: 884–893. https://doi.org/10.1002/art.30235.

    Article  PubMed  CAS  Google Scholar 

  71. Huang, H., S.C. Huang, D.J. Hua, Q.Q. Sun, H. Cen, and X.F. Xin. 2017. Interaction analysis between BLK rs13277113 polymorphism and BANK1 rs3733197 polymorphism, MMEL1/TNFRSF14 rs3890745 polymorphism in determining susceptibility to rheumatoid arthritis. Autoimmunity 50: 403–408. https://doi.org/10.1080/08916934.2017.1377191.

    Article  PubMed  Google Scholar 

  72. Mahoney, J.M., J. Taroni, V. Martyanov, T.A. Wood, C.S. Greene, P.A. Pioli, M.E. Hinchcliff, and M.L. Whitfield. 2015. Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Computational Biology 11: e1004005. https://doi.org/10.1371/journal.pcbi.1004005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Burbelo, P.D., K. Ambatipudi, and I. Alevizos. 2014. Genome-wide association studies in Sjogren’s syndrome: what do the genes tell us about disease pathogenesis? Autoimmunity Reviews 13: 756–761. https://doi.org/10.1016/j.autrev.2014.02.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Miller, F.W., R.G. Cooper, J. Vencovsky, L.G. Rider, K. Danko, L.R. Wedderburn, et al. 2013. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis and Rheumatism 65: 3239–3247. https://doi.org/10.1002/art.38137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Simpfendorfer, K.R., B.E. Armstead, A. Shih, W. Li, M. Curran, N. Manjarrez-Orduno, et al. 2015. Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. Arthritis & rheumatology 67: 2866–2876. https://doi.org/10.1002/art.39301.

    Article  CAS  Google Scholar 

  76. Malkiel, S., A.N. Barlev, Y. Atisha-Fregoso, J. Suurmond, and B. Diamond. 2018. Plasma cell differentiation pathways in systemic lupus erythematosus. Frontiers in Immunology 9: 427. https://doi.org/10.3389/fimmu.2018.00427.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Hemon, P., Y. Renaudineau, M. Debant, N. Le Goux, S. Mukherjee, W. Brooks, et al. 2017. Calcium signaling: from normal B cell development to tolerance breakdown and autoimmunity. Clinical Reviews in Allergy & Immunology 53: 141–165. https://doi.org/10.1007/s12016-017-8607-6.

    Article  CAS  Google Scholar 

  78. Delgado-Vega, A.M., M.G. Dozmorov, M.B. Quiros, Y.Y. Wu, B. Martinez-Garcia, S.V. Kozyrev, et al. 2012. Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein. Annals of the Rheumatic Diseases 71: 1219–1226. https://doi.org/10.1136/annrheumdis-2011-200987.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Zhou, Y., X. Li, G. Wang, and X. Li. 2016. Association of FAM167A-BLK rs2736340 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Immunological Investigations 45: 336–348. https://doi.org/10.3109/08820139.2016.1157812.

    Article  PubMed  CAS  Google Scholar 

  80. Zeng, C., C. Fang, H. Weng, X. Xu, T. Wu, and W. Li. 2017. B-cell lymphocyte kinase polymorphisms rs13277113, rs2736340, and rs4840568 and risk of autoimmune diseases: a meta-analysis. Medicine 96: e7855. https://doi.org/10.1097/MD.0000000000007855.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Chen, S., W. Wu, J. Li, Q. Wang, Y. Li, Z. Wu, et al. 2015. Single nucleotide polymorphisms in the FAM167A-BLK gene are associated with polymyositis/dermatomyositis in the Han Chinese population. Immunology Research 62: 153–162. https://doi.org/10.1007/s12026-015-8646-0.

    Article  CAS  Google Scholar 

  82. Zhang, Z., K.J. Zhu, Q. Xu, X.J. Zhang, L.D. Sun, H.F. Zheng, J.W. Han, C. Quan, S.Q. Zhang, L.Q. Cai, S.X. Xu, X.B. Zuo, H. Cheng, and S. Yang. 2010. The association of the BLK gene with SLE was replicated in Chinese Han. Archives of Dermatological Research 302: 619–624. https://doi.org/10.1007/s00403-010-1029-4.

    Article  PubMed  CAS  Google Scholar 

  83. Guthridge, J.M., R. Lu, H. Sun, C. Sun, G.B. Wiley, N. Dominguez, S.R. Macwana, C.J. Lessard, X. Kim-Howard, B.L. Cobb, K.M. Kaufman, J.A. Kelly, C.D. Langefeld, A.J. Adler, I.T.W. Harley, J.T. Merrill, G.S. Gilkeson, D.L. Kamen, T.B. Niewold, E.E. Brown, J.C. Edberg, M.A. Petri, R. Ramsey-Goldman, J.D. Reveille, L.M. Vilá, R.P. Kimberly, B.I. Freedman, A.M. Stevens, S.A. Boackle, L.A. Criswell, T.J. Vyse, T.W. Behrens, C.O. Jacob, M.E. Alarcón-Riquelme, K.L. Sivils, J. Choi, Y.B. Joo, S.Y. Bang, H.S. Lee, S.C. Bae, N. Shen, X. Qian, B.P. Tsao, R.H. Scofield, J.B. Harley, C.F. Webb, E.K. Wakeland, J.A. James, S.K. Nath, R.R. Graham, and P.M. Gaffney. 2014. Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. American Journal of Human Genetics 94: 586–598. https://doi.org/10.1016/j.ajhg.2014.03.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Laird, R.M., K. Laky, and S.M. Hayes. 2010. Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing gammadelta T cells. Journal of Immunology 185: 6518–6527. https://doi.org/10.4049/jimmunol.1002766.

    Article  CAS  Google Scholar 

  85. Samuelson, E.M., R.M. Laird, A.C. Maue, R. Rochford, and S.M. Hayes. 2012. Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunology and Cell Biology 90: 620–629. https://doi.org/10.1038/icb.2011.76.

    Article  PubMed  CAS  Google Scholar 

  86. Wu, Y.Y., I. Georg, A. Diaz-Barreiro, N. Varela, B. Lauwerys, R. Kumar, et al. 2015. Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels. Journal of Immunology 194: 5692–5702. https://doi.org/10.4049/jimmunol.1402736.

    Article  CAS  Google Scholar 

  87. Zhou, X.J., X.L. Lu, S.K. Nath, J.C. Lv, S.N. Zhu, H.Z. Yang, L.X. Qin, M.H. Zhao, Y. Su, International Consortium on the Genetics of Systemic Lupus Erythematosus, N. Shen, Z.G. Li, and H. Zhang. 2012. Gene-gene interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in systemic lupus erythematosus. Arthritis and Rheumatism 64 (1): 222–231. https://doi.org/10.1002/art.33318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Manjarrez-Orduno, N., E. Marasco, S.A. Chung, M.S. Katz, J.F. Kiridly, K.R. Simpfendorfer, et al. 2012. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nature Genetics 44: 1227–1230. https://doi.org/10.1038/ng.2439.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Dallari, S., M. Macal, M.E. Loureiro, Y. Jo, L. Swanson, C. Hesser, P. Ghosh, and E.I. Zuniga. 2017. Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses. Nature Communications 8: 14830. https://doi.org/10.1038/ncomms14830.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Iwabuchi, N., Y. Wu, P.N. Hai, E. Ido, J. Kang, J.B. Bolen, et al. 1996. Expression of exogenous p59 fyn modulates signaling in an immature B cell line, WEHI-231. Immunology Letters 51: 181–185. https://doi.org/10.1016/0165-2478(96)02575-8.

    Article  PubMed  CAS  Google Scholar 

  91. Yasunaga, M., T. Yagi, N. Hanzawa, M. Yasuda, Y. Yamanashi, T. Yamamoto, S. Aizawa, Y. Miyauchi, and S. Nishikawa. 1996. Involvement of Fyn tyrosine kinase in progression of cytokinesis of B lymphocyte progenitor. The Journal of Cell Biology 132: 91–99. https://doi.org/10.1083/jcb.132.1.91.

    Article  PubMed  CAS  Google Scholar 

  92. Rongish, B.J., and W.H. Kinsey. 2000. Transient nuclear localization of Fyn kinase during development in zebrafish. The Anatomical Record 260: 115–123. https://doi.org/10.1002/1097-0185(20001001)260:2<115::AID-AR10>3.0.CO;2-C.

    Article  PubMed  CAS  Google Scholar 

  93. Battistello, E., N. Katanayeva, E. Dheilly, D. Tavernari, M.C. Donaldson, L. Bonsignore, M. Thome, A.L. Christie, M.A. Murakami, O. Michielin, G. Ciriello, V. Zoete, and E. Oricchio. 2018. Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma. Blood 131: 2345–2356. https://doi.org/10.1182/blood-2017-10-809210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. King, C. 2009. New insights into the differentiation and function of T follicular helper cells. Nature Reviews. Immunology 9: 757–766. https://doi.org/10.1038/nri2644.

    Article  PubMed  CAS  Google Scholar 

  95. Isharat, Y., K. Robin, M. Laurel, R.J. Johnston, D. Daniel, H. Kyle, et al. 2010. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). Journal of Immunology 185: 190–202. https://doi.org/10.4049/jimmunol.0903505.

    Article  CAS  Google Scholar 

  96. Chan, B., A. Lanyi, H.K. Song, J. Griesbach, M. Simarro-Grande, F. Poy, D. Howie, J. Sumegi, C. Terhorst, and M.J. Eck. 2003. SAP couples Fyn to SLAM immune receptors. Nature Cell Biology 5: 155–160. https://doi.org/10.1038/ncb920.

    Article  PubMed  CAS  Google Scholar 

  97. Rodriguez-Alba, J.C., M.E. Moreno-Garcia, C. Sandoval-Montes, V.H. Rosales-Garcia, and L. Santos-Argumedo. 2008. CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen. Blood 111: 3644–3652. https://doi.org/10.1182/blood-2007-08-107714.

    Article  PubMed  CAS  Google Scholar 

  98. Masato, OJIJoBS. 2012. Regulation of the Src family kinases by Csk. International Journal of Biological Sciences 8 (10): 1385–1397. https://doi.org/10.7150/ijbs.5141.

    Article  CAS  Google Scholar 

  99. Cannons, J.L., L.J. Yu, D. Jankovic, S. Crotty, R. Horai, M. Kirby, S. Anderson, A.W. Cheever, A. Sher, and P.L. Schwartzberg. 2006. SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. The Journal of Experimental Medicine 203: 1551–1565. https://doi.org/10.1084/jem.20052097.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Fernàndez-Martínez, J., M. Zacchini, and I. Fleck. 1999. Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling. International Immunology 11: 1441–1449. https://doi.org/10.1093/intimm/11.9.1441.

    Article  Google Scholar 

  101. Kuiper, R.P., E.F. Schoenmakers, S.V. van Reijmersdal, J.Y. Hehir-Kwa, A.G. van Kessel, F.N. van Leeuwen, et al. 2007. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 21: 1258–1266. https://doi.org/10.1038/sj.leu.2404691.

    Article  PubMed  CAS  Google Scholar 

  102. Curtiss, M.L., B.S. Hostager, E. Stepniak, M. Singh, N. Manhica, J. Knisz, et al. 2011. Fyn binds to and phosphorylates T cell immunoglobulin and mucin domain-1 (Tim-1). Molecular immunology 48: 1424–1431. https://doi.org/10.1016/j.molimm.2011.03.023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Cardone, M.H. 1998. Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318–1321. https://doi.org/10.1126/science.282.5392.1318.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study was funded by the National Natural Science Foundation of China (No. U1803129, 81473223, and 81673444).

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui Province, China

    Xianzheng Zhang, Dan Mei, Lingling Zhang & Wei Wei

Authors
  1. Xianzheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZX and MD participated in the design of the manuscript and contributed to making figures and tables. ZL and WW contributed in revision. All authors contributed equally to this work and approved the final manuscript.

Corresponding authors

Correspondence to Lingling Zhang or Wei Wei.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Mei, D., Zhang, L. et al. Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases. Inflammation 44, 423–433 (2021). https://doi.org/10.1007/s10753-020-01355-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01355-1

KEY WORDS

Search

Navigation