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  • Review Article
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The role of semaphorins in immune responses and autoimmune rheumatic diseases

Key Points

  • Semaphorins have important roles in regulating various responses of the immune system.

  • Semaphorins are associated with the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

  • Semaphorins show promise as diagnostic markers and/or therapeutic targets for the treatment of rheumatic diseases.

Abstract

Semaphorins have a well-characterized role in guiding axon repulsion during development; however, the important contribution of these proteins in immunity is becoming increasingly clear. Immunoregulatory semaphorins, termed 'immune semaphorins', have roles in regulating immune cell activation, differentiation, mobility and migration. These proteins are also intimately associated with the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This Review discusses the pathogenic functions of immune semaphorins, as well as the potential use of these molecules as diagnostic markers and therapeutic targets for the treatment of autoimmune diseases.

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Figure 1: Immune semaphorin and receptor interactions.
Figure 2: The involvement of immune semaphorins in various aspects of immune responses.
Figure 3: The involvement of immune semaphorins in rheumatoid arthritis pathogenesis.
Figure 4: Involvement of SEMA4D in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

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References

  1. Kolodkin, A. L., Matthes, D. J. & Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75, 1389–1399 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Toyofuku, T. et al. Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat. Cell Biol. 6, 1204–1211 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Gu, C. et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307, 265–268 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Casazza, A. et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J. Clin. Invest. 120, 2684–2698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Maione, F. et al. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 119, 3356–3372 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Maione, F. et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin. Invest. 122, 1832–1848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 17, 1473–1480 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Takegahara, N. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat. Cell Biol. 8, 615–622 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Toyofuku, T. et al. Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival. Genes Dev. 26, 816–829 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nojima, S. et al. A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. Nat. Commun. 4, 1406 (2013).

    Article  PubMed  Google Scholar 

  12. Bougeret, C. et al. Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation. J. Immunol. 148, 318–323 (1992).

    CAS  PubMed  Google Scholar 

  13. Kumanogoh, A. et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13, 621–631 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Shi, W. et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13, 633–642 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Kumanogoh, A. et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22, 305–316 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Suzuki, K. et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1 integrin. Nature 446, 680–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Takamatsu, H. et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat. Immunol. 11, 594–600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Suzuki, K., Kumanogoh, A. & Kikutani, H. Semaphorins and their receptors in immune cell interactions. Nat. Immunol. 9, 17–23 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Kumanogoh, A. & Kikutani, H. Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nat. Rev. Immunol. 13, 802–814 (2013).

    Article  PubMed  Google Scholar 

  21. Pasterkamp, R. J. Getting neural circuits into shape with semaphorins. Nat. Rev. Neurosci. 13, 605–618 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Takamatsu, H. & Kumanogoh, A. Diverse roles for semaphorin-plexin signaling in the immune system. Trends Immunol. 33, 127–135 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Tamagnone, L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 22, 145–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Miller, L. E. et al. Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 50, 1156–1163 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Catalano, A. The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J. Immunol. 185, 6373–6383 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Takagawa, S. et al. Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis. BMC Musculoskelet. Disord. 14, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gras, C. et al. Secreted semaphorin 5A activates immune effector cells and is a biomarker for rheumatoid arthritis. Arthritis Rheumatol. 66, 1461–1471 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Chapoval, S. P. Semaphorin 4A as novel regulator and promising therapeutic target in rheumatoid arthritis. Arthritis Res. Ther. 17, 313 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang, L. et al. Expression of Semaphorin 4A and its potential role in rheumatoid arthritis. Arthritis Res. Ther. 17, 227 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yoshida, Y. et al. Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production: pathogenic and therapeutic implications. Arthritis Rheumatol 67, 1481–1490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xie, J. & Wang, H. Semaphorin 7A as a potential immune regulator and promising therapeutic target in rheumatoid arthritis. Arthritis Res. Ther. 19, 10 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nakano, S. et al. Down-regulation of CD72 and increased surface IgG on B cells in patients with lupus nephritis. Autoimmunity 40, 9–15 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Vadasz, Z. et al. The involvement of immune semaphorins and neuropilin-1 in lupus nephritis. Lupus 20, 1466–1473 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Vadasz, Z. & Toubi, E. Semaphorin 3A — a marker for disease activity and a potential putative disease-modifying treatment in systemic lupus erythematosus. Lupus 21, 1266–1270 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Vadasz, Z. et al. A regulatory role for CD72 expression on B cells in systemic lupus erythematosus. Semin. Arthritis Rheum. 43, 767–771 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Vadasz, Z. et al. Increased soluble CD72 in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin. Immunol. 164, 114–118 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Gao, H. et al. Expression and clinical significance of Semaphorin 3A in serum and mononuclear cells in patients with systemic lupus erythematosus [Chinese]. Zhonghua Yi Xue Za Zhi 97, 370–374 (2017).

    CAS  PubMed  Google Scholar 

  38. Gan, Y. et al. Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease. Arthritis Rheum. 63, 2484–2494 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Besliu, A. et al. Peripheral blood lymphocytes analysis detects CD100/SEMA4D alteration in systemic sclerosis patients. Autoimmunity 44, 427–436 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Rimar, D. et al. Semaphorin 3A: an immunoregulator in systemic sclerosis. Rheumatol. Int. 35, 1625–1630 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Nishide, M. et al. Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis. Ann. Rheum. Dis. 76, 1440–1448 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Xie, G. et al. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 65, 2457–2468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mazzotta, C. et al. Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis. Arthritis Res. Ther. 17, 221 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Catalano, A. et al. Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107, 3321–3329 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Yamamoto, M. et al. Plexin-A4 negatively regulates T lymphocyte responses. Int. Immunol. 20, 413–420 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Wen, H., Lei, Y., Eun, S. Y. & Ting, J. P. Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J. Exp. Med. 207, 2943–2957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yamashita, N. et al. Anti-Semaphorin 3A neutralization monoclonal antibody prevents sepsis development in lipopolysaccharide-treated mice. Int. Immunol. 27, 459–466 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Choi, Y. I. et al. PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity 29, 888–898 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Movassagh, H., Shan, L., Mohammed, A., Halayko, A. J. & Gounni, A. S. Semaphorin 3E deficiency exacerbates airway inflammation, hyperresponsiveness, and remodeling in a mouse model of allergic asthma. J. Immunol. 198, 1805–1814 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Movassagh, H. et al. Semaphorin 3E alleviates hallmarks of house dust mite-induced allergic airway disease. Am. J. Pathol. 187, 1566–1576 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Tamagnone, L. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37, 314–325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Delgoffe, G. M. et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501, 252–256 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Peng, H. Y., Gao, W., Chong, F. R., Liu, H. Y. & Zhang, J. I. Semaphorin 4A enhances lung fibrosis through activation of Akt via PlexinD1 receptor. J. Biosci. 40, 855–862 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Toyofuku, T. et al. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. EMBO J. 26, 1373–1384 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rennert, P. D. et al. T cell, Ig domain, mucin domain-2 gene-deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation. J. Immunol. 177, 4311–4321 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Mogie, G. et al. Neuroimmune semaphorin 4A as a drug and drug target for asthma. Int. Immunopharmacol. 17, 568–575 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Nakagawa, Y. et al. Identification of semaphorin 4B as a negative regulator of basophil-mediated immune responses. J. Immunol. 186, 2881–2888 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Ishida, I. et al. Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int. Immunol. 15, 1027–1034 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Oinuma, I., Ishikawa, Y., Katoh, H. & Negishi, M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305, 862–865 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Kumanogoh, A. et al. Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment. Int. Immunol. 17, 1277–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Hall, K. T. et al. Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc. Natl Acad. Sci. USA 93, 11780–11785 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Granziero, L. et al. CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood 101, 1962–1969 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Kumanogoh, A. et al. Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J. Immunol. 169, 1175–1181 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Kataoka, T. R., Kumanogoh, A., Bandara, G., Metcalfe, D. D. & Gilfillan, A. M. CD72 negatively regulates KIT-mediated responses in human mast cells. J. Immunol. 184, 2468–2475 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Goldberg, J. L. et al. An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J. Neurosci. 24, 4989–4999 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sadanandam, A., Rosenbaugh, E. G., Singh, S., Varney, M. & Singh, R. K. Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis. Microvasc. Res. 79, 1–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Matsuoka, R. L. et al. Class 5 transmembrane semaphorins control selective Mammalian retinal lamination and function. Neuron 71, 460–473 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Artigiani, S. et al. Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep. 5, 710–714 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. O'Connor, B. P. et al. Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses. Proc. Natl Acad. Sci. USA 105, 13015–13020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pasterkamp, R. J., Peschon, J. J., Spriggs, M. K. & Kolodkin, A. L. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398–405 (2003).

    Article  PubMed  Google Scholar 

  72. Kong, J. S. et al. Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis. Arthritis Rheum. 62, 179–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Patnaik, A. et al. Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-Semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors. Clin. Cancer Res. 22, 827–836 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. LaGanke, C. et al. Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. Neurol. Neuroimmunol. Neuroinflamm 4, e367 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sierra, J. R. et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J. Exp. Med. 205, 1673–1685 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Evans, E. E., Paris, M., Smith, E. S. & Zauderer, M. Immunomodulation of the tumor microenvironment by neutralization of Semaphorin 4D. Oncoimmunology 4, e1054599 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Van de Velde, H., von Hoegen, I., Luo, W., Parnes, J. R. & Thielemans, K. The B-cell surface protein CD72/Lyb-2 is the ligand for CD5. Nature 351, 662–665 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Akatsu, C. et al. CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J. Exp. Med. 213, 2691–2706 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wieczorek, S. et al. The SEM6A6 locus is not associated with granulomatosis with polyangiitis or other forms of antineutrophil cytoplasmic antibody-associated vasculitides in Europeans: comment on the article by Xie et al. Arthritis Rheumatol. 66, 1400–1401 (2014).

    Article  PubMed  Google Scholar 

  80. Bertram, A. et al. Circulating ADAM17 level reflects disease activity in proteinase-3 ANCA-associated vasculitis. J. Am. Soc. Nephrol. 26, 2860–2870 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully thank K.Mogi (Nihonbashi Medical) for help with editing the figures. This work was supported by research grants from Japan Agency for Medical Research and Development (AMED)-Core Research for Evolutional Science and Technology (CREST) and AMED (A.K.); Center of Innovation (COI) stream and Sports Research Innovation Project (SRIP) grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (A.K.); and from the Ministry of Health, Labour and Welfare of Japan (A.K.).

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Correspondence to Atsushi Kumanogoh.

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Nishide, M., Kumanogoh, A. The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nat Rev Rheumatol 14, 19–31 (2018). https://doi.org/10.1038/nrrheum.2017.201

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