Altered Expression of B Cell Receptor Signaling Pathway Genes in Peripheral Blood of Patients with Multiple Sclerosis
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Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease and has adverse implications. The exact mechanism of its pathogenesis is not fully understood and remains to be elucidated. In the current study we aimed to identify key genes that can serve as potential biomarkers and therapeutic targets for MS and shed light on pathogenesis mechanisms involved in MS.
We analyzed a gene expression dataset (GES21942) and found 266 differentially expressed genes (DEGs) including 183 upregulated and 83 downregulated genes in MS patients compared to controls. Then we conducted pathway enrichment on DEGs and selected the top enriched pathway i.e., B cell receptor signaling pathway, and 5 genes of this pathway (CR2, BLK, BLNK, RASGRP3, and KRAS) for further investigation in our clinical samples. We recruited 50 MS patients and 50 controls and assessed the expression of selected genes in the circulation of patients versus controls.
Expression of CR2, BLK, BLNK, and RASGRP3 were significantly higher in MS cases compared with controls. There was no significant difference in expression of KRAS between patients and controls. All of the selected genes with differential expression had noticeable diagnostic power and CR2 was the most robust gene in differentiating MS cases from controls. Additionally, a combination of genes resulted in enhanced diagnostic power.
Collectively our results suggest that the B cell receptor signaling pathway and the selected genes from this pathway may be implicated in the pathogenesis of MS and each of these genes can be considered as potential diagnostic biomarkers and therapeutic targets.
1. Dobson R, Giovannoni G. Multiple sclerosis–a review. Eur J Neurol. 2019;26(1):27-40.
2. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS. Mult Scler. 2020;26(14):1816-21.
3. Almasi-Hashiani A, Sahraian MA, Eskandarieh S. Evidence of an increased prevalence of multiple sclerosis: a population-based study of Tehran registry during 1999–2018. BMC Neurol. 2020;20:1-7.
4. Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3).
5. Van der Mei I, Lucas RM, Taylor B, Valery P, Dwyer T, Kilpatrick TJ, et al. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler. 2016;22(4):461-9.
6. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev. 2010;9(5):A387-A94.
7. Mosca L, Mantero V, Penco S, La Mantia L, De Benedetti S, Marazzi MR, et al. HLA-DRB1* 15 association with multiple sclerosis is confirmed in a multigenerational Italian family. Funct Neurol. 2017;32(2):83.
8. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010;9(7):727-39.
9. Goodin DS. The pathogenesis of multiple sclerosis. Clin Exp Neuroimmunol. 2015;6:2-22.
10. Greenfield AL, Hauser SL. B‐cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. 2018;83(1):13-26.
11. Jelcic I, Sospedra M, Martin R. When a T cell engages a B cell: novel insights in multiple sclerosis. Swiss Med Wkly. 2020;150(3536):w20330-w.
12. Kemppinen A, Kaprio J, Palotie A, Saarela J. Systematic review of genome-wide expression studies in multiple sclerosis. BMJ Open. 2011;1(1):e000053.
13. Xu ZB, Feng X, Zhu WN, Qiu ML. Identification of key genes and microRNAs for multiple sclerosis using bioinformatics analysis. Medicine. Medicine (Baltimore). 2021;100(48).
14. Irizarry RA, Hobbs B, Collin F, Beazer‐Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4(2):249-64.
15. Sospedra M. B cells in multiple sclerosis. Curr Opin Neurol. 2018;31(3):256-62.
16. Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. 2018;19(7):696-707.
17. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(4):1089-104.
18. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175-89.
19. Wu H, Boackle SA, Hanvivadhanakul P, Ulgiati D, Grossman JM, Lee Y, et al. Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus. PNAS. 2007;104(10):3961-6.
20. Rickert RC. Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr Opin Immunol. 2005;17(3):237-43.
21. Lindblom RP, Aeinehband S, Ström M, Al Nimer F, Sandholm K, Khademi M, et al. Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function. Clin Immunol. 2016;166:89-95.
22. Brimnes MK, Hansen BE, Nielsen LK, Dziegiel MH, Nielsen CH. Uptake and presentation of myelin basic protein by normal human B cells. PLoS One. 2014;9(11):e113388.
23. Hu X, Tomlinson S, Barnum SR. Targeted inhibition of complement using complement receptor 2-conjugated inhibitors attenuates EAE. Neurosci Lett. 2012;531(1):35-9.
24. Turkoglu R, Yilmaz V, Ozdemir O, Akbayir E, Benbir G, Arsoy E, et al. Peripheral blood B cell subset ratios and expression levels of B cell-associated genes are altered in benign multiple sclerosis. Mult Scler Relat Disord. 2021;52:103019.
25. Simpfendorfer KR, Olsson LM, Manjarrez Orduño N, Khalili H, Simeone AM, Katz MS, et al. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum Mol Genet. 2012;21(17):3918-25.
26. Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL, et al. Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. PNAS. 1994;91(20):9524-8.
27. Bernal-Quirós M, Wu YY, Alarcón-Riquelme ME, Castillejo-López C. BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling. PLoS One. 2013;8(3):e59842.
28. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. NEJM. 2008;358(9):900-9.
29. Deshmukh HA, Maiti AK, Kim-Howard XR, Rojas-Villarraga A, Guthridge JM, Anaya JM, et al. Evaluation of 19 autoimmune disease-associated loci with rheumatoid arthritis in a Colombian population: evidence for replication and gene-gene interaction. J Rheumatol. 2011;38(9):1866-70.
30. Gourh P, Agarwal SK, Martin E, Divecha D, Rueda B, Bunting H, et al. Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. J Autoimmun. 2010;34(2):155-62.
31. Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, et al. Association of EBF1, FAM167A (C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes Immun. 2011;12(2):100-9.
32. Wen Y, Jing Y, Yang L, Kang D, Jiang P, Li N, et al. The regulators of BCR signaling during B cell activation. Blood Sci. 2019;1(02):119-29.
33. Liubchenko GA, Appleberry HC, Striebich CC, Franklin KE, Derber LA, Holers VM, et al. Rheumatoid arthritis is associated with signaling alterations in naturally occurring autoreactive B-lymphocytes. J Autoimmun. 2013;40:111-21.
34. Tang W-Y, Zhang Y-H, Zhang Y-S, Liao Y, Luo J-S, Liu J-H, et al. Abnormal thymic B cell activation and impaired T cell differentiation in pristane-induced lupus mice. Immunol Lett. 2021;231:49-60.
35. Simpfendorfer KR, Armstead BE, Shih A, Li W, Curran M, Manjarrez‐Orduño N, et al. Autoimmune disease–associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class‐switched B cells. Arthritis Rheumatol. 2015;67(11):2866-76.
36. Stone JC. Regulation and function of the RasGRP family of Ras activators in blood cells. Genes Cancer. 2011;2(3):320-34.
37. Coughlin JJ, Stang SL, Dower NA, Stone JC. The role of RasGRPs in regulation of lymphocyte proliferation. Immunol Lett. 2006;105(1):77-82.
38. Coughlin JJ, Stang SL, Dower NA, Stone JC. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J Immunol. 2005;175(11):7179-84.
39. An XJ, Xia Y, Li J, Dong LY, Wang YJ, Yang J, et al. RasGRP3 in peripheral blood mononuclear cells is associated with disease activity and implicated in the development of systemic lupus erythematosus. Am J Transl Res. 2019;11(3):1800.
40. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234-7.
41. Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta ML, Gunnarsson I, et al. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet. 2013;21(9):994-9.
42. Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell. 2018;175(1):85-100. e23.
2. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS. Mult Scler. 2020;26(14):1816-21.
3. Almasi-Hashiani A, Sahraian MA, Eskandarieh S. Evidence of an increased prevalence of multiple sclerosis: a population-based study of Tehran registry during 1999–2018. BMC Neurol. 2020;20:1-7.
4. Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3).
5. Van der Mei I, Lucas RM, Taylor B, Valery P, Dwyer T, Kilpatrick TJ, et al. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler. 2016;22(4):461-9.
6. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev. 2010;9(5):A387-A94.
7. Mosca L, Mantero V, Penco S, La Mantia L, De Benedetti S, Marazzi MR, et al. HLA-DRB1* 15 association with multiple sclerosis is confirmed in a multigenerational Italian family. Funct Neurol. 2017;32(2):83.
8. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010;9(7):727-39.
9. Goodin DS. The pathogenesis of multiple sclerosis. Clin Exp Neuroimmunol. 2015;6:2-22.
10. Greenfield AL, Hauser SL. B‐cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. 2018;83(1):13-26.
11. Jelcic I, Sospedra M, Martin R. When a T cell engages a B cell: novel insights in multiple sclerosis. Swiss Med Wkly. 2020;150(3536):w20330-w.
12. Kemppinen A, Kaprio J, Palotie A, Saarela J. Systematic review of genome-wide expression studies in multiple sclerosis. BMJ Open. 2011;1(1):e000053.
13. Xu ZB, Feng X, Zhu WN, Qiu ML. Identification of key genes and microRNAs for multiple sclerosis using bioinformatics analysis. Medicine. Medicine (Baltimore). 2021;100(48).
14. Irizarry RA, Hobbs B, Collin F, Beazer‐Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4(2):249-64.
15. Sospedra M. B cells in multiple sclerosis. Curr Opin Neurol. 2018;31(3):256-62.
16. Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. 2018;19(7):696-707.
17. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(4):1089-104.
18. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175-89.
19. Wu H, Boackle SA, Hanvivadhanakul P, Ulgiati D, Grossman JM, Lee Y, et al. Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus. PNAS. 2007;104(10):3961-6.
20. Rickert RC. Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr Opin Immunol. 2005;17(3):237-43.
21. Lindblom RP, Aeinehband S, Ström M, Al Nimer F, Sandholm K, Khademi M, et al. Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function. Clin Immunol. 2016;166:89-95.
22. Brimnes MK, Hansen BE, Nielsen LK, Dziegiel MH, Nielsen CH. Uptake and presentation of myelin basic protein by normal human B cells. PLoS One. 2014;9(11):e113388.
23. Hu X, Tomlinson S, Barnum SR. Targeted inhibition of complement using complement receptor 2-conjugated inhibitors attenuates EAE. Neurosci Lett. 2012;531(1):35-9.
24. Turkoglu R, Yilmaz V, Ozdemir O, Akbayir E, Benbir G, Arsoy E, et al. Peripheral blood B cell subset ratios and expression levels of B cell-associated genes are altered in benign multiple sclerosis. Mult Scler Relat Disord. 2021;52:103019.
25. Simpfendorfer KR, Olsson LM, Manjarrez Orduño N, Khalili H, Simeone AM, Katz MS, et al. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum Mol Genet. 2012;21(17):3918-25.
26. Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL, et al. Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. PNAS. 1994;91(20):9524-8.
27. Bernal-Quirós M, Wu YY, Alarcón-Riquelme ME, Castillejo-López C. BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling. PLoS One. 2013;8(3):e59842.
28. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. NEJM. 2008;358(9):900-9.
29. Deshmukh HA, Maiti AK, Kim-Howard XR, Rojas-Villarraga A, Guthridge JM, Anaya JM, et al. Evaluation of 19 autoimmune disease-associated loci with rheumatoid arthritis in a Colombian population: evidence for replication and gene-gene interaction. J Rheumatol. 2011;38(9):1866-70.
30. Gourh P, Agarwal SK, Martin E, Divecha D, Rueda B, Bunting H, et al. Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. J Autoimmun. 2010;34(2):155-62.
31. Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, et al. Association of EBF1, FAM167A (C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes Immun. 2011;12(2):100-9.
32. Wen Y, Jing Y, Yang L, Kang D, Jiang P, Li N, et al. The regulators of BCR signaling during B cell activation. Blood Sci. 2019;1(02):119-29.
33. Liubchenko GA, Appleberry HC, Striebich CC, Franklin KE, Derber LA, Holers VM, et al. Rheumatoid arthritis is associated with signaling alterations in naturally occurring autoreactive B-lymphocytes. J Autoimmun. 2013;40:111-21.
34. Tang W-Y, Zhang Y-H, Zhang Y-S, Liao Y, Luo J-S, Liu J-H, et al. Abnormal thymic B cell activation and impaired T cell differentiation in pristane-induced lupus mice. Immunol Lett. 2021;231:49-60.
35. Simpfendorfer KR, Armstead BE, Shih A, Li W, Curran M, Manjarrez‐Orduño N, et al. Autoimmune disease–associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class‐switched B cells. Arthritis Rheumatol. 2015;67(11):2866-76.
36. Stone JC. Regulation and function of the RasGRP family of Ras activators in blood cells. Genes Cancer. 2011;2(3):320-34.
37. Coughlin JJ, Stang SL, Dower NA, Stone JC. The role of RasGRPs in regulation of lymphocyte proliferation. Immunol Lett. 2006;105(1):77-82.
38. Coughlin JJ, Stang SL, Dower NA, Stone JC. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J Immunol. 2005;175(11):7179-84.
39. An XJ, Xia Y, Li J, Dong LY, Wang YJ, Yang J, et al. RasGRP3 in peripheral blood mononuclear cells is associated with disease activity and implicated in the development of systemic lupus erythematosus. Am J Transl Res. 2019;11(3):1800.
40. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234-7.
41. Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta ML, Gunnarsson I, et al. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet. 2013;21(9):994-9.
42. Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell. 2018;175(1):85-100. e23.
| Files | ||
| Issue | Vol 23 No 2 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i2.15324 | |
| Keywords | ||
| B cell B cell receptor signaling pathway Gene expression Multiple sclerosis | ||
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How to Cite
1.
Jalili S, Shirzad H, Mousavi Nezhad SA. Altered Expression of B Cell Receptor Signaling Pathway Genes in Peripheral Blood of Patients with Multiple Sclerosis. Iran J Allergy Asthma Immunol. 2024;23(2):182-196.
