466
Views
1
CrossRef citations to date
0
Altmetric
Review Article

Immune repertoire: Revealing the “real-time” adaptive immune response in autoimmune diseases

, , & ORCID Icon
Pages 61-75 | Received 18 Dec 2020, Accepted 03 Feb 2021, Published online: 02 Mar 2021

References

  • Nielsen SCA, Boyd SD. Human adaptive immune receptor repertoire analysis – past, present, and future. Immunol Rev. 2018;284:9–23.
  • Cowell LG. The diagnostic, prognostic, and therapeutic potential of adaptive immune receptor repertoire profiling in cancer. Cancer Res. 2020;80:643–654.
  • Liu X, Wu J. History, applications, and challenges of immune repertoire research. Cell Biol Toxicol. 2018;34:441–457.
  • Warren EH, Matsen FAT, Chou J. High-throughput sequencing of B- and T-lymphocyte antigen receptors in hematology. Blood. 2013;122:19–22.
  • Li N, Yuan J, Tian W, et al. T-cell receptor repertoire analysis for the diagnosis and treatment of solid tumor: a methodology and clinical applications. Cancer Commun (Lond). 2020;40:473–483.
  • Shay T, Kang J. Immunological Genome Project and systems immunology. Trends Immunol. 2013;34:602–609.
  • Sui W, Hou X, Zou G, et al. Composition and variation analysis of the TCR β-chain CDR3 repertoire in systemic lupus erythematosus using high-throughput sequencing. Mol Immunol. 2015;67:455–464.
  • Shi B, Yu J, Ma L, et al. Short-term assessment of BCR repertoires of SLE patients after high dose glucocorticoid therapy with high-throughput sequencing. Springerplus. 2016;5:75.
  • Harden JL, Hamm D, Gulati N, et al. Deep sequencing of the T-cell receptor repertoire demonstrates polyclonal T-cell infiltrates in psoriasis. F1000Res. 2015;4:460.
  • Lo KC, Sullivan E, Bannen RM, et al. Comprehensive profiling of the rheumatoid arthritis antibody repertoire. Arthritis Rheumatol. 2020;72:242–250.
  • Wang Y, Lloyd KA, Melas I, et al. Rheumatoid arthritis patients display B-cell dysregulation already in the naive repertoire consistent with defects in B-cell tolerance. Sci Rep. 2019;9:19995.
  • Muraro PA, Robins H, Malhotra S, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124:1168–1172.
  • Amoriello R, Greiff V, Aldinucci A, et al. The TCR repertoire reconstitution in multiple sclerosis: comparing one-shot and continuous immunosuppressive therapies. Front Immunol. 2020;11:559.
  • Chien YH, Meyer C, Bonneville M. γδ T cells: first line of defense and beyond. Annu Rev Immunol. 2014;32:121–155.
  • Fichtner AS, Ravens S, Prinz I. Human γδ TCR repertoires in health and disease. Cells. 2020;9:800.
  • Lefranc MP, Giudicelli V, Duroux P, et al. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015;43:D413–D422.
  • Alt FW, Yancopoulos GD, Blackwell TK, et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. Embo J. 1984;3:1209–1219.
  • Freeman JD, Warren RL, Webb JR, et al. Profiling the T-cell receptor beta-chain repertoire by massively parallel sequencing. Genome Res. 2009;19:1817–1824.
  • Marks C, Deane CM. How repertoire data are changing antibody science. J Biol Chem. 2020;295:9823–9837.
  • Schatz DG, Baltimore D. Stable expression of immunoglobulin gene V(D)J recombinase activity by gene transfer into 3T3 fibroblasts. Cell. 1988;53:107–115.
  • Oettinger MA, Schatz DG, Gorka C, et al. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248:1517–1523.
  • Schatz DG, Swanson PC. V(D)J recombination: mechanisms of initiation. Annu Rev Genet. 2011;45:167–202.
  • Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature. 1988;334:395–402.
  • Kaplinsky J, Arnaout R. Robust estimates of overall immune-repertoire diversity from high-throughput measurements on samples. Nat Commun. 2016;7:11881.
  • Eisenberg RA. Secondary receptor editing in the generation of autoimmunity. Autoimmun Rev. 2012;11:787–789.
  • Edry E, Melamed D. Receptor editing in positive and negative selection of B lymphopoiesis. J Immunol. 2004;173:4265–4271.
  • Schroeder HW Jr. Similarity and divergence in the development and expression of the mouse and human antibody repertoires. Dev Comp Immunol. 2006;30:119–135.
  • Papavasiliou FN, Schatz DG. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell. 2002;109 Suppl:S35–S44.
  • Kleinstein SH, Louzoun Y, Shlomchik MJ. Estimating hypermutation rates from clonal tree data. J Immunol. 2003;171:4639–4649.
  • Li Z, Woo CJ, Iglesias-Ussel MD, et al. The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev. 2004;18:1–11.
  • Janda A, Eryilmaz E, Nakouzi A, et al. Variable region identical IgA and IgE to Cryptococcus neoformans capsular polysaccharide manifest specificity differences. J Biol Chem. 2015;290:12090–12100.
  • Methot SP, Di Noia JM. Molecular mechanisms of somatic hypermutation and class switch recombination. Adv Immunol. 2017;133:37–87.
  • Robins H. Immunosequencing: applications of immune repertoire deep sequencing. Curr Opin Immunol. 2013;25:646–652.
  • Liu S, Hou XL, Sui WG, et al. Direct measurement of B-cell receptor repertoire’s composition and variation in systemic lupus erythematosus. Genes Immun. 2017;18:22–27.
  • Venturi V, Quigley MF, Greenaway HY, et al. A mechanism for TCR sharing between T cell subsets and individuals revealed by pyrosequencing. J Immunol. 2011;186:4285–4294.
  • Warren RL, Freeman JD, Zeng T, et al. Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res. 2011;21:790–797.
  • Wardemann H, Yurasov S, Schaefer A, et al. Predominant autoantibody production by early human B cell precursors. Science. 2003;301:1374–1377.
  • Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18:716–724.
  • Liao HX, Lynch R, Zhou T, et al., NISC Comparative Sequencing Program. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013;496:469–476.
  • Sabouri Z, Schofield P, Horikawa K, et al. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc Natl Acad Sci USA. 2014;111:E2567–E2575.
  • Reed JH, Jackson J, Christ D, et al. Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization. J Exp Med. 2016;213:1255–1265.
  • Maecker HT, Lindstrom TM, Robinson WH, et al. New tools for classification and monitoring of autoimmune diseases. Nat Rev Rheumatol. 2012;8:317–328.
  • Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, et al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology. 2013;57:2390–2398.
  • Durcan L, O'Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet. 2019;393:2332–2343.
  • Meffre E, Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol. 2008;20:632–638.
  • Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001;1:147–153.
  • Furie R, Petri M, Zamani O, et al., BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918–3930.
  • Fraser NL, Rowley G, Field M, et al. The VH gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus. Arthritis Res Ther. 2003;5:R114–R121.
  • Tipton CM, Fucile CF, Darce J, et al. Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat Immunol. 2015;16:755–765.
  • Odendahl M, Jacobi A, Hansen A, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165:5970–5979.
  • Bashford-Rogers RJM, Bergamaschi L, McKinney EF, et al. Analysis of the B cell receptor repertoire in six immune-mediated diseases. Nature. 2019;574:122–126.
  • Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–1533.
  • Silberstein LE, Jefferies LC, Goldman J, et al. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood. 1991;78:2372–2386.
  • Pascual V, et al. Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4-21 gene segment is responsible for the major cross-reactive idiotype. J Immunol. 1991;146:4385–4391.
  • Stevenson FK, Longhurst C, Chapman CJ, et al. Utilization of the VH4-21 gene segment by anti-DNA antibodies from patients with systemic lupus erythematosus. J Autoimmun. 1993;6:809–825.
  • Isenberg DA, McClure C, Farewell V, et al. Correlation of 9G4 idiotope with disease activity in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases. 1998;57:566–570.
  • Kraj P, Friedman DF, Stevenson F, et al. Evidence for the overexpression of the VH4-34 (VH4.21) Ig gene segment in the normal adult human peripheral blood B cell repertoire. J Immunol. 1995;154:6406–6420.
  • Yin L, Hou W, Liu L, et al. IgM repertoire biodiversity is reduced in HIV-1 infection and systemic lupus erythematosus. Front Immunol. 2013;4:373.
  • Ekiert DC, Kashyap AK, Steel J, et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature. 2012;489:526–532.
  • Whittle JRR, Zhang R, Khurana S, et al. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA. 2011;108:14216–14221.
  • Pejchal R, Walker LM, Stanfield RL, et al. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc Natl Acad Sci U S A. 2010;107:11483–11488.
  • Watanabe A, Su KY, Kuraoka M, et al. Self-tolerance curtails the B cell repertoire to microbial epitopes. JCI Insight. 2019;4:e122551.
  • Yurasov S, Wardemann H, Hammersen J, et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med. 2005;201:703–711.
  • Aguilera I, Melero J, Nuñez-Roldan A, et al. Molecular structure of eight human autoreactive monoclonal antibodies. Immunology. 2001;102:273–280.
  • Meffre E, Milili M, Blanco-Betancourt C, et al. Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. J Clin Invest. 2001;108:879–886.
  • Meffre E, Schaefer A, Wardemann H, et al. Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies. J Exp Med. 2004;199:145–150.
  • Elhanati Y, Sethna Z, Marcou Q, et al. Inferring processes underlying B-cell repertoire diversity. Philos Trans R Soc London, Ser B. 2015;370:20140243.
  • Hoehn KB, Fowler A, Lunter G, et al. The Diversity and Molecular Evolution of B-Cell Receptors during Infection. Mol Biol Evol. 2016;33:1147–1157.
  • Jacobi AM, Hansen A, Burmester GR, et al. Enhanced mutational activity and disturbed selection of mutations in V(H) gene rearrangements in a patient with systemic lupus erythematosus. Autoimmunity. 2000;33:61–76.
  • Dörner T, Heimbächer C, Farner NL, et al. Enhanced mutational activity of Vkappa gene rearrangements in systemic lupus erythematosus. Clin Immunol. 1999;92:188–196.
  • Dörner T, Foster SJ, Farner NL, et al. Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus. J Clin Invest. 1998;102:688–694.
  • Jia Y, Zhao L, Wang C, et al. Anti-double-stranded DNA isotypes and anti-C1q antibody improve the diagnostic specificity of systemic lupus erythematosus. Dis Markers. 2018; 2018:4528547.
  • Witte T. IgM antibodies against dsDNA in SLE. Clin Rev Allergy Immunol. 2008;34:345–347.
  • Dema B, Pellefigues C, Hasni S, et al. Autoreactive IgE is prevalent in systemic lupus erythematosus and is associated with increased disease activity and nephritis. PloS One . 2014;9:e90424.
  • Villalta D, Bizzaro N, Bassi N, et al. Anti-dsDNA antibody isotypes in systemic lupus erythematosus: IgA in addition to IgG anti-dsDNA help to identify glomerulonephritis and active disease. PloS One. 2013;8:e71458.
  • Fanouriakis A, Kostopoulou M, Cheema K, et al. Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79:1028.2–723.
  • Wang C, Pan HF, Ye DQ. The therapeutic potential of the targeted autoreactive B lymphocytes by rituximab in SLE. Autoimmun Rev. 2012;11:373.
  • Witt M, Grunke M, Proft F, et al., German Registry of Autoimmune Diseases (GRAID) Investigators. Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) – results from a nationwide cohort in Germany (GRAID). Lupus. 2013;22:1142–1149.
  • Sfikakis PP, Karali V, Lilakos K, et al. Clonal expansion of B-cells in human systemic lupus erythematosus: evidence from studies before and after therapeutic B-cell depletion. Clin Immunol. 2009;132:19–31.
  • Demaison C, David D, Fautrel B, et al. V(H) gene-family representation in peripheral activated B cells from systemic lupus erythematosus (SLE) patients. Clin Exp Immunol. 1996;104:439–445.
  • Bashford-Rogers RJM, Smith KGC, Thomas DC. Antibody repertoire analysis in polygenic autoimmune diseases. Immunology. 2018;155:3–17.
  • Datta SK, Kaliyaperumal A, Mohan C, et al. T helper cells driving pathogenic anti-DNA autoantibody production in lupus: nucleosomal epitopes and CD40 ligand signals. Lupus. 1997;6:333–336.
  • Desai-Mehta A, Mao C, Rajagopalan S, et al. Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus. J Clin Invest. 1995;95:531–541.
  • Kita Y, Kuroda K, Mimori T, et al. T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus. J Invest Dermatol. 1998;110:41–46.
  • Wang Y, Chen S, Chen J, et al. Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome highlight T cell-initiated autoimmunity. Ann Rheum Dis. 2020;79:268–275.
  • Thapa DR, Tonikian R, Sun C, et al. Longitudinal analysis of peripheral blood T cell receptor diversity in patients with systemic lupus erythematosus by next-generation sequencing. Arthritis Res Ther. 2015;17:132.
  • Moore E, Huang MW, Jain S, et al. The T cell receptor repertoire in neuropsychiatric systemic lupus erythematosus. Front Immunol. 2020;11:1476.
  • Liu X, Zhang W, Zhao M, et al. T cell receptor β repertoires as novel diagnostic markers for systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis. 2019;78:1070–1078.
  • Li Z, Long M, ChunMei L, et al. Composition and variation analysis of TCR β-chain CDR3 repertoire in the thymus and spleen of MRL/lpr mouse at different ages. Immunogenetics. 2015;67:25–37.
  • Ye X, Wang Z, Ye Q, et al. High-throughput sequencing-based analysis of T cell repertoire in lupus nephritis. Front Immunol. 2020;11:1618.
  • Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263–271.
  • Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385–422.
  • Boehncke WH, Schön MP. Psoriasis. Lancet. 2015;386:983–994.
  • Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014;32:227–255.
  • Chang JC, Smith LR, Froning KJ, et al. CD8+ T-cells in psoriatic lesions preferentially use T-cell receptors V beta 3 and/or V beta 13.1 genes. Ann N Y Acad Sci. 1995;756:370–381.
  • Menssen A, et al. Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol. 1995;155:4078–4083.
  • Robins HS, Campregher PV, Srivastava SK, et al. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood. 2009;114:4099–4107.
  • Cao X, Wa Q, Wang Q, et al. High throughput sequencing reveals the diversity of TRB-CDR3 repertoire in patients with psoriasis vulgaris. Int Immunopharmacol. 2016;40:487–491.
  • Tsuda K, Yamanaka K, Kondo M, et al. Ustekinumab improves psoriasis without altering T cell cytokine production, differentiation, and T cell receptor repertoire diversity. PLoS One. 2012;7:e51819.
  • Prinz JC, Vollmer S, Boehncke WH, et al. Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris. Eur J Immunol. 1999;29:3360–3368.
  • Bour H, Puisieux I, Even J, et al. T-cell repertoire analysis in chronic plaque psoriasis suggests an antigen-specific immune response. Hum Immunol. 1999;60:665–676.
  • Diluvio L, Vollmer S, Besgen P, et al. Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris. J Immunol. 2006;176:7104–7111.
  • Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18002.
  • Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–1372.
  • Tan YC, Kongpachith S, Blum LK, et al. Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis. Arthritis Rheumatol. 2014;66:2706–2715.
  • Kerkman PF, Rombouts Y, van der Voort EIH, et al. Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72:1259–1263.
  • Edwards JCW, Szczepański L, Szechiński J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572–2581.
  • Samuels J, Ng YS, Coupillaud C, et al. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med. 2005;201:1659–1667.
  • Samuels J, Ng YS, Coupillaud C, et al. Human B cell tolerance and its failure in rheumatoid arthritis. Ann N Y Acad Sci. 2005;1062:116–126.
  • Vencovský J, et al. Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope. Rheumatology. 2002;41:401–410.
  • Voswinkel J, Pfreundschuh M, Gause A. Evidence for a selected humoral immune response encoded by VH4 family genes in the synovial membrane of a patient with RA. Ann N Y Acad Sci. 1997;815:312–315.
  • Doorenspleet ME, Klarenbeek PL, de Hair MJH, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis. 2014;73:756–762.
  • Tak PP, Doorenspleet ME, de Hair MJH, et al. Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2017;76:1924–1930.
  • Amara K, Steen J, Murray F, et al. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med. 2013;210:445–455.
  • Morbach H, Wiegering V, Richl P, et al. Activated memory B cells may function as antigen-presenting cells in the joints of children with juvenile idiopathic arthritis. Arthritis Rheum. 2011;63:3458–3466.
  • Pollastro S, Klarenbeek PL, Doorenspleet ME, et al. Non-response to rituximab therapy in rheumatoid arthritis is associated with incomplete disruption of the B cell receptor repertoire. Ann Rheum Dis. 2019;78:1339–1345.
  • Imberti L, Scarsi M, Zanotti C, et al. Reduced T-cell repertoire restrictions in abatacept-treated rheumatoid arthritis patients. J Transl Med. 2015;13:12.
  • Wagner UG, Koetz K, Weyand CM, et al. Perturbation of the T cell repertoire in rheumatoid arthritis. PNAS. 1998;95:14447–14452.
  • Even J, Lim A, Puisieux I, et al. T-cell repertoires in healthy and diseased human tissues analysed by T-cell receptor beta-chain CDR3 size determination: evidence for oligoclonal expansions in tumours and inflammatory diseases. Res Immunol. 1995;146:65–80.
  • Jiang X, Wang S, Zhou C, et al. Comprehensive TCR repertoire analysis of CD4+ T-cell subsets in rheumatoid arthritis. J Autoimmun. 2020;109:102432.
  • Chang CM, Hsu YW, Wong HSC, et al. Characterization of T-cell receptor repertoire in patients with rheumatoid arthritis receiving biologic therapies. Dis Markers. 2019;2019:1–12.
  • Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26:27–40.
  • Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378:169–180.
  • Thompson AJ, Baranzini SE, Geurts J, et al. Multiple sclerosis. Lancet. 2018;391:1622–1636.
  • Walter MA, Gibson WT, Ebers GC, et al. Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region. J Clin Invest. 1991;87:1266–1273.
  • Warren KG, Catz I. Autoantibodies to myelin basic protein within multiple sclerosis central nervous system tissue. J Neurol Sci. 1993;115:169–176.
  • Spadaro M, Winklmeier S, Beltrán E, et al. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol. 2018;84:315–328.
  • Beltrán E, Obermeier B, Moser M, et al. Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain. 2014;137:2703–2714.
  • Palanichamy A, Apeltsin L, Kuo TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med. 2014;6:248ra106.
  • Colombo M, Dono M, Gazzola P, et al. Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol. 2000;164:2782–2789.
  • Qin Y, Duquette P, Zhang Y, et al. Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Lab Invest. 2003;83:1081–1088.
  • Lehmann-Horn K, Wang SZ, Sagan SA, et al. B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. JCI Insight. 2016;1:e87234.
  • Eggers EL, Michel BA, Wu H, et al. Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight. 2017;2:e92724.
  • Stern JNH, Yaari G, Vander Heiden JA, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014;6:248ra107.
  • Cepok S, Rosche B, Grummel V, et al. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain. 2005;128:1667–1676.
  • Maurer MA, Tuller F, Gredler V, et al. Rituximab induces clonal expansion of IgG memory B-cells in patients with inflammatory central nervous system demyelination. J Neuroimmunol. 2016;290:49–53.
  • Baranzini SE, Jeong MC, Butunoi C, et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol. 1999;163:5133–5144.
  • Lomakin YA, Zakharova MY, Stepanov AV, et al. Heavy-light chain interrelations of MS-associated immunoglobulins probed by deep sequencing and rational variation. Mol Immunol. 2014;62:305–314.
  • Lutter L, Spierings J, van Rhijn-Brouwer FCC, et al. Resetting the T cell compartment in autoimmune diseases with autologous hematopoietic stem cell transplantation: an update. Front Immunol. 2018;9:767.
  • Planas R, Metz I, Martin R, et al. Detailed characterization of T cell receptor repertoires in multiple sclerosis brain lesions. Front Immunol. 2018;9:509.
  • Lossius A, Johansen JN, Vartdal F, et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol. 2014;44:3439–3452.
  • Jelcic I, Al Nimer F, Wang J, et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell. 2018;175:85–100. e123.
  • Alves Sousa ADP, Johnson KR, Ohayon J, et al. Comprehensive analysis of TCR-β repertoire in patients with neurological immune-mediated disorders. Sci Rep. 2019;9:344.
  • Paroni M, Maltese V, De Simone M, et al. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses. J Allergy Clin Immunol. 2017;140:797–808.
  • Börnsen L, Christensen JR, Ratzer R, et al. Effect of natalizumab on circulating CD4+ T-cells in multiple sclerosis. PLoS One. 2012;7:e47578.
  • Warnke C, Mausberg AK, Stettner M, et al. Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis. Neurology. 2013;81:1400–1408.
  • Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998;339:285–291.
  • Finkelsztejn A, Brooks JB, Paschoal FM Jr, et al. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG. 2011;118:790–797.
  • Ramien C, Yusko EC, Engler JB, et al. T cell repertoire dynamics during pregnancy in multiple sclerosis. Cell Rep. 2019;29:810–815. e814.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.