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. 2006 Apr 5;14(2):164–174. doi: 10.1111/j.1750-3639.2004.tb00049.x

Detection of Ectopic B‐cell Follicles with Germinal Centers in the Meninges of Patients with Secondary Progressive Multiple Sclerosis

Barbara Serafini 1, Barbara Rosicarelli 1, Roberta Magliozzi 1, Egidio Stigliano 2, Francesca Aloisi 1,✉
PMCID: PMC8095922  PMID: 15193029

Abstract

Multiple sclerosis (MS) is characterized by synthesis of oligoclonal immunoglobulins and the presence of B‐cell clonal expansions in the central nervous system (CNS). Because ectopic lymphoid tissue generated at sites of chronic inflammation is thought to be important in sustaining immunopathological processes, we have investigated whether structures resembling lymphoid follicles could be identified in the CNS of MS patients. Sections from post‐mortem MS brains and spinal cords were screened using immunohistochemistry for the presence of CD20+ B‐cells, CD3+ T‐cells, CD 138+ plasma cells and CD21+, CD35+ follicular dendritic cells, and for the expression of lymphoid chemokines (CXCL13, CCL21) and peripheral node addressin (PNAd). Lymphoid follicle‐like structures containing B‐cells, T‐cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out of 3 patients with secondary progressive MS, but not in relapsing remitting and primary progressive MS. We also show that proliferating B‐cells are present in intrameningeal follicles, a finding which is suggestive of germinal center formation. No follicle‐like structures were detected in parenchymal lesions. The formation of ectopic lymphoid follicles in the meninges of patients with MS could represent a critical step in maintaining humoral autoimmunity and in disease exacerbation.

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REFERENCES

  • 1. Ansel KM, Cyster JG (2001) Chemokines in lymphopoiesis and lymphoid organ development. Curr Opin Immunol 13:172–179. [DOI] [PubMed] [Google Scholar]
  • 2. Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine‐driven positive feedback loop organizes lymphoid follicles. Nature 406: 309–314. [DOI] [PubMed] [Google Scholar]
  • 3. Archelos JJ, Hartung HP (2000) Pathogenetic role of autoantibodies in neurological diseases. Trends Neurosci 23:317–327. [DOI] [PubMed] [Google Scholar]
  • 4. Armengol MP, Juan M, Lucas‐Martin A, Fernandez‐Figueras MT, Jaraquemada D, Gallart T, Pujol‐Borrell R (2001) Thyroid autoimmune disease: demonstration of thyroid antigen‐specific B‐cells and recombination‐activating gene expression in chemokine‐containing active intrathyroidal germinal centers. Am J Pathol 159:861–873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CC, Oksenberg JR (1999) B‐cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 163:5133–5144. [PubMed] [Google Scholar]
  • 6. Bø L Vedeler CA, Nyland HI, Trapp BD, Mørk SJ (2003) Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 62:723–732. [DOI] [PubMed] [Google Scholar]
  • 7. Bofill M, Akbar AN, Amlot PL (2000) Follicular dendritic cells share a membrane‐bound protein with fibroblasts. J Pathol 191:217–226. [DOI] [PubMed] [Google Scholar]
  • 8. Colombo M, Dono M, Gazzola P, Roncella S, Valetto A, Chiorazzi N, Mancardi GL, Ferrarini M (2000) Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol 164:2782–2789. [DOI] [PubMed] [Google Scholar]
  • 9. Cyster JG (2000) Leukocyte migration: scent of the T zone. Curr Biol 10:R30–R33. [DOI] [PubMed] [Google Scholar]
  • 10. Cyster JG, Ansel KM, Reif K, Ekland EH, Hyman PL, Tang HL, Luther SA, Ngo VN (2000) Follicular stromal cells and lymphocyte homing to follicles. Immunol Rev 176:181–193. [DOI] [PubMed] [Google Scholar]
  • 11. de Groot CJ, Bergers E, Kamphorst W, Ravid R, Polman CH, van der Barkhof F, Valk P (2001) Post‐mortem MRI‐guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions. Brain 124: 1635–1645. [DOI] [PubMed] [Google Scholar]
  • 12. Esiri MM (1977) Immunoglobulin‐containing cells in multiple‐sclerosis plaques. Lancet 2:478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Fan L, Reilly CR, Luo Y, Dorf ME, Lo D (2000) Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol 164:3955–3959. [DOI] [PubMed] [Google Scholar]
  • 14. Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170–175. [DOI] [PubMed] [Google Scholar]
  • 15. Gommerman JL, Browning JL (2003) Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3:642–655. [DOI] [PubMed] [Google Scholar]
  • 16. Guseo A, Jellinger K (1975) The significance of perivascular infiltrations in multiple sclerosis. J Neurol 211:51–60. [DOI] [PubMed] [Google Scholar]
  • 17. Hemmer B, Archelos JJ, Hartung HP (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3:291–301. [DOI] [PubMed] [Google Scholar]
  • 18. Hjelmstrom P (2001) Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol 69:331–339. [PubMed] [Google Scholar]
  • 19. Hjelmstrom P, Fjell J, Nakagawa T, Sacca R, Cuff CA, Ruddle NH (2000) Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am J Pathol 156:1133–1138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, WeiT, Wu L , Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) Human cerebrospinal fluid central memory CD4+ T‐cells: evidence for trafficking through choroid plexus and meninges via P‐selectin. Proc Natl Acad Sci U S A 100:8389–8394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Kosco‐Vilbois MH, Scheidegger D (1995) Follicular dendritic cells: antigen retention, B‐cell activation, and cytokine production. Curr Top Microbiol Immunol 201:69–82. [DOI] [PubMed] [Google Scholar]
  • 22. Lassmann H, Brück W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7:115–121. [DOI] [PubMed] [Google Scholar]
  • 23. Liu YJ, Banchereau J (1996) The paths and molecular controls of peripheral B‐cell development. Immunologist 4:55–66. [Google Scholar]
  • 24. Lowenstein PR (2002) Immunology of viral‐vector‐mediated gene transfer into the brain: an evolutionary and developmental perspective. Trends Immunol 23:23–30. [DOI] [PubMed] [Google Scholar]
  • 25. Luther SA, Lopez T, Bai W, Hanhan, D , Cyster JG (2000) BLC expression in pancreatic islets causes B‐cell recruitment and lymphotoxin dependent lymphoid neogenesis. Immunity 12:471–481. [DOI] [PubMed] [Google Scholar]
  • 26. Magliozzi M, Columba‐Cabezas S, Serafini B, Aloisi F (2004) Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle‐like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 148:11–23. [DOI] [PubMed] [Google Scholar]
  • 27. Massaro AR (1998) Are there indicators of re‐myelination in blood or CSF of multiple sclerosis patients. Mult Scler 4:228–231. [DOI] [PubMed] [Google Scholar]
  • 28. Matsumoto Y, Fujiwara M (1987) The immunopathology of adoptively transferred experimental allergic encephalomyelitis (EAE) in Lewis rats. Part 1. Immunohistochemical examination of developing lesions of EAE. J Neurol Sci 77:35–47. [DOI] [PubMed] [Google Scholar]
  • 29. Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2: 123–128. [DOI] [PubMed] [Google Scholar]
  • 30. Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG (1999) Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T‐cell areas of the spleen. J Exp Med 189:403–412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Niehaus A, Shi J, Grzenkowski M, Diers‐Fenger M, Archelos J, Hartung HP, Toyka K, Bruck W, Trotter J (2000) Patients with active relapsing‐remitting multiple sclerosis synthesize antibodies recognizing oligodendrocyte progenitor cell surface protein: implications for remyelination. Ann Neurol 48:362–371. [PubMed] [Google Scholar]
  • 32. Ohta M, Ohta K (2002) Detection of myelin basic protein in cerebrospinal fluid. Expert Rev Mol Diagn 2:627–633. [DOI] [PubMed] [Google Scholar]
  • 33. Owens GP, Burgoon MP, Anthony J, Kleinschmidt‐DeMasters BK, Gilden DH (2001) The immunoglobulin G heavy chain repertoire in multiple sclerosis plaques is distinct from the heavy chain repertoire in peripheral blood lymphocytes. Clin Immunol 98:258–263. [DOI] [PubMed] [Google Scholar]
  • 34. Owens GP, Ritchie AM, Burgoon MP, Williamson RA, Corboy JR, Gilden DH (2003) Single‐cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B‐cell response in multiple sclerosis cerebrospinal fluid. J Immunol 171:2725–2733. [DOI] [PubMed] [Google Scholar]
  • 35. Ozawa K, Suchanek G, Breitschopf H, Bruck W, Budka H, Jellinger K, Lassmann H (1994) Patterns of oligodendroglia pathology in multiple sclerosis. Brain 117:1311–1322. [DOI] [PubMed] [Google Scholar]
  • 36. Petzold A, Eikelenboom MJ, Gveric D, Keir G, Chapman M, Lazeron RH, Cuzner ML, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G (2002) Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 125:1462–1473. [DOI] [PubMed] [Google Scholar]
  • 37. Prineas JW (1979) Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 203: 1123–1125. [DOI] [PubMed] [Google Scholar]
  • 38. Prineas JW, Graham JS (1981) Multiple sclerosis: capping of surface immunoglobulin G on macrophages engaged in myelin breakdown. Ann Neurol 10:149–158. [DOI] [PubMed] [Google Scholar]
  • 39. Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP (2001) Immunopathology of secondary‐progressive multiple sclerosis. Ann Neurol 50:646–657. [DOI] [PubMed] [Google Scholar]
  • 40. Prineas JW, Wright RG (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest 38:409–421. [PubMed] [Google Scholar]
  • 41. Qin Y, Duquette P, Zhang Y, Olek M, Da RR, Richardson J, Antel JP, Talbot P, Cashman NR, Tourtellotte WW, Wekerle H, Van Den Noort S (2003) 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 83:1081–1088. [DOI] [PubMed] [Google Scholar]
  • 42. Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J (1998) Clonal expansion and somatic hypermutation of V(H) genes of B‐cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102:1045–1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Raine CS, Cannella B, Hauser SL, Genain CP (1999) Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen‐specific antibody mediation. Ann Neurol 46:144–160. [DOI] [PubMed] [Google Scholar]
  • 44. Ransohoff RM, Kivisakk P, Kidd G (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–581. [DOI] [PubMed] [Google Scholar]
  • 45. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI (1994) A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 117:759–765. [DOI] [PubMed] [Google Scholar]
  • 46. Ruddle NH (1999) Lymphoid neo‐organogenesis: lymphotoxin's role in inflammation and development. Immunol Res 19:119–125. [DOI] [PubMed] [Google Scholar]
  • 47. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren‐Herlenius M, Jonsson R (2003) Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum 48:3187–3201. [DOI] [PubMed] [Google Scholar]
  • 48. Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H (1998) Multiple sclerosis: in situ evidence for antibody‐ and complement‐mediated demyelination. Ann Neurol 43: 465–471. [DOI] [PubMed] [Google Scholar]
  • 49. Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C (1998) Antigen‐driven clonal proliferation of B‐cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren's syndrome. J Clin Invest 102:578–581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Streeter PR, Rouse BT, Butcher EC (1988) Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol 107:1853–1862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Takemura, S , Braun A, Crowson C, Kurtin PJ, Cofield RH, O'Fallon WM, Goronzy JJ, Weyand, CM (2001) Lymphoi neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080. [DOI] [PubMed] [Google Scholar]
  • 52. Tew JG, Wu J, Fakher M, Szakal AK, Qin D (2001) Follicular dendritic cells: beyond the necessity of T‐cell help. Trends Immunol 22:361–367. [DOI] [PubMed] [Google Scholar]
  • 53. Tourtellotte WW, Walsh MJ, Baumhefner RW, Staugaitis SM, Shapshak P (1984) The current status of multiple sclerosis intra‐blood‐brain‐barrier IgG synthesis. Ann N Y Acad Sci 436:52–67. [DOI] [PubMed] [Google Scholar]
  • 54. Traugott U, Raine CS (1979) Acute experimental allergic encephalomyelitis. Myelin basic protein‐reactive T‐cells in the circulation and in meningeal infiltrates. J Neurol Sci 42:331–336. [DOI] [PubMed] [Google Scholar]
  • 55. Uccelli A, Concione A, Ferretti E, Giunti D, Zappia E, Fais F, Casazza S, Garello L, Mancardi GL, Pistoia V (2003) A full maturation process of B‐cells into the CSF suggests the existence of in‐trathecal lymphoid‐like compartment in subjects with multiple sclerosis and other inflammatory disorders of the central nervous system. Multiple Sclerosis 9:S66. [Google Scholar]
  • 56. van Nierop K, de Groot C (2002) Human follicular dendritic cells: function, origin and development. Semin Immunol 14:251–257. [DOI] [PubMed] [Google Scholar]
  • 57. Walsh MJ, Murray JM (1998) Dual implication of 2′,3′‐cyclic nucleotide 3′ phosphodiesterase as major autoantigen and C3 complement‐binding protein in the pathogenesis of multiple sclerosis. J Clin Invest 101:1923–1931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Weninger W, Carlsen HS, Goodarzi M, Moazed F, Crowley MA, Baekkevold ES, Cavanagh LL, von Andrian UH (2003) Naive T‐cell recruitment to nonlymphoid tissues: a role for endothelium‐expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J Immunol 170:4638–4648. [DOI] [PubMed] [Google Scholar]
  • 59. Weyand CM, Goronzy JJ (2003) Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci 987:140–149. [DOI] [PubMed] [Google Scholar]
  • 60. Weyand CM, Kurtin PJ, Goronzy JJ (2001) Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol 159:787–793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Wingerchuk DM, Lucchinetti CF, Noseworthy JH (2001) Multiple sclerosis: current pathophysiological concepts. Lab Invest 81:263–281. [DOI] [PubMed] [Google Scholar]
  • 62. Wucherpfennig KW, Catz I, Hausmann S, Strominger JL, Steinman L, Warren KG (1997) Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA‐DR2‐restricted T‐cell clones from multiple sclerosis patients identity of key contact residues in the B‐cell and T‐cell epitopes. J Clin Invest 100:1114–1122. [DOI] [PMC free article] [PubMed] [Google Scholar]

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