During the past decade, most strategies for treatment of multiple sclerosis (MS) have been derived from work using the experimental allergy encephalomyelitis model. They presume that MS is mediated by T-helper (Th)1 cells that enter the CNS and attack myelin. These treatments try to shift Th1 cells to Th2 cells and also attempt to prevent entry of Th1 cells into the CNS.
For decades, the diagnosis of MS has depended heavily on the presence of oligoclonal immunoglobulin (Ig)G bands in the cerebrospinal fluid (CSF) Citation[1]. These bands must be a consequence of Th2 cell-dependent antigen-challenged immunity for many reasons.
Antigen-driven intrathecal B-cell activation and differentiation is Th2 dependent Citation[2]. Molecular studies of the Ig heavy chain (Ig-VH) genes expressed by B cells and plasma cells in the CSF and in MS lesions demonstrate that Citation[3–6]:
| • | There is antigen-driven B-cell somatic hypermutation; | ||||
| • | T–B-cell interactions occur in germinal centers, where both memory B cells and plasma cells undergo clonal selection and differentiation; | ||||
| • | Clonal B cells and plasma cells specifically migrate into the CNS. | ||||
Hypermutated monoclonal B cells are the first finding in patients with evolving MS and are well developed before diagnostic oligoclonal bands and magnetic resonance imaging lesions are demonstrated Citation[7]. Increased intrathecal oligoclonal Ig synthesis during MS progression suggests ongoing Th2-dependent B-cell and plasma-cell proliferation and differentiation in the CNS of MS patients.
Antibodies from these plasma cells will attack tissue in MS brains Citation[8]. It had been hypothesized that neuronal loss in MS was secondary to demyelination. However, antibodies from these clonal plasma cells bind to axons in a majority of MS brains Citation[9,10]. Antibodies in the CSF directly attack axonal and neuronal antigens, including axolemma Citation[11], neurofilament-L Citation[12], collapsin response mediated protein (CRMP)-5 Citation[13] and gangliosides Citation[14]. Glyceraldehyde-3 phosphate dehydrogenase and/or triosephosphate isomerase were identified as antigens that drive B-cell clonal expansion in the CSF and in lesions Citation[15]. These enzymes are critical for neuronal function and survival.
Binding also results in activation of complement and phagocytes. Plasma cells in normal-appearing white matter and lesions are depositing antibodies on nerve cells and fibers. We find colocalization of IgG and C5 in plaques, active lesions and adjacent normal-appearing white matter. These are convincing data that antibody-related complement activation proceeds in MS brain Citation[16]. The Fc region of these antibodies binds Fc receptors on macrophages and probably microglia that ingest antibody and antigen. This causes release of phagocyte oxidase and hydrolytic enzymes producing inflammation and Wallerian degeneration Citation[17].
Although interferon-β has been shown to be effective, their long-term impact on brain atrophy and progression of clinical disability in MS is uncertain. Imaging studies demonstrate gray matter loss in early MS in areas unrelated to white-matter lesions Citation[18]. Most studies of atrophy show a linear decline of neurons from the beginning of MS that is largely unaffected by interferon-β. Long-term disability in MS is highly correlated with gray matter atrophy and minimally correlated with the white-matter lesions. It is common to find cognitive decline very early in MS. The dreaded arrival of dementia does not appear to be removed by the robust use of interferon-β. To date, transplants have brought with them a substantial increase in atrophy. The hegemony of interferon-β in the treatment of MS is degraded by this evidence and suggests that B-cell strategies require further study. Use of atrophy markers including optical-coherence tomography of the optic disk must be more prominent in outcome measures.
References
- Dick G. President’s address. The etiology of multiple sclerosisProc. R. Soc. Med.69, 611–615 (1976).
- Banchereau J, de Paoli P, Valle A, Garcia E, Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science251, 70–72 (1991).
- Haubold K, Owens GP, Kaur P, Ritchie AM, Gilden DH, Bennett JL. B-lymphocyte and plasma cell clonal expansion in monosymptomatic optic neuritis cerebrospinal fluid. Ann. Neurol.56, 97–107 (2004).
- Qin YF, Duquette P, Zhang YP, Talbot P, Poole R, Antel J. Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J. Clini. Invest.102, 1045–1050 (1998).
- Colombo M, Dono M, Gazzola P et al. Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J. Immunol.164, 2782–2789 (2000).
- Baranzini SE, Jeong MC, Butunoi C et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J. Immunol.163, 5133–5144 (1999).
- 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. S. Lab. Invest.83, 1081–1088 (2003).
- Genain CP, Cannella B, Hauser SL, Raine CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat. Med.5, 170–175 (1999).
- Zhang Y, Da RR, Hilgenberg LG et al. Clonal expansion of IgA-positive plasma cells and axon-reactive antibodies in MS lesions.J. Neuroimmunol.167, 120–130 (2005).
- Zhang Y, Da RR, Gu WZ et al. Axon reactive B cells clonally expanded in the cerebrospinal fluid of patients with multiple sclerosis. J. Clin. Immunol.25, 252–262 (2005).
- Rawes JA, Calabres VP, Khan OA, DeVries GH. Antibodies to the axolemma-enriched fraction in the cerebrospinal fluid and serum of patients with multiple sclerosis and other neurological diseases. Mult. Scler.3, 363–369 (1997).
- Silber E, Semra YK, Gregson NA, Sharief MK. Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology58, 1372–1381 (2002).
- Cross SA, Salomao DR, Parisi JE et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann. Neurol.54, 38–50 (2003).
- Sadatipour BT, Greer JM, Pender MP. Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann. Neurol.44, 980–983 (1998).
- Kolln J, Ren HM, Da RR et al. Triosephosphate isomerase- and glyceraldehyde-3-phosphate dehydrogenase-reactive autoantibodies in the cerebrospinal fluid of patients with multiple sclerosis.J. Immunol.177, 5652–5658 (2006).
- Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol.47, 707–717 (2000).
- Bagasra O, Michaels FH, Zheng YM et al. Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis.Proc. Natl Acad. Sci. USA92, 12041–12045 (1995).
- De Stefano N, Matthews PM, Filippi M et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology60, 1157–1162 (2003).