The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

Abstract

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS.

Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM

“…Data from pathological studies indicate that PPMS is characterized by a global inflammatory process, with diffuse axonal injury in the white matter and cortical demyelination; 8,35 and the evidence for diffuse pathology, with demyelination and axonal loss, but less overt inflammation, is consistent with an antibodymediated pathogenesis. 36 Moreover, inflammatory infiltrates from PPMS lesions were found to have fewer CD3 T-lymphocytes and fewer macrophages when compared with RR and SPMS, but no differences in the quantity of plasma cells have been reported. 37 The more recent concept is that in the progressive phases inflammation is not absent, but is compartmentalized within the CNS, trapped behind an intact blood-brain barrier, 38,39 and in this context the inflammatory tissue injury may be sustained by the formation of B cell follicle-like lymphatic tissue, containing clusters of B and plasma cells, 40,41 found only in chronic progressive MS.…”

High-Density Peptide Microarray Analysis of IgG Autoantibody Reactivities in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients

“…Though, in the CSF data set, this pattern was dominated by four PPMS patients with relatively high total CSF IgG levels (PPMS_05, PPMS_07, PPMS_09, and PPMS_10), the serum antibody profiles pointed to a broadened immune response in the PPMS cohort as well. It may be speculated whether this reflects the PPMS patients' higher grade of disability (Table I) and/or diffuse rather than focal CNS inflammation (45). An earlier study by Quintana et al with microarrays containing Ͻ370 peptides analyzed serum antibody signatures in RRMS and PPMS as well.…”

Toward biomarkers in multiple sclerosis: new advances

“…Among these there are the progressive forms of MS [96], and other diseases close to MS, such as neuromyelitis optica (NMO) or Devic disease [97], Marbur [98] or Schilder disease [99]. A biomarker would ideally be of major importance if able to differentiate these different diseases and anticipate their faster clinical evolution.…”