Humoral Immunity As Indirect Evidence For Autoimmunity In Ms

The humoral arm of the immune system has been implicated in the pathogenesis of MS. The findings of oligoclonal bands (OCBs) and increased levels of intrathecal immunoglobulins (Igs) in more than 90% of MS patients strongly suggest involvement of B-cells in MS. The Igs found in MS CSF include IgG, IgA, IgM, and IgD (92). B-cells, plasma cells, and Ig are typically present in MS lesions, and at times have been identified in normal-appearing white matter of MS patients (93,94). Even in the very earliest cases examined, Ig and immune complexes have been observed consistently, suggesting a role for the humoral immune system from disease onset (95). An ongoing histological study of active MS lesions from biopsies and autopsies has found that the most common pattern of pathology involves Igs and complement, as well as mononuclear leukocyte infiltration (96).

Numerous studies have linked B-cells and antibody to MS prognosis. CSF cell phenotypes were assayed in 60 MS patients, and the results were correlated with clinical progression. Those patients displaying a "B-cell dominant'' phenotype, with high percentages of B-cells, plasma cells, and IgG in CSF, had significantly faster disease progression (r = 0.57; P < 0.0009) than MS patients with a "monocytes dominant" phenotype (97). Increased concentrations of Abs in CSF of MS patients correlate with episodes of MS worsening (98). Excessive CSF free kappa light chains, a byproduct of Ig production, is correlated with poor prognosis (99). IgM and IgG in the CSF typically demonstrate a pattern of limited clonality, referred to as OCBs because of the banding pattern observed when concentrated CSF is electrophoresed through agarose. The presence or absence of CSF OCBs is correlated with MS prognosis. Patients lacking CSF OCBs typically have a more benign course (100). Studies from this laboratory suggested that higher numbers of CSF-specific OCBs at MS onset is associated with poorer clinical outcome (101).

Although CSF IgG is typically the only Ig isotype measured by clinical laboratories, published studies indicate that CSF IgM levels and OCBs composed of IgM may also portend a worse prognosis, perhaps with better accuracy than magnetic resonance imaging (MRI) (102,103). The presence of IgM OCBs in the initial diagnostic spinal tap has been associated with both increased disability accumulation (P < 0.002) and with conversion to secondary progressive MS (P < 0.0009) (104).

Molecular studies indicate that production of Abs in the CNS of MS patients is antigen-driven, making an indirect case for autoimmunity. The complementarity-determining regions (CDR) of Abs are the antigen-binding sites, and include the Ig heavy-chain variable (VH) region. Somatic hypermutations occur in the CDR when B-cells are exposed to their antigen; these mutations often lead to amino acid substitutions that enhance Ig affinity for target antigen leading to "affinity maturation.''

In antigen-driven responses, mutations accumulate in Ig gene regions that contact antigen at a higher rate than in regions that have no antigen contact. In antigen-driven responses, mutations resulting in amino acid substitutions accumulate more than "silent" mutations. A number of studies have observed alterations typical of antigen-driven responses in CSF B-cells or B-cells in brain lesions of MS patients, indicating that B-cells have encountered their specific antigen in the CNS. These studies bolster the autoimmune hypothesis of MS pathogenesis.

Several groups of investigators have performed these studies with very consistent results. For example, in one study, IgG VH sequences from two acute MS plaques from a single patient were examined and compared with IgG VH sequences in subacute sclerosing panencephalitis (SSPE) brain and normal human brain. As expected, IgG purified from both the SSPE and MS brains displayed OCBs, whereas the normal human brain displayed a more heterogeneous Ig pattern. When the VH regions were cloned and sequenced, VH4 usage predominated within MS lesions, although the majority of sequences at the two sites from the one MS patient were different. All CDR sequences from the acute MS plaques displayed mutations compared to the germline (105). The same group later reported on studies of two additional MS brains where, once again, genes encoding Ig within MS plaques were more restricted in gene segment usage than germline, displayed multiple mutations, and had a high percentage of replacement mutations in the CDRs. This same pattern was noted in SSPE brain tissues, where there is a known antigenic stimulus, measles virus (106).

MOG is a minor protein component of CNS myelin, comprising less than 0.05% of myelin protein. However, this glycoprotein elicits a strong B-cell response (107), perhaps because MOG localizes to the outer surface of myelin and oligoden-droglia. Humans can develop both cellular and humoral immune response to MOG (108-110). Arguably, B-cell and antibody responses to both MOG (111) and MBP (112) are somewhat more prevalent in MS patients than in controls. These antibodies may be the result, rather than the cause, of CNS pathology.

If the anti-myelin antibodies are critical to MS pathogenesis, they should be present at onset. Investigators have reported that in patients with a single isolated clinical demyelinating syndrome suggestive of MS, the presence of myelin-reactive IgM Abs in serum may predict the development of clinically definite MS. Of 103 patients initially presenting with neurologic symptoms suggesting demyelinating brain lesions evident on MRI, and OCBs in the CSF, serum samples were tested for Abs to MOG and MBP. Not all patients displayed anti-myelin antibodies, but those that did were more likely to have a second attack within two years than the seronegative patients. Those initially exhibiting both anti-MOG and anti-MBP Abs were most likely to have an early relapse (113).

Axonal damage is a common component of MS plaques, believed to be irreversible in the CNS. Neurofilaments are axonal cytoskeletal proteins. CSF antibodies against the 68 kDa light subunit of neurofilaments have been reported in the progressive forms of MS (114). Their presence in the CSF of MS patients has been correlated with lesion burden and cerebral atrophy, as detected by MRI (115). Cerebral atrophy in MS patients is thought to reflect diffuse axonal loss.

The above data constitute circumstantial evidence for the humoral immune response in MS pathogenesis. However, humoral immunity may not be completely detrimental in MS. Antibodies might also mediate CNS repair, as suggested by one group of investigators who have identified antibodies directed against oligoden-drocytes, that appear to promote remyelination (116).

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