Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of unknown cause that afflicts the central nervous system. MS is typified by a highly clonally restricted antigen-driven antibody response that is confined largely to the central nervous system. The major antigenic targets of this response and the role of antibody in disease pathogenesis remain unclear. To help resolve these issues, we cloned the IgG repertoire directly from active plaque and periplaque regions in MS brain and from B cells recovered from the cerebrospinal fluid of a patient with MS with subacute disease. We found that high-affinity anti-DNA antibodies are a major component of the intrathecal IgG response in the patients with MS that we studied. Furthermore, we show DNAspecific monoclonal antibodies rescued from two subjects with MS as well as a DNA-specific antibody rescued from an individual suffering from systemic lupus erythematosus bound efficiently to the surface of neuronal cells and oligodendrocytes. For two of these antibodies, cell-surface recognition was DNA dependent. Our findings indicate that anti-DNA antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders, such as MS and systemic lupus erythematosus.

Antibody response in MOG35–55 induced EAE

“…In regards to our data, one can propose that in EAE, TLR9 and/or TLR7 stimulation induced by DNA-and RNA-associated antigens, respectively, may play a major role in the activation of dendritic cells and B cells, and could contribute to the propagation of inflammatory reactions in affected tissues. In support to our findings, early reports have indicated the presence of antibodies to DNA and RNA in the CSF and serum from patients with MS (Schuller et al, 1978) and that anti-DNA antibodies are a major component of intrathecal B cell responses in MS (Williamson et al, 2001). Overall, our data therefore suggest that anti-nucleic acid antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders such as MS and Lupus.…”

Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis

“…Coldreactive lymphocytotoxic antibodies have been identified in patients with MS, and have been found to correlate with Ig levels in the CSF (Weiner and Schocket, 1979) and disease progression (Scott and Spitler, 1983). Antibodies against dsDNA have been demonstrated to compose a significant fraction of the intrathecal IgG in patients with MS, and can be found in brain plaques and CSF of patients with MS. Two of the anti-dsDNA antibodies obtained from patients with MS were also able to react with the surface of oligodendrocytes and neuronal cells, suggesting that, similar to our antibodies obtained from a mouse with EAE, which also recognize dsDNA, these antibodies are polyreactive (Williamson et al, 2001). However, in contrast to the antibodies obtained from the mouse with P-EAE, the anti-dsDNA antibodies obtained from patients with MS did not react with MOG (Williamson et al, 2001).…”

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

“…High-affinity anti-DNA Abs was recently shown to be major component of the intrathecal IgG in cerebrospinal fluid and brain of MS patients [48]. Moreover, DNase abzymes from SLE and MS patients are cytotoxic and induce cell death by apoptosis [16,59].…”