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Abstract
Multiple sclerosis is a complex genetic disease associated with inflammation in the CNS white matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. This review discusses new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understanding of and therapies for this disease.
Authors
David A. Hafler
Plasma or plasmacytoid cells in multiple sclerosis?
Submitter: Colin L. Crawford | clcraw13@hotmail.com
Imperial College of Medicine, UK
Published April 27, 2004
In his article on multiple sclerosis (MS), Hafler (1) has drawn attention to the presence of ‘plasma cells’ in MS lesions. Immunoglobulin was demonstrated in these cells in MS in light microscopy sections; however, there is heavy cross staining of macrophages and astrocytes (2), and verification of immunoglobulin using immuno- electronmicroscopy has not been reported. Prineas (3), in describing this type of cell in MS lesions noted that in some of them, there were segments of thickened plasma membrane covered by basement membrane. Very similar modified patches of plasma membrane have been described in mononuclear cells, also found in MS (3). Thus two types of cell in MS lesions contain this type of structure, which is very similar to the subplasmalemmal linear densities (SPLDs) present on mononuclear cells in sarcoidosis (4). Although the plasma cell represents an end stage in differentiation and does not divide further, a binucleate form is very common in MS (2,5). For these reasons, it is possible that the cells in MS, may be plasmacytoid cells rather than plasma cells. Plasmacytoid cells were originally described in patients with lymphomas and resemble plasma cells in appearance, but do not secrete immunoglobulin. They are the precursors of epithelioid cells in sarcoidosis and have also have been found to contain SPLDs (6). In sarcoidosis, giant cells due to fusion are common, so that the binucleate cells in multiple sclerosis could also arise by cell fusion rather than division.
The plasmacytoid cell has now been identified as a type of dendritic cell (P-DC) in peripheral blood that produces large amounts of interferon alpha. They are found in skin lesions, present in lupus erythematosus (7) and are increased tenfold in the cerebrospinal fluid (CSF) of patients with early multiple sclerosis. Pashenkov and Link (8) comment that ‘CSF DCs might be recruited directly from the blood or shed from inflamed tissues’. As P-DC cells can be readily identified by their high levels of interleukin-3 receptor alpha chain (CD123), it ought to be possible to confirm their presence/absence in MS lesions.
P-DC cells have not been demonstrated in Experimental Allergic Encephalomyelitis, which is an acute response to myelin basic protein. In an experimental autioimmune peripheral nerve model to study non- lepromatous leprosy, a granulomatous disorder similar to sarcoidosis, we have demonstrated mononuclear cells with SPLDs (9) and plasma-like cells using a non-myelin antigen (10).
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3. Prineas, J.W., and Wright, R.G. 1978. Macrophages, lymphocytes and plasma cells in the perivascular compartment in chronic multiple sclerosis lesions. Lab. Invest. 38: 409-421.
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7. Farkas, L., Beiske, K., Lund-Johansen, F., Brandtzaeg, P., and Jahnse, F.L. 2001. Plasmacytoid dendritic cells (natural interferon-alpha/bet- producing cells) accumulate in cutaneous lupus erythematosus lesions. Am. J. Pathol. 159: 237- 243.
8. Pashenkov, M., and Link, H. 2002. Dendritic cells and immune responses in the central nervous system . Trends Immunol. 23: 69-70.
9. Crawford, C.L., and Hardwicke, P.M.D. 1993. Subplasmalemmal linear densities in mononuclear cells induced by an antigen in human sensory nerve. J. Anat 182: 129-130.
10. Crawford, C.L., and Hardwicke, P.M.D. 1979. Somatic unmyelinated fibre degeneration in rabbits with granulomatous hypersensitivity produced by a non-myelin fraction in sensory peripheral nerve. Acta Neuropath. 45: 1-7.
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