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We investigated the paraclinical profile of monosymptomatic optic neuritis (ON) and its prognosis for multiple sclerosis (MS). The correct identification of patients with very early MS carrying a high risk for conversion to clinically definite MS is important when new treatments are emerging that hopefully will prevent or at least delay future MS. We conducted a prospective single observer and population-based study of 147 consecutive patients (118 women, 80%) with acute monosymptomatic ON referred from a catchment area of 1.6 million inhabitants between January 1, 1990 and December 31, 1995. Of 116 patients examined with brain MRI, 64 (55%) had three or more high signal lesions, 11 (9%) had one to two high signal lesions, and 41 (35%) had a normal brain MRI. Among 143 patients examined, oligoclonal IgG (OB) bands in CSF only were demonstrated in 103 patients (72%). Of 146 patients analyzed, 68 (47%) carried the DR15,DQ6,Dw2 haplotype. During the study period, 53 patients (36%) developed clinically definite MS. The presence of three or more MS-like MRI lesions as well as the presence of OB were strongly associated with the development of MS (p < 0.001). Also, Dw2 phenotype was related to the development of MS (p = 0.046). MRI and CSF studies in patients with ON give clinically important information regarding the risk for future MS.

Acute unilateral monosymptomatic optic neuritis (ON) is a common first manifestation of MS if associated with multiple MS-like lesions on brain MRI and oligoclonal IgG bands (OB) in the CSF, whereas ON patients lacking these laboratory abnormalities are considered to have a good prognosis regarding future MS development. Several cytokines involved in immune regulation are upregulated in blood and even more noticeable in CSF in MS. To study a possible relation between cytokine profiles and presence versus absence of MS-like brain MRI lesions and CSF OB, we used in situ hybridization to examine mRNA expression of the proinflammatory interleukin-12 (IL-12), interferon-γ, and tumor necrosis factor-α and the immune response downregulating IL-10, transforming growth factor-β and IL-4 in blood and CSF mononuclear cells (MNC) from 59 patients with untreated ON. There were no differences in numbers of MNC in blood or CSF expressing any of the cytokines under study, upon subgrouping the ON patients regarding presence (n = 31) versus absence (n = 28) of MRI lesions, presence (n = 45) versus absence (n=14) of OB, or duration after onset of ON (1 month, n = 29). Similarly, no differences were observed for numbers of myelin basic protein-reactive blood MNC expressing any of these cytokines after subrouping according to these variables. Our findings suggest that the cytokine profile, as examined in this study, is less useful to determine the risk of future development of clinically definite MS in ON patients or as indicator for therapeutic interventions in ON. An upregulation of both pro- and anti-inflammatory cytokines in ON patients seems to be more related to the CNS disease per se, whether limited to the optic nerve or not, than to the inflammatory process characteristic for MS.

The TH1 vs non-TH1 cytokine balance in Guillain-Barré syndrome (GBS) is unknown. Using enzyme-linked immunospot (ELISPOT) assays, we observed elevated numbers of interleukin (IL)-6 and IL-10-secreting blood mononuclear cells (BMNC) during the acute phase in untreated patients, and low levels of tumor necrosis factor α-secreting BMNC in the recovery phase of GBS. Numbers of IL-12p70-secreting BMNC were not affected over the course of GBS. The non-TH1 cytokine profile observed early in GBS may explain the self-limited clinical course associated with GBS.

T cells recognizing the myelin components myelin basic protein (MBP) and proteolipid protein (PLP) are increased in multiple sclerosis (MS), and there are elevated numbers of T cells recognizing the nicotinic acetylcholine receptor (AChR) in myasthenia gravis (MG). However, the cytokine repertoires in these diseases are largely unknown. We adopted in situ hybridization with radiolabeled complementary DNA oligonucleotide probes to enumerate mononuclear cells that expressed the T-helper type 1 (Th1) cell-related interferon-gamma (IFN-gamma) and Th2-associated interleukin-4 (IL-4) after short-term culture in the presence of autoantigen. High numbers of IFN-gamma and IL-4 mRNA-expressing cells in response to MBP and PLP were detected in patients with untreated MS, and to AChR in MG. The levels of IFN-gamma and IL-4 mRNA-positive cells in MS after culture in the presence of AChR, and in MG after culture in the presence of MBP or PLP, did not differ from those detected after culture without antigen. The CSF of MS patients contained four- to eightfold more myelin protein-reactive IFN-gamma and IL-4 expressing cells. The findings imply that MS and MG are associated with mixed Th1- and Th2-like cell responses directed to organ-specific target antigens.

We describe two families with conjugal multiple sclerosis. Onset of symptoms in the husbands occurred 11 and 17 years after onset of relapsing/remitting symptoms in their wives. There were no similarities regarding clinical manifestations of MS within each family. Evaluation of T-cell repertoire by enumeration of cells secreting interferon-gamma in response to proteolipid protein (PLP), myelin basic protein (MBP), and to various synthetic MBP peptides revealed similar patterns of T-cell reactivity within the families both in MS-affected parents and unaffected children. Genomic HLA-DR-DQ typing showed that T-cell reactivity was independent of HLA class II phenotype. Analysis of B-cell responses in blood showed low numbers of cells secreting IgG, IgA, or IgM antibodies against MBP, PLP, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein both in MS-affected and unaffected family members. In conclusion, our study of two families with conjugal MS has shown a dominant T-cell response against the same MBP peptide within the family both in MS-affected parents and unaffected children, and this T-cell response seems to be independent of the HLA class II phenotypes of the family members.

Monosymptomatic unilateral optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS) in which increased numbers of autoimmune T and B cells, recognizing different myelin autoantigens including myelin basic protein (MBP) and its peptides, have been implicated in a hypothetical immunopathogenesis. Using an immunospot assay to detect specific antibodies secreted by individual cells, we analyzed the B-cell repertoire to MBP and its amino acid residues 1-20, 63-88, 110-128, and 148-165 in blood and CSF from patients with ON and MS, and from controls. There were cells secreting IgG antibodies to MBP and the four peptides in blood at mean numbers of 0.9 to 4.6 per 105 mononuclear cells, without differences between the three patient groups. Mostly, more than 100-fold more B cells with these specificities per 105 cells were found in CSF from the patients with ON and MS, without differences between these two groups but with many fewer in CSF from controls. None of the four included MBP peptides represented an immunodominant B-cell epitope in either ON or MS, and the B-cell response was not more restricted in ON than in MS. The autonomy of the autoimmune B-cell response in CSF was further supported by the pronounced asynchrony of the repertoire to the four MBP peptides in CSF compared with blood in individual patients. The large numbers of MBP- and MBP peptide-reactive B cells in CSF in early MS, as manifested by ON, could play a major role in the immunopathogenesis and perpetuation of MS. Alternatively, they could represent myelin breakdown or restoration.

An autoimmune response to myelin basic protein (MBP) has been proposed to participate in the development of the chronic neurologic manifestations that may accompany Borrelia burgdorferi -induced Lyme disease. Using an immunospot assay, we counted cells secreting antibodies to MBP. Anti-MBP IgG antibody-secreting cells were detected in CSF from eight of 13 consecutive patients with Lyme neuroborreliosis irrespective of stage of disease. The numbers were between 1/370 and 1/5,000 CSF cells (mean, 1/1,250 in the 13 patients). The highest numbers were encountered in two patients with severe signs of CNS involvement. The numbers decreased in parallel with clinical improvement after treatment. Anti-MBP IgG antibody-secreting cells were also observed in the CSF from patients with a variety of other inflammatory diseases of the nervous system, and their role in the development of tissue damage remains unsettled. Anti-MBP IgG antibody-secreting cells were not detected in the patients9 blood, reflecting accumulation of this autoantibody response to CSF.

IgG from individual cerebrospinal fluid (CSF) and sera from patients with multiple sclerosis and from controls was isolated by protein A-Sepharose column chromatography and tested in the tadpole optic nerve system for myelinotoxic activity. Oligoclonal IgG was present in all multiple sclerosis CSF specimens used. All IgG preparations yielded optic nerve myelin lesions, indicating that IgG has myelinotoxic activity. Significantly higher numbers of myelin lesions were obtained with IgG prepared from multiple sclerosis CSF compared to control CSF IgG.

The myelinotoxic activity of unconcentrated cerebrospinal fluid (CSF) from eight optic neuritis (ON) and five multiple sclerosis (MS) patients with oligoclonal IgG, and from five ON patients without oligoclonal IgG, was tested in the tadpole optic nerve system. CSF from ON or MS patients with oligoclonal CSF IgG gave a significantly greater number of myelinotoxic lesions than did CSF from ON patients without oligoclonal CSF IgG, CSF from control patients, or physiologic saline. Induction of myelinotoxic lesions may be coupled with the presence of oligoclonal IgG. The findings support the hypothesis that there are two different forms of ON, of which one, characterized by oligoclonal IgG in the CSF. is more closely related to MS.

The frequencies of the HLA antigens A3, B7, and Dw2, previously related with multiple sclerosis, were investigated in 26 patients with acute aseptic meningitis and oligoclonal immunoglobulins in cerebrospinal fluid (CSF), but not in serum when investigated by agarose gel electrophoresis. HLA antigen frequencies were similar in patients with aseptic meningitis and controls. The oligoclonal immune response within the central nervous system in aseptic meningitis is not associated with the same HLA antigens found in patients with multiple sclerosis.

Oligoclonal immunoglobulin (Ig) bands were found in cerebrospinal fluid (CSF) by agarose gel electrophoresis and thin-layer polyacrylamide gel isoelectric focusing in 10 patients with cerebral infarction and 2 patients with transient ischemic attacks. Immunofixation revealed that the oligoclonal Ig was of the G class. One patient also had a band of free lambda light chains. The appearance of oligoclonal IgG during the course disease was observed in one patient, and the disappearance in six patients. Only three patients had elevated CSF IgG levels or abnormal synthesis rate of IgG in the nervous system. The oligoclonal reaction observed in acute cerebrovascular disease may reflect a polyclonal B-cell activation within the central nervous system after brain tissue damage.

Migration properties and occurrence of antibodies against myelin basic protein (MBP) in paired CSF and serum specimens from patients with multiple sclerosis (MS) were demonstrated after agarose isoelectric focusing, immunoblot transfer, and immunoperoxidase staining. Oligoclonal IgG antibody bands directed against MBP were found in the CSF of 9 of 28 patients with MS (32%), but not in the CSF of any of 34 patients with other neurologic diseases. No serum showed anti-MBP antibody bands. The CSF anti-MBP antibodies migrated to the anodal region of the IgG area in a different fashion from oligoclonal IgG and anti-measles IgG antibodies, which were detected in parallel. The anti-MBP bands were transient in three of seven patients whom we studied consecutively. Enzyme-linked immunosorbent assay (ELISA) of serum and CSF for detection of IgG reactivity against MBP showed absorbance values above 2 standard deviations of controls in 44% of the MS patients and in 21% of those with other neurologic diseases. Results of this assay correlated partly with those of the immunoblot assay. ELISA positive and immunoblot negative results might be due to a broad polyclonal anti-MBP antibody response.