During the initial three years of work our studies focused on the humoral immune response in Multiple Sclerosis (MS). We found that the intrathecal synthesis of free kappa light chains manifest by markedly increased concentrations of free kappa chains in cerebrospinal fluid (CSF) was a consistent, early, and stable abnormality in MS patients. In contrast, we have not yet observed this abnormality in patients with noninfectious diseases of the nervous system; patients with culture-established CNS infections characteristically exhibited an IgG-lambda intrathecal humoral immune response. Thus, our work to date suggests that exaggerated intrathecal synthesis of free kappa chains is not only a consistent abnormality in MS, but is also remarkably specific for MS compared with the relative nonspecificity of other IgG abnormalities. Studies proposed for the subsequent three years of support will logically follow from the initial studies. We propose carefully- designed prospective clinical studies designed to determine the relevance of humoral immune abnormalities in Ms. First, we will conduct a prospective study to determine how to use CSF parameters to predict the rate and severity of disease progression in MS. This study is important because of our total inability to predict the likely disease severity in individual MS patient early in the course of this extremtly variable disease. In addition to causing distress for all concerned, this results in marked heterogeneity within groups in therapeutic trials, confounding interpretation of treatment efficacy. Second, we will determine the prognostic value of CSF IgG abnormalities in predicting progression to disseminated disease in individuals with monosymptomatic disease. Third, we will determine the optimal test or combination of tests for the diagnosis of MS in particular clinical settings. We will use receiver operating characteristics and decision analysis to propose clinically useful algorithms based on the generated data. These studies offer the promise of clarifying the clinical relevance of humoral immune abnormalities in the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020303-05
Application #
3400595
Study Section
Neurology C Study Section (NEUC)
Project Start
1984-07-01
Project End
1991-03-31
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Aikens, J E; Reinecke, M A; Pliskin, N H et al. (1999) Assessing depressive symptoms in multiple sclerosis: is it necessary to omit items from the original Beck Depression Inventory? J Behav Med 22:127-42
Rudick, R A; Medendorp, S V; Namey, M et al. (1995) Multiple sclerosis progression in a natural history study: predictive value of cerebrospinal fluid free kappa light chains. Mult Scler 1:150-5
Rudick, R A; Ransohoff, R M (1992) Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity. Arch Neurol 49:265-70
Stanescu, G L; Swick, A R; Tuohy, V K et al. (1991) Sensitive competitive-binding ELISAs for quantifying free kappa and lambda light chains in cerebrospinal fluid. J Clin Lab Anal 5:206-11
Rudick, R A; French, C A; Breton, D et al. (1989) Relative diagnostic value of cerebrospinal fluid kappa chains in MS: comparison with other immunoglobulin tests. Neurology 39:964-8
DeCarli, C; Menegus, M A; Rudick, R A (1987) Free light chains in multiple sclerosis and infections of the CNS. Neurology 37:1334-8
French, C A; Tracy, R P; Rudick, R A et al. (1986) Simultaneous determination of cerebrospinal fluid oligoclonal bands and the ""gamma-protein index"" by agarose electrophoresis and densitometry. Clin Chem 32:84-7
Rudick, R A; Jacobs, L; Kinkel, P R et al. (1986) Isolated idiopathic optic neuritis. Analysis of free kappa-light chains in cerebrospinal fluid and correlation with nuclear magnetic resonance findings. Arch Neurol 43:456-8
Rudick, R A; Pallant, A; Bidlack, J M et al. (1986) Free kappa light chains in multiple sclerosis spinal fluid. Ann Neurol 20:63-9
Knutson, D W; Rudick, R A; Herndon, R M (1985) Isolation of model soluble immune complexes in the fluid phase by monoclonal anti-IgG-ferritin antibodies. Scand J Immunol 21:1-9

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