Spirochaetes, Lyme disease, and multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to D Gay.
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Evidence of a direct link between chronic sinusitis and multiple sclerosis (MS) prompted examination of the old "spirochaetal hypothesis". This hypothesis has not been shown to be erroneous and a spirochaetal infection of the central nervous system could explain the specific pathological, immunological, and epidemiological features of MS.
In an analysis of general practice records the rate of chronic sinusitis was significantly greater in 92 patients with multiple sclerosis (MS) than in matched controls (p less than 0.0001). MS and chronic sinus infection were also significantly associated in the timing of attacks, in the age at which patients suffered their attacks, and in the seasonal pattern of attacks.
Prolonged corticosteroid therapy produces a major degree of protein catabolism. Short-term treatment with ACTH or glucocorticoids results, in males, in a fall in plasma testosterone levels. In order to determine the origin of this hypogonadism, the testicular function was investigated in 18 men under prolonged glucocorticoid treatment. The mean plasma testosterone level in men treated for less than 3 months (5.9 +/- 0.8 ng/ml) was not statistically different from that obtained in controls (7.5 +/- 0.5 ng/ml; P greater than 0.05). However, the mean plasma luteinizing hormone level was significantly higher in these patients than in controls (8.2 +/- 1.9 mUl/ml vs 3.6 +/- mUl/ml respectively; P less than 0.001). In patients treated for more than 2 years, the mean plasma testosterone level (3.8 +/- 0.6 ng/ml) was significantly lower than in controls (P less than 0.001), but the mean plasma luteinizing hormone level was normal (5 +/- 1 mUl/ml). Plasma testosterone levels are negatively correlated with the daily dose of glucocorticoid (r = -0.81; P less than 0.001). The free testosterone index was within normal range in 5 of the 9 men under prolonged steroid therapy, near the lower limit of normality in 2 men and definitely low in 2 other men. The gonadotrophin response to the luteinizing hormone releasing hormone was normal, whereas the testicular response to human chorionic gonadotrophin was reduced. These data suggest that prolonged treatment with steroidal anti-inflammatory agents influences both gonadotrophic and testicular function and may be associated with true hypoandrogenism.
Antibody inhibition studies were done to determine which molecules on the surface of the T cell hybridomas other than their receptors for antigen plus IAd were involved in interaction with antigen-presenting B cells, with artificial IAd membranes on glass beads, or with anti-receptor antibodies coupled to Sepharose beads. We found that T cell LFA-1 was only involved when B cells were used to present antigen plus IAd, whereas T cell L3T4 was involved in the response of T cells to antigen plus IAd either on cells or in artificial membranes, but not if anti-receptor antibodies were used to stimulate the T cells. From these results we concluded that LFA-1 may be involved in the recognition of a ligand on cells that was not present in artificial membranes, but that L3T4 might interact with a nonpolymorphic portion of class II molecules present in both intact antigen-presenting cells and the antigen-presenting artificial membranes.
We have studied the role of the murine lymphocyte function associated antigen-1 (LFA-1) in the major histocompatibility complex (MHC)-restricted responses of a panel of T-cell hybridomas to protein antigens. Monoclonal antibodies to LFA-1 showed a differential blocking effect in these responses that correlated with the overall "sensitivity" of a given hybrid to antigen and MHC as defined by other criteria already reported. This result differs completely from similar experiments in the CTL system where all clones regardless of their overall "avidity" for target cells are very sensitive to the blocking effects of anti-LFA-1. Further, we show that no blocking effects are observed in the response of our hybridomas when Class I or Class II transfected fibroblasts or cultured 3T3 fibroblasts are used as synthetic antigen presenting cells and the result is unaltered by preincubation of such cells with interferon-gamma (IFN-gamma).
We have constructed a hybrid E beta gene by replacing the second exon of the Ed beta gene (which encodes the majority of the beta 1 protein domain) with the corresponding exon from the Eb beta gene. The hybrid gene has been introduced into a d haplotype host, the lymphoma beta-cell line A20-2J, and an E alpha E beta dimer composed of the endogenous Ed alpha chain and the product of the hybrid Ed beta/Eb beta gene was immunoprecipitated from extracts of transfected cells with an Ed alpha Eb beta-specific monoclonal antibody. Transfected cells have acquired the ability to present antigen to Ed alpha Eb beta-restricted helper T-cell hybridomas, indicating that the second exon of the gene for the E beta chain encodes sequences required for the restricted recognition of the antigen-presenting cell by the class II-restricted responder T-cell.
The intense stereotyped gnawing induced by high doses of apomorphine is almost abolished by large bilateral lesions of the superior colliculus. It has been argued that the feeding produced by electrical stimulation of the lateral hypothalamic area is closely related to dopamine-mediated oral stereotypies; if so, it might be expected that lesions of the superior colliculus would also disrupt stimulation-bound feeding. Feeding was obtained from 14 hypothalamic electrodes in 8 hooded Lister rats. Subsequent electrolytic lesions of the superior colliculus had no overall effect on this behaviour from 13 of the 14 electrodes, even though the lesions reduced the gnawing induced by 8-20 mg/kg apomorphine to less than 10% of its preoperative intensity. It is concluded that stimulation-bound feeding and apomorphine-induced gnawing are not dependent on identical neural circuitry, and therefore stimulation-bound feeding is probably not mediated by the nigrotectal pathway.
Two different techniques are utilized: aerosol with 198Au particles (size 0.5-15 micron) and different gaz mixtures (air; O2 20% + He 80+; O2 60% + N2 40%; O2 60% + He 40%) with 133Xe and registration of the regional distribution along a wash-in (upper, middle and basal) of every lung (gamma camer, computer, Polaroid photographs, scans), performed in three groups of subjects (normal: 5, bronchogenic carcinoma: 11 and chronic bronchitis: 5). Modifications of the airway distribution and blood gas data according to the technical approach (particularly, variations of densities and viscosities) are compared with results in normal subjects.
Utilizing a PFC assay to quantitate the polyclonal activation of human peripheral blood B lymphocytes, we have investigated the induction and functional activity of MLC-derived human helper factor(s). Our data demonstrate that highly purified responder T cells, but not B or null cells, are required for the elaboration of MLC helper factor(s) that trigger the in vitro differentiation of B lymphocytes into PFC. Helper factor can trigger B cell maturation in the absence of helper T cells, since complement- (C) mediated lysis of the small (less than 5%) fraction of T cells present in anti-F(ab)2 immunoabsorbent column purified B cell population eliminates the PWM induced, but not the helper factor-induced PFC response. Responder T cells required for helper factor production do not bear surface membrane Ia, since alpha p23,30 + C treatment of this population does not affect helper factor generation. In contrast, alpha p23,30 + C treatment of the allogeneic stimulator cell population eliminates helper factor production. Taken together, these results demonstrate that interaction between Ia-bearing stimulator cells and Ia- responder T cells is required for the production of MLC-derived helper factor. In additional experiments, we determined that alpha p23,30, in the absence of C, totally abrogates the PFC response triggered by MLC helper factors. This result suggests an important role for Ia antigens in the functional activity of preformed helper factor molecules.
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Mature T cells segregate phenotypically into one of two classes: those that express the surface glycoprotein CD4, and those that express the glycoprotein CD8. The CD4 molecule is expressed primarily on helper T cells whereas CD8 is found on cytotoxic and suppressor cells. A more stringent association exists, however, between these T-cell subsets and the major histocompatibility complex (MHC) gene products recognized by their T-cell receptors (TCRs). CD8+ lymphocytes interact with targets expressing class I MHC gene products, whereas CD4+ cells interact with class II MHC-bearing targets. To explain this association, it has been proposed that these 'accessory' molecules bind to monomorphic regions of the MHC proteins on the target cell, CD4 to class II and CD8 to class I products. This binding could hold the T cell and its target together, thus improving the probability of the formation of the trimolecular antigen: MHC: TCR complex. Because the TCR on CD4+ cells binds antigen in association with class II MHC, it has been difficult to design experiments to detect the association of CD4 with a class II molecule. To address this issue, we devised a xenogeneic system in which human CD4 complementary DNA was transfected into the murine CD4-, CD8- T-cell hybridoma 3DT-52.5.8, the TCR of which recognizes the murine class I molecule H-2Dd. The murine H-2Dd-bearing target cell line, P815, was cotransfected with human class II HLA-DR alpha, beta and invariant chain cDNAs. Co-culture of the parental T-cell and P815 lines, or of one parental and one transfected line resulted in a low baseline response. In contrast, a substantial increase in response was observed when CD4+ 3DT-52.5.8 cells were co-cultured with HLA-DR+ P815 cells. This result strongly indicates that CD4:HLA-DR binding occurs in this system and that this interaction augments T-cell activation.
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