This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed.

The biological actions of the endogenous cannabinoid anandamide are terminated by carrier-mediated transport into neurons and Ž . astrocytes, followed by enzymatic hydrolysis. Anandamide transport is inhibited by the compound N-4-hydroxyphenyl arachidonylamide Ž . AM404 . AM404 potentiates several responses elicited by administration of exogenous anandamide, suggesting that it may also protect endogenous anandamide from inactivation. To test this hypothesis, we studied the effects of AM404 on the plasma levels of anandamide Ž . Ž y1 using high-performance liquid chromatographyrmass spectrometry HPLCrMS . Systemic administration of AM404 10 mg kg . intraperitoneal, i.p. caused a gradual increase of anandamide in rat plasma, which was significantly different from untreated controls at 60 and 120 min after drug injection. In plasma, both AM404 and anandamide were associated with a plasma protein, which we identified Ž . 4-methyl-1 H-pyrazole-3-carboxamideP hydrochloride SR141716A, 0.5 mg kg , i.p . These results are consistent with the hypothesis that AM404 inhibits anandamide inactivation in vivo. q

In vitro modulation of the cytokine network by MTX, increasing Th2 cytokines and decreasing Th1 cytokines, could explain its antiinflammatory and immunoregulatory actions in vivo during the treatment of RA.

The binding ability of 23 overlapping peptides, all derived from the CB11 fragment of CII, was tested on several HLA-DR molecules associated or not with disease susceptibility. These experiments were performed on a variety of cells expressing different HLA-DR molecules, using both indirect and direct binding assays. The CII (256-271) fragment was shown to bind to a restricted population among which the HLA-DR molecules associated with susceptibility to rheumatoid arthritis. The results also clearly indicate that the binding specificity of CII (256-271), among the DR4 molecules, is controlled by the nature of the HLA-DR molecule beta-chain residues 71 and 74, residues previously shown by X-ray crystallography to be involved in the HLA-DR/peptide interaction. The human CII (256-271) peptide is thus likely to play a role in the disease process.

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