Genetic predisposition to rheumatoid arthritis (RA) is linked to the MHC class II allele HLA-DR4. The charge of the amino acid at DRbeta71 in the peptide-binding site appears to be critical in discriminating DR molecules linked to increased disease susceptibility. We have determined the 2.5 A x-ray structure of the DR4 molecule with the strongest linkage to RA (DRB1*0401) complexed with a human collagen II peptide. Details of a predicted salt bridge between lysine DRbeta71 and aspartic acid at the P4 peptide position suggest how it may participate in both antigen binding and TCR activation. A model is proposed for the DR4 recognition of collagen II (261-273), an antigen immunodominant in human-transgenic mouse models of RA.

The p38 MAP kinase signal transduction pathway is an important regulator of proinflammatory cytokine production and inflammation. Defining the roles of the various p38 family members, specifically p38␣ and p38␤, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38␣ or p38␤ kinase has been rendered resistant to the effects of specific inhibitors along with p38␤ knock-out mice to dissect the biological function of these specific kinase isoforms. Mice harboring a T106M mutation in p38␣ are resistant to pharmacological inhibition of LPS-induced TNF production and collagen antibody-induced arthritis, indicating that p38␤ activity is not required for acute or chronic inflammatory responses. LPS-induced TNF production, however, is still completely sensitive to p38 inhibitors in mice with a T106M point mutation in p38␤. Similarly, p38␤ knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38␣ isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.

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The proliferative response of colonic epithelial cells to methylazoxymethanol (MAM) was followed in 1,2-dimethylhydrazine (DMH)-sensitive SWR/J, moderately resistant C57BL/6J, and resistant AKR/J strains. Untreated AKR mice had a significantly lower labeling index (L1) a shorter proliferative compartment (PC), and a smaller percentage of DNA synthesizing cells in the middle third of the crypts than did the SWR strain. SWR had the highest Ll, the widest PC, and the largest percentage of DNA synthesizing cells in the middle third of the crypts. C57BL/6 mice had characteristics that lay between the sensitive and resistant strains. Pooled data from 1 week after the fifth and sixth injections and 12 weeks after the first MAM injection revealed that extension of the PC had occurred in all strains, but it was only the DMH-sensitive SWR strain that showed extension of the PC to the upper third of the crypt, the greatest shift of proliferating cells to the middle and upper third of crypts, and the greatest increase in Ll. The AKR strain demonstrated these proliferative alterations least, and the C57BL/6 strain fell between them. This differential response to MAM among the strains mimicked that previously reported by us when DMH was investigated. The similarity in response of the colonic epithelial cells of each strain to either a direct-acting (MAM) or indirect-acting carcinogen (DMH) would support the concept that susceptability to this family of carcinogens is directly related to the genetically controlled indigenous proliferative characteristics of the colon.