Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.

6 -dependent dioxygenase family (2OG oxygenases). Crystallographic and spectroscopic studies imply that the enzyme⅐Fe⅐2OG intermediate has an octahedral metal coordination, with three of the coordination sites occupied by the 2-oxo-acid of 2OG and a water molecule. In some cases, binding of substrate to this complex has been shown to induce loss of the iron bound water so enabling dioxygen binding. Oxidative decarboxylation of 2OG results in the formation of a ferryl species (Fe(VI)ϭO) that effects oxidation of the substrate/cosubstrate with the regeneration of Fe(II) at the active site (for review, see Refs. 1-3). In addition, spectroscopic studies have demonstrated that interaction of the non-iron-ligated oxygen atom of the carboxylate side chain of the metal binding Asp/Glu residue with the iron bound water molecule has a role in oxygen activation (4).Hydroxylation is the most common reaction catalyzed by the 2OG oxygenases, but family members also catalyze other oxidative reactions including demethylations, desaturations, epoxidations, and rearrangements. Related enzymes, which do not employ 2OG as a co-substrate, have been shown to catalyze oxidative fragmentations and cyclization reactions (for review, see Refs. 2 and 5). Recently, two 2OG oxygenases have been reported to catalyze oxidative halogenations (6, 7); the structure of one of these halogenases, SyrB2, revealed that the iron was coordinated by only two enzyme-derived His residues (8). The carboxylate-bearing residue found in all prior 2OG oxygenase structures was substituted by an Ala in SyrB2 apparently leaving sufficient space for a chloride ion to fill the vacant iron coordination site.Four 2OG oxygenases are known to be involved in regulation of the hypoxic response in humans via the post-translational hydroxylation of specific residues in the ␣-subunit of hypoxiainducible factor (HIF): three prolyl hydroxylases (9, 10) and an asparagine hydroxylase (FIH, factor inhibiting HIF (11-13)). Hydroxylation of specific proline residues signals for the proteolytic destruction of HIF-␣ (9, 10), whereas hydroxylation of an asparagine residue (Asn-803 in human HIF-1␣) (Fig. 1) in the C-terminal transactivation domain blocks recruitment of *