Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptide analogues containing reversed peptide bonds between each residue along the peptide sequence (retro-inverso modification) have been analyzed for their antigenic and in vivo immunogenic properties in the MHC II and Th cell response context. Two antigenic peptides were selected for this study, namely peptide 103-115 of poliovirus VP1, which is involved in the production of Abs that neutralize the infectivity of the virus, and peptide 435-446 from the third constant region of mouse heavy chain IgG2a allopeptide gamma 2ab, which mimics a corneal Ag implicated in autoimmune keratitis. In a competition assay performed in vitro using reference hybridomas of known MHC class II restriction, both retro-inverso analogues bound (although more weakly in our test) to I-Ad and/or I-Ed class II molecules. However, in both cases, this lower affinity was apparently largely compensated in vivo, as a T cell response (with IL-2 secretion), equivalent to that obtained with the wild-type peptides, was observed following immunization of BALB/c mice with the retro-inverso analogues. Moreover, these T cells proliferated and produced IL-2 in response to the cognate peptides. It is concluded that the T cell receptors of T cells primed in vivo with the retro-inverso analogues readily cross-react with parent and retro-inverso analogue-MHC complexes. The approach of using pseudopeptides containing changes involving the backbone, and not the orientation of side chains, may thus be promising to design potent immunogens for class II-restricted T cells.
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PMID:In vivo T helper cell response to retro-inverso peptidomimetics. 931 21

Infection of the mouse cornea with herpes simplex virus (HSV) results in an immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in which the principal orchestrator is the CD4+ T cell. The mouse genotype largely determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of viral replication as well as anti-HSV immune responses were similar in both strains, it was determined whether resistance was due to failure of CD4+ T cells to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice resulted in HSK lesions indistinguishable from those caused by similar transfers of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T cell populations as well as with unfractionated splenocytes from the resistant mice. These results show that while intact C.B-17 mice exhibit resistance to HSK, they possess potentially pathogenic CD4+ T cells in their repertoire. The data suggest that the HSV-infected SCID mouse provides a proinflammatory microenvironment that overrides regulatory controls and/or cause activation of quiescent cells into aggressive effector T cells that orchestrate HSK.
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PMID:Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell function between euthymic host and reconstituted SCID recipients. 955 4

The IgG2a(b) heavy chain allopeptide determinant gamma2a(b) 436-451 (Kabat numbering) presented by the major histocompatibility complex (MHC) class II molecule I-Ad is recognized by T cells which cross-react with a corneal self antigen and with the UL6 protein of the herpes simplex virus which induce autoimmune keratitis, and is the target of Th1 clones that suppress IgG2a(b) production in vivo. In the gamma2a(b) peptide/l-Ad complex, tyrosine438 is the first primary anchor (P1) and residues 440-445 encompass the T cell receptor contact residues. Amino-terminal elongation of gamma2a(b) 437-451 by a single residue (P-2) augmented the I-Ad binding capacity 10-fold and the antigenicity 55-195-fold. This was a function of the peptide main chain, since non-conservative substitutions were accepted. The gamma2a(b) peptide also bound HLA-DR1, and amino-terminal extension by a single aromatic amino acid at P-3 augmented binding 15-fold. The interaction between HLA-DR1 and P-3 specifically required an aromatic peptide side chain, and computer simulations indicated that the aromatic ring at P-3 engaged conserved HLA-DR1 phenylalanine residues at the edge of the peptide binding groove. Thus, these data demonstrate that residues amino terminal to P1 may substantially increase peptide affinity for MHC class II by main chain-dependent as well as side chain-dependent interactions, and imply that the HLA-DR1 motif should be extended to include an aromatic amino acid at P-3.
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PMID:N-terminal elongation of a peptide determinant beyond the first primary anchor improves binding to H-2 I-Ad and HLA-DR1 by backbone-dependent and aromatic side chain-dependent interactions, respectively. 993

The murine MHC class II variant I-Ad confers susceptibility to herpes simplex virus (HSV)-induced keratitis and relative protection against type 1 diabetes mellitus. The association to these autoimmune diseases appears to be largely determined by the peptide sidechain specificity of the P9 pocket, which we therefore have analyzed in detail. Assessment of T-cell responses and I-Ad binding capacity of position 446-substituted analogs of an IgG2a allotype b (IgG2a(b)) heavy chain peptide demonstrates that engagement of the P9 pocket is crucial for effective peptide presentation. Sidechain size rather than charge decides the capacity to engage the P9 pocket. Thus, small, uncharged sidechains are accepted, whereas acidic and aromatic amino acids as well as lysine and arginine are disfavored. The specificity of the P9 pocket of I-Ad (serine beta57) is distinct from that of the diabetes-associated I-Ag7 (aspartic acid beta57), supporting the contention that the polymorphism at residue beta57 influences diabetes susceptibility via P9-specific effects on the repertoires of self peptides presented to T cells. Furthermore, the data rationalize the susceptibility to HSV-induced keratitis conferred by the a and the protection conferred by the b allotypes of the IgG2a heavy chain. Keratitogenic T cells, which cross-react with the viral UL6 protein and a corneal antigen, are silenced in IgG2a(b) mice because of antigenic mimicry with gamma2a(b) 435-451. Our finding that the lysine P9 residue of the corresponding gamma2a(a) allopeptide precludes high-affinity binding to I-Ad indicates that the susceptibility of IgG2a(a) mice reflects inefficient thymic presentation of autologous IgG2a and thus failure to purge the T-cell repertoire of the pathogenic clones.
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PMID:The P9 peptide sidechain specificity of I-Ad. 1065 74