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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cell reactivity toward self MHC class II molecules has been recognized in syngeneic MLR in a number of studies, where the T cells are believed to recognize the combination of self/nonself peptide and self MHC molecule. We investigated the stimulation of T cell proliferation by synthetic peptides of sequences corresponding to the first polymorphic amino terminal domain of alpha- and beta-chains of self I-A molecules. Both unprimed and primed T cells responded to a number of peptides of alpha 1 and beta 1 domains of self I-Ad molecules. The response was dependent on the presentation of I-Ad peptides by syngeneic APC and was blocked by anti-class II MHC mAb. Upon further investigation it was observed that I-Ad peptides could inhibit the stimulation of Ag-specific MHC class II-restricted T cell hybridoma due to self presentation of peptides rather than to direct binding of free peptides to the TCR, further supporting their affinity/interaction with intact self MHC class II molecules. The peptide I-A beta d 62-78 showed high affinity toward intact self MHC II molecule as determined by the inhibition of Ag-specific T cell stimulation and yet was nonstimulatory for syngeneic T cells, therefore representing an MHC determinant that may have induced self tolerance. Thus we have shown that strong T cell proliferative responses can be generated in normal mice against the peptides derived from self MHC class II molecules and these cells are part of the normal T cell repertoire. Therefore complete tolerance toward potentially powerful immunodominant but cryptic determinants of self Ag may not be necessary to prevent autoimmune diseases.
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PMID:T cells that recognize peptide sequences of self MHC class II molecules exist in syngeneic mice. 164 18

Interphotoreceptor retinoid binding protein (IRBP) is a glycoprotein that localizes in the retina and induces inflammatory changes in this tissue in immunized animals. Certain IRBP-derived peptide determinants are also immunopathogenic, and we have previously shown that these determinants could be either immunodominant or cryptic. Lymphocytes sensitized against the cryptic peptides do not recognize whole IRBP in vitro, and yet these lymphocytes must recognize the protein in vivo to initiate the autoimmune pathogenic process. We have examined here two hypothetical explanations for this dissociation: 1) It is possible that when IRBP is processed in vitro, immunodominant peptide determinants compete with the cryptic ones and inhibit their interaction with the MHC molecules on the APC. This explanation was ruled out here by the finding that the immunodominant peptide 1179-1191 ("W10") did not inhibit the response to a cryptic one, 1158-1180 ("R4"), when added at equivalent and even moderately higher concentrations. 2) The second hypothesis proposes that the cryptic antigenic sites are not generated from IRBP by the APC in vitro, whereas enzymes in the retina digest the protein to yield fragments that generate these antigenic sites upon processing by the APC. In line with this hypothesis, we have found that cleavage of IRBP by certain endoproteinases (Asp-N, Glu-C, or V-8) produced molecules that were recognized in culture by lymphocytes sensitized to the immunopathogenic but cryptic peptide R4. This study, therefore, describes a putative Ag processing mechanism that results in IRBP recognition and, consequently, the initiation of an autoimmune process by lymphocytes sensitized against a cryptic peptide. Furthermore, experiments with R4 and other cryptic peptides have shown that cleavage fragments of up to 38 residues in length can be presented by APC, to stimulate lymphocytes sensitized against these peptides. No responses were stimulated, however, by fragments of 75 or more residues. The data thus provide new insights into the processing and presentation of cryptic peptide determinants by APC.
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PMID:Recognition of peptides that are immunopathogenic but cryptic. Mechanisms that allow lymphocytes sensitized against cryptic peptides to initiate pathogenic autoimmune processes. 170 61

T cell responses against complex antigens are often directed against a limited set of immunodominant determinants. We have studied this phenomenon at the level of cellularly processed peptides recognized by CTL in the B6 anti-BALB.B minor histocompatibility (H) barrier, comprising at least 29 antigen loci. B6 anti-BALB.B CTL always recognized three reverse phase HPLC fractions in BALB.B eluates, whether the latter were obtained from cell lysates or immunoaffinity purified class I molecules. One of these immunodominant epitopes (termed IDE-1) was H-2Db restricted, and two (termed IDE-2 and IDE-3) were H-2Kb restricted. B6 mice were immunized with spleen cells from B6 congenic mice carrying single minor H loci from BALB.B with the aim to assign IDE to given minor H loci and to investigate whether additional epitopes could be identified in the absence of the immunodominant ones. IDE-3 was found to be associated to the locus H-28; in addition five so called cryptic epitopes were defined. Induction of CTL against these epitopes required immunization with cells of the congenic strain; BALB.B spleen cells failed to immunize. One subgroup of these epitopes (those associated to H-8, H-19 and H-25) were nevertheless found to be processed and loaded in class I molecules of BALB.B cells, while there was no evidence for this for H-35 and H-36. For 10 additional congenic strains, no CTL response was detected. The results are discussed in relation to the genetic and molecular basis of minor H antigens, and mechanisms for epitope dominance operating at the level of the APC or responding T cells.
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PMID:Dominant and cryptic antigens in the MHC class I restricted T cell response across a complex minor histocompatibility barrier: analysis and mapping by elution of cellular peptides. 757

In this review, we first consider the inherent structural constraints for binding of a peptide to MHC class II molecules. Such parameters at the site of TCR recognition are dependent upon the efficient generation of the antigenic determinant during natural processing of the whole protein antigen. Strikingly, only a minor fraction of such potential determinants on an antigen are presented in an immunodominant manner, while the remaining peptides are silent (cryptic). Why one determinant is selected while the majority are neglected is still unresolved, but we review the experimental evidence pertaining to this choice. Thus, features of the antigen remote from the actual determinant can either steer processing toward disclosure or revelation of a determinant, or interfere with the binding of peptides to MHC (hinderotopy). The evidence is reviewed for "MHC-guided processing," where the unfolding antigen binds at an early stage to an MHC molecule through its most available and affine agretope and then is trimmed down to final size, while the rest of the molecule, including cryptic determinants, is discarded. Different MHC molecules can compete for determinants at an early stage of processing when the antigen is close to its original length. There are shifts in the hierarchy of display of dominant and cryptic determinants, and these shifts relate to local inflammatory states, to changes in the state or composition of the APC population, and to aspects of exogenous vs endogenous processing. The impact of this differential display of determinants on tolerance and autoimmunity is discussed.
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PMID:Dominance and crypticity of T cell antigenic determinants. 768 17

To identify the immunogenic and immunopathogenic sites present in human S-Antigen (S-Ag), 40 overlapping peptides that span the whole length of the S-Ag molecule were synthesized and tested in the Lewis rat model of experimental autoimmune uveitis. The most pathogenic sequences were 180-200, 340-360 and 350-370. Ten peptide sequences were identified that induced visible inflammation in the eye. A total of 23 peptides gave an in-vitro proliferative response following immunization in animals. The ability to generate an immune response was not linked to the pathogenic capacity of the sequence. The most pathogenic sequence, 340-360, was only weakly proliferative. Peptide 180-200 and peptide 340-360 gave higher T-cell proliferative responses, but these were lower than the maximal proliferative response observed with non-pathogenic sequences. In animals immunized with whole S-Ag, the majority of the determinants did not elicit a proliferative response, indicating that in S-Ag, the majority of the immunogenic determinants are cryptic and are not presented by the APC located in the lymph nodes.
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PMID:Human S-antigen: presence of multiple immunogenic and immunopathogenic sites in the Lewis rat. 769 88

T helper cells, which recognize allopeptides processed and presented by self APC, contribute to the generation of both cellular and humoral immune responses against allogeneic transplants. We have explored the hypothesis that the indirect T cell recognition pathway is initiated by soluble MHC antigens and that it can be suppressed by high doses of synthetic peptides corresponding to the dominant alloepitope. T cells from a DR11/7 responder were immunized in vitro with recombinant HLA-DR4 (rDR4). Experiments using partially overlapping synthetic peptides showed that the resulting T cell line (TCL) recognized a single dominant epitope mapping within residues 69-88 of the first domain of the DR4 molecule. In vitro immunization with synthetic allopeptides corresponding to other polymorphic regions, were unable to elicit T cell reactivity against rDR4, although at least one of these peptides (corresponding to residues 13-27) was immunogenic, behaving like a cryptic epitope. The rDR4-specific TCL expressed a limited TCR repertoire and provided help to autologous B cells for the production of specific antibodies. The T cell blastogenic response as well as the transcription and secretion of IL-4 (but not IL-2) was efficiently suppressed by high doses of the dominant allopeptide. These findings support the concept that selective immunointervention of indirect allorecognition can be achieved by use of high doses of antigen or TCR vaccination, as proposed for autoimmune diseases.
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PMID:Suppression of the indirect pathway of T cell reactivity by high doses of allopeptide. 882 75

Cellular immune responses are directed against a narrow set of immunodominant peptides derived from complex antigens. By contrast, epitopes that are hidden or infrequent targets of immune responses have been termed cryptic or subdominant. Although the identification of immunodominant epitopes is important for vaccine development, understanding immunological reactivity to cryptic or subdominant epitopes may hold clues to autoimmunity. We have examined the role of antigen-presenting (APC) cells in the selection of class Ii-restricted epitopes for display to T lymphocytes. The formation and MHC-restricted presentation of distinct antigenic epitopes is directly dependent upon processing and ligand binding reactions within APC. A novel MHC heterodimer, HLA-DM, facilitates the binding and presentation of peptides by class II DR, DP, and DQ molecules. We have demonstrated that some epitopes derived from endogenous antigens bind class II proteins independent of DM, whereas the presentation of other endogenous peptides is greatly influenced by DM expression. Targeting of exogenous antigens into specialized processing compartments within APC appears to overcome the requirement for DM in antigen presentation. These studies suggest HLA-DM may play a role in epitope selection and immunodominance.
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PMID:Antigen-presenting cells and the selection of immunodominant epitopes. 941 28

Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the chromosomal region 12q15, are very frequent among benign mesenchymal tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. These HMGIC aberrations are caused by characteristic structural chromosomal aberrations, either visible by conventional cytogenetics or as cryptic abnormalities. Some of these aberrations of chromosome 12 are not specific for particular tumor entities but can occur in a variety of tumors with HMGIC abnormalities. One such example is the pericentric inversion inv(12)(p11.2q15). Starting from the ectopic sequence derived from an HMGIC fusion transcript of an aggressive angiomyxoma with such an inversion we established three PAC clones covering the breakpoint region 12p11 and cloned part of a yet unknown gene in 12p11.2, which is fused to the third exon of HMGIC. Using fluorescence in situ hybridization with these PACs we were able to show that the same region was involved by 12p11.2 aberrations in lipomas, aggressive angiomyxomas, and pulmonary chondroid hamartomas.
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PMID:Cloning and molecular characterization of part of a new gene fused to HMGIC in mesenchymal tumors. 946 69

Thyroglobulin (Tg)-specific Abs occur commonly in thyroid disease, but it is not clear to what extent they affect Tg processing and presentation to T cells. Here we show that generation of the nondominant pathogenic Tg epitope (2549-2560), containing thyroxine (T4) at position 2553 (T4(2553)), is augmented by Tg-specific IgG mAbs that facilitate FcR-mediated internalization of Tg. However, other mAbs of the same (IgG1) subclass enhanced Tg uptake by APC but had no effect on the generation of this peptide. Treatment of APC with chloroquine or glutaraldehyde abrogated enhanced generation of T4(2553). The boosting effect was selective, since the enhancing mAbs did not facilitate generation of the neighboring cryptic (2495-2511) peptide, which is also pathogenic in mice. When Tg was simultaneously complexed to a mAb reactive with T4(2553) and to a mixture of boosting mAbs, the presentation of this epitope was totally suppressed. These results suggest that Tg-specific Abs alter Tg processing and may boost or suppress the presentation of nondominant pathogenic determinants during the course of disease.
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PMID:Enhancing or suppressive effects of antibodies on processing of a pathogenic T cell epitope in thyroglobulin. 1035 39

T cells constitute the pathogenic effector cell population in autoimmune myocarditis in BALB/c mice. Using mice rendered deficient for B cells by a targeted disruption to the IgM transmembrane domain or by treatment with anti-IgM Ab from birth, we asked whether B cells are a critical APC in the induction of autoimmune myocarditis. B cell-deficient mice immunized with cardiac myosin develop myocarditis comparable in incidence and severity to that in wild-type mice, suggesting that autoreactive T cells that cause myocarditis in BALB/c mice are activated by macrophages or dendritic cells. Since it does not appear that presentation of cryptic epitopes is critical for the breakdown of self tolerance, potentially pathogenic T cells recognizing dominant myosin epitopes must have escaped tolerization. Either anatomic sequestration of cardiac myosin peptide-MHC complexes or subthreshold presentation of cardiac myosin peptides by conventional APC can explain the survival of these autoreactive T cells.
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PMID:Autoimmune myocarditis does not require B cells for antigen presentation. 1055 48


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