"Exon-shuffling" maps control of antibody- and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A beta.

Germain, Ronald N.; Ashwell, Jonathan D.; Lechler, Robert I.; Margulies, David H.; Nickerson, Kathleen M.; Suzuki, Gen; Tou, Jenny Y. L.

doi:10.1073/pnas.82.9.2940

Cited by 88 publications

(34 citation statements)

References 42 publications

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“…Immunization with fibroblasts co-expressing MHC class II and thyroid antigens RT4.15HP fibroblasts [8] (kindly provided by Dr R. Germain, NIH, Bethesda, MD) were stably transfected with the cDNA for human TSHR or human thyroid peroxidase (TPO) and selection with G418 (400 mg/ml) as previously described [3,9]. TSHR expression was determined by 125 I-TSH binding to transfected RT4.15HP monolayers, and TPO expression by flow cytometry with a human TPO autoantibody Fab (WR1.7) and PE-conjugated anti-human k (Caltag, Burlingame, CA).…”

Section: Methodsmentioning

confidence: 99%

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Yan

Guo

Pichurin

et al. 2000

Clinical and Experimental Immunology

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SUMMARYAKR/N mice injected with fibroblasts expressing MHC class II (RT4.15HP cells) and the TSH receptor (TSHR) develop antibodies similar to those in Graves' disease. We were unable to analyse the subclass of these antibodies because of unexpectedly high non-specific binding by ELISA or flow cytometry. The non-specific binding reflected generalized immune activation which occurred even when the fibroblasts did not express the TSHR. However, the IgG subclasses were determined for thyroid peroxidase (TPO) antibodies induced using TPO-expressing RT4.14HP cells and found to be IgG2a . IgG1. This Th1 pattern is consistent with spontaneous secretion of interferon-gamma (but not IL-4 or IL-10) by splenocytes from injected mice. The Th1 bias was related to fibroblast injection because conventional immunization of the same mouse strain with purified TPO and adjuvant induced a Th2 response (IgG1 .. IgG2a). Further, untransfected fibroblasts themselves induced powerful, non-specific proliferative responses when used as antigen-presenting cells (APC) in vitro. Flow cytometry revealed that the RT4.15HP fibroblasts (and TSHR-and TPO-transfected derivatives) expressed B7-1. Unexpected constitutive expression of this key molecule may bypass the requirement for up-regulation of other costimulatory molecules involved in T cell stimulation. Our data support the concept that RT4.15HP fibroblasts present the TSHR (or TPO), at least for initiating the immune response. However, the accompanying generalized immune stimulation creates difficulties for analysis of TSHR-specific T and B lymphocytes. On the other hand, extension of the model to TPO, an easier antigen to study, will facilitate analysis of murine T cell responses likely to resemble those in human thyroid autoimmunity.

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Section: Methodsmentioning

confidence: 99%

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Yan

Guo

Pichurin

et al. 2000

Clinical and Experimental Immunology

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“…RT2.3.3.HD6, I-Ad-transfected L-cell fibroblasts, was provided by R. Germain (National Institutes of Health, Bethesda, MD) (14). TNC-R3.1, a thymic nurse cell line from a AKR/J (H-2k) mouse that shows properties similar to thymic nurse cells, was transfected with genomic I-Ad genes (a and is) linked to class I MHC Kb promoter and selected for their cell-surface expression (15).…”

Section: Methodsmentioning

confidence: 99%

Cellular and peptide requirements for in vitro clonal deletion of immature thymocytes.

Iwabuchi

Nakayama

McCoy

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…A remarkable property of Ia molecules is the extensive intraspecies polymorphism present in the membrane-distal (NH2-terminal) external domain. This allelic variation is the basis for Ia-restricted antigen recognition by T cells (2,3).…”

mentioning

confidence: 99%

Cytoplasmic domain affects membrane expression and function of an Ia molecule.

Griffith

Ghogawala²,

Nabavi³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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The association of foreign antigen with Ia molecules on the surface ofantigen-presenting cells is necessary for the interaction with the clonally distributed antigen receptor on T cells and is therefore critical in the initiation and polypeptide expression on the cell surface (50% of wild-type levels), an increased half-life of Ak polypeptide in the cell, and a specific limited defect in antigen presentation.

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"Exon-shuffling" maps control of antibody- and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A beta.

Cited by 88 publications

References 42 publications

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Cellular and peptide requirements for in vitro clonal deletion of immature thymocytes.

Cytoplasmic domain affects membrane expression and function of an Ia molecule.

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