Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu, Devraj; Horváth, Stephen; Matsumoto, Isao; Fremont, Daved H.; Allen, Paul M.

doi:10.4049/jimmunol.164.11.5788

The Journal of Immunology

2000

DOI: 10.4049/jimmunol.164.11.5788

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Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Devraj Basu

Stephen Horváth

Isao Matsumoto

et al.

Abstract: KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42–56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282–294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR’s dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor’s cross-reactivity critically depends upon a T… Show more

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Cited by 78 publications

(66 citation statements)

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“…This implies that mutants evade immune system detection more easily as an epitope becomes more similar to self peptides, which in turn suggests that the immune system could drive pathogens to express epitopes that mimic self. These "molecular mimics" could either trigger autoimmune responses by activating T cells that cross-react to a self peptide [36,37] or evade immune surveillance. …”

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The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to foreign peptides similar to self peptides will have a lower average cross-reactivity than cells responding to epitopes dissimilar to self. IntroductionThe ability of an individual T cell to recognize related antigenic peptides is an essential part of the body's defense against mutating pathogens. T cells detect intracellular pathogens by binding to foreign peptides presented by major histocompatibility complex (MHC)-encoded proteins on the surfaces of infected cells or on specialized antigen-presenting cells [1][2][3]. Although T cells are specific to their cognate peptides, they crossreact with many others [4]. It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].T cell recognition of antigen is determined by binding interactions of T cell receptors (TCR) with peptide-MHC complexes (pMHC). Each T cell expresses thousands of copies of identical TCR that bind with high affinity to their cognate peptide presented by MHC. T cells detect the presence of pathogens when their receptors have sufficiently high affinity for the pMHC on a target cell and remain in contact with pMHC for a time sufficient to generate a stimulatory signal. Because the pMHC presents a single binding target for the TCR [7], both the peptide and the structure of the presenting MHC molecule play a role in determining affinity.TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10]. During positive selection, T cells that have an extremely low avidity to self peptides bound to MHC die by neglect [11][12][13]. It is believed that this process eliminates T cells that ha...

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mentioning

confidence: 99%

The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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“…However, once the pathogenic antibodies have been elicited by the autoimmune reaction, there is no further requirement for lymphoid cells, and the antibodies alone can transfer full-blown arthritis to naive lymphocyte-deficient hosts (5,6). Studies of the K/BxN model also indicated that ubiquitous antigens can be the target of arthritogenic antibodies: those in K/BxN mice recognize the widespread glycolytic enzyme glucose-6-phosphate isomerase (GPI) (7)(8)(9). Does GPI also serve as a target in human diseases?…”

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confidence: 99%

Low prevalence of antibodies to glucose‐6‐phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders

Matsumoto

Lee

Goldbach‐Mansky

et al. 2003

Arthritis & Rheumatism

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118

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Objective. Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects.Methods. Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting.Results. Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus.Conclusion. No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

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“…Disease incidence is 100% in BxN mice with the KRN Tg, whereas no disease is detected in Tg(Ϫ) BxN mice (1). KRN T cells recognize a peptide from the glycolytic enzyme glucose-6-phosphate-isomerase (GPI) bound to I-A g7 (3,4). B cells from these mice also recognize GPI as an autoantigen (3).…”

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Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node

Mandik-Nayak

Wipke

Shih

et al. 2002

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

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K͞BxN mice develop an inflammatory joint disease with many features characteristic of rheumatoid arthritis. In this model, the KRN transgenic T cells and nontransgenic B cells both recognize the glycolytic enzyme glucose-6-phosphate-isomerase (GPI) as an autoantigen. Here, we followed the anti-GPI B cell response that naturally arises in K͞BxN mice. The anti-GPI B cell response was robust and arose at the same time as the development of serum anti-GPI autoantibody and joint inflammation. Surprisingly, although GPI was expressed systemically, the anti-GPI B cell response was focused to the lymph nodes (LN) draining the distal joints where arthritis was evident. In lymphotoxin-␤ receptor-Ig-treated mice, which lack LNs, the development of arthritis was completely inhibited up to 5-6 weeks. At later times, some arthritis did develop, but at a significantly reduced level. Thus, in this spontaneous model of autoimmunity, the LNs draining the distal joints are essential for both the inhibition and amplification of the arthritogenic B cell response. These findings imply that the immune physiology of a joint is unique, resulting in a local immune response to a systemic autoantigen.

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Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Cited by 78 publications

References 42 publications

The effects of thymic selection on the range of T cell cross‐reactivity

The effects of thymic selection on the range of T cell cross‐reactivity

Low prevalence of antibodies to glucose‐6‐phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders

Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node

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