Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

Luppi, Patrizia; Zanone, Maria M.; Hyöty, Heikki; Rudert, William A.; Haluszczak, Catherine; Alexander, Angela; Bertera, Suzanne; Becker, Dorothy J.; Trucco, Massimo

doi:10.1007/s001250051559

Cited by 48 publications

(35 citation statements)

References 34 publications

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“…A number of studies have found an association with DR4 (34)(35)(36)(37), although this finding was certainly not universal (38)(39)(40). A lesser number of HLA-association studies included DQ typing (41)(42)(43)(44), and considered together these fail to reach any consensus about the nature of susceptibility alleles. However, given the possibility that DR4 may sometimes be associated, because DR4 is in linkage disequilibrium with DQ8, it may be that in the affected DR4 individuals it is actually the DQ8 molecule that plays a major role in disease initiation and͞or progression.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Elliott

Liu

Yuan

et al. 2003

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

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A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IA␤ failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ-and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.I diopathic dilated cardiomyopathy (IDCM) describes a condition whereby previously healthy individuals develop lifethreatening heart failure associated with enlargement of the heart, but with no apparent underlying cause (1, 2). The cardiac pathology seen in the majority of IDCM patients indicates a recent or more long-standing immune-mediated inflammatory process within the muscle tissue of the heart (i.e., myocarditis) (3,4). IDCM patients often demonstrate circulating anticardiac autoantibodies, and the myocarditis is generally thought to arise from an autoimmune response against cardiac tissues (5). Research on IDCM has been hampered by the lack of an appropriate animal model, that is, a model where animals develop disease spontaneously, show severe life-threatening pathology, and display an immunological and histological picture similar to that seen in humans with IDCM.The human MHC class II molecule DQ8 (i.e., haplotype DQA1*0301, DQB1*0302) is known to be associated with type 1 diabetes (T1D). To map DQ8-restricted T cell epitopes for T1D autoantigens we crossed DQ8 transgenic nonobese diabetic (NOD) mice with a NOD MHC class II ␤-chain knockout line (6). Because the resulting animals express the human MHC class II molecule but not the mouse, any CD4 ϩ T cells arising would be restricted to the human MHC molecule. We chose the NOD strain because it is known to have defects in self-tolerance, which we hypothesized would aid our efforts to induce immune responses against self-antigens such as GAD65. Although replacement of the murine T1D-asso...

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Section: Discussionmentioning

confidence: 99%

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Elliott

Liu

Yuan

et al. 2003

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

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“…We expect the presence of new biochemically detectable autoantibody markers, and likely T-cell proliferation assays [8,9,57,58] will surely be identified in individuals carrying 2 HLA-DQ high-risk haplotypes who are negative for conventional antibody markers. This will increase our capacity to identify subjects who will develop insulin-requiring diabetes.…”

Section: Discussionmentioning

confidence: 99%

Progression to insulin-requiring diabetes in seronegative prediabetic subjects: the role of two HLA-DQ high-risk haplotypes

et al. 2002

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“…A TCR comparison between human samples is not feasible because the repertoire is randomly formed in each individual and shaped by the individual's MHC polymorphisms. Luppi et al (37) had reported an increased frequency of circulating Vb7, Vb1, and Vb17 T cells in PBMCs from recently diagnosed T1D patients, as compared with control subjects. In contrast, the frequency of Vb families containing monoclonal expansions in PBMCs from the T1D patient studied was not different from healthy control subjects (data not shown).…”

Section: Cdr3 Length (Aa)mentioning

confidence: 99%

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Codina-Busqueta

Scholz

Torres

et al. 2011

The Journal of Immunology

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Autoreactive T cells, responsible for the destruction of pancreatic β cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient’s peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR β-chain variable expansions were detected for Vβ1, Vβ7, Vβ11, Vβ17, and Vβ22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vβ22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR β-chain variable repertoire. The same Vβ22 TCR was detected in the patient’s PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vβ22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient’s spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells.

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Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

Cited by 48 publications

References 34 publications

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Progression to insulin-requiring diabetes in seronegative prediabetic subjects: the role of two HLA-DQ high-risk haplotypes

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

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