T‐cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans

Frankl, J; Thearle, Marie S.; Desmarais, Cindy; Bogardus, Clifton; Krakoff, Jonathan

doi:10.1002/dmrr.2720

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…The complementarity determining region 3 (CDR3) of T and B cell receptor molecules plays a critical role in antigen binding [29], and abnormalities of IGH CDR3 length and hydrophobicity profile have a major impact on immune competence and self/non-self discrimination [37, 38]. A shorter CDR3 length was observed for both total and unique TRB (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

et al. 2016

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Purpose DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay. Methods We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings. Results In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved. Conclusions We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.

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Section: Resultsmentioning

confidence: 99%

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

et al. 2016

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“…In the peripheral T cells of patients with T2DM, the utilization of the V or J genes (especially TRBV7-8) and the amino acid lengths of the TCR CDR3 regions were significantly altered. These alterations were closely associated with an increased risk of diabetes [ 19 ]. Our study also found that the utilization of the V and/or J genes was altered in patients with AS, suggesting the relationship between TCR repertoires and atherosclerosis development.…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing of the T cell receptor β repertoire reveals signature patterns and clonal drift in atherosclerotic plaques and patients

et al. 2017

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The T cell receptor (TCR) β repertoire directly reflects the status of T cell function. Meanwhile, the immune/inflammatory responses regulated by T cells are the critical determinants of atherosclerosis development. However, due to technical limitations, the composition and molecular characteristics of the TCR repertoire in atherosclerotic patients have not been fully elucidated. In the present study, we use powerful immune repertoire sequencing technology to study this issue. Results show that the utilization of V and/or J genes and the diversity of TCRβ repertoire in atherosclerotic plaques are significantly reduced compared to those in the peripheral blood of normal subjects and atherosclerotic patients. The frequencies of the common T cell clones with certain lengths of the complement determining region 3 regions are notably different among all groups. The high-frequency common clones are also increased in the atherosclerotic plaques compared to that in the other two groups. The expansion of several T cell clonotypes (V29-1J2-1, V20-1J1-6, V6-3J2-7 and V11-2J2-2) is validated in atherosclerotic patients. In short, this study reveals that the diversity of TCR β repertoire significantly decreases in atherosclerotic plaques, probably because of the reduced utilization of VJ genes and marked expansion of some T cell subclones. It provides the basis for understanding the roles of T lymphocytes in the pathogenesis of atherosclerosis.

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“…20 T-cell receptor complementarity determining region 3 length is shorter in SAI participants with T2DM and associated with increased risk of diabetes. 21 Many autoimmune diseases show an association with certain human leukocyte antigen (HLA) haplotypes, usually involving the major histocompatibility complex class II, which encodes for genes that are important for immune response regulation. 22 A single-nucleotide polymorphism (SNP) that tags an HLA haplotype (HLA-DRB1*16:02) protective for T2DM and associated with increased insulin secretion was identified in this SAI population.…”

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confidence: 99%

Autoantibodies against PFDN2 are associated with an increased risk of type 2 diabetes: A case‐control study

Chang

Piaggi

Hanson

et al. 2017

Diabetes Metabolism Res

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T‐cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans

Abstract: These results indicate that T-cell autoimmunity may be an important component in progression to T2DM in Pima Indians.

Cited by 11 publications

References 41 publications

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

Deep sequencing of the T cell receptor β repertoire reveals signature patterns and clonal drift in atherosclerotic plaques and patients

Autoantibodies against PFDN2 are associated with an increased risk of type 2 diabetes: A case‐control study

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