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  • American Association for the Advancement of Science (AAAS)  (4)
  • 1
    Online Resource
    Online Resource
    Deep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity
    American Association for the Advancement of Science (AAAS) ; 2022
    In:  Science Translational Medicine Vol. 14, No. 627 ( 2022-01-12)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 14, No. 627 ( 2022-01-12)
    Abstract: Individuals with Down syndrome show cellular and clinical features of dysregulated aging of the immune system, including a shift from naïve to memory T cells and increased incidence of autoimmunity. However, a quantitative understanding of how various immune compartments change with age in Down syndrome remains lacking. Here, we performed deep immunophenotyping of a cohort of individuals with Down syndrome across the life span, selecting for autoimmunity-free individuals. We simultaneously interrogated age- and sex-matched healthy controls and people with type 1 diabetes as a representative autoimmune disease. We built an analytical software, IMPACD (Iterative Machine-assisted Permutational Analysis of Cytometry Data), that enabled us to rapidly identify many features of immune dysregulation in Down syndrome shared with other autoimmune diseases. We found quantitative and qualitative dysregulation of naïve CD4 + and CD8 + T cells in individuals with Down syndrome and identified interleukin-6 as a candidate driver of some of these changes, thus extending the consideration of immunopathologic cytokines in Down syndrome beyond interferons. We used immune cellular composition to generate three linear models of aging (immune clocks) trained on control participants. All three immune clocks demonstrated advanced immune aging in individuals with Down syndrome. One of these clocks, informed by Down syndrome–relevant biology, also showed advanced immune aging in individuals with type 1 diabetes. Orthologous RNA sequencing–derived immune clocks also demonstrated advanced immune aging in individuals with Down syndrome. Together, our findings demonstrate an approach to studying immune aging in Down syndrome that may have implications in other autoimmune diseases.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abi4888
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression
    American Association for the Advancement of Science (AAAS) ; 2016
    In:  Science Translational Medicine Vol. 8, No. 356 ( 2016-09-14)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 8, No. 356 ( 2016-09-14)
    Abstract: Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6–specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. IL-6–induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6–stimulated CD4 + T cells from patients revealed previously unreported IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due, in part, to an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6–targeted therapeutic intervention such as the one that is being currently tested (NCT02293837).
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aad9943
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2016
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  • 3
    Online Resource
    Online Resource
    Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Translational Medicine Vol. 13, No. 583 ( 2021-03-03)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 583 ( 2021-03-03)
    Abstract: We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; P = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1 + TIGIT + CD8 + T cells ( r = 0.44, P = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8 + T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abc8980
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer–mediated autoimmune diabetes
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Advances Vol. 5, No. 8 ( 2019-08-02)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 5, No. 8 ( 2019-08-02)
    Abstract: Human leukocyte antigen (HLA)–DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer–restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer–specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell receptor (TCR) contact, stronger disease-associated responses to cross-reactive, immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at the α chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65 250–266 peptide and in silico analysis reveal the DQ α52 residue located within the N-terminal edge of the peptide-binding cleft for the enhanced T cell reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide complexes. Accordingly, a structurally promiscuous but nondegenerate TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer–mediated autoimmune diabetes.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.aaw9336
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
    detail.hit.zdb_id: 2810933-8
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