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1.
PLoS One ; 15(9): e0236921, 2020.
Article in English | MEDLINE | ID: mdl-32986722

ABSTRACT

The receptor for advanced glycation endproducts (RAGE) is expressed in T cells after activation with antigen and is constitutively expressed in T cells from patients at-risk for and with type 1 diabetes mellitus (T1D). RAGE expression was associated with an activated T cell phenotype, leading us to examine whether RAGE is involved in T cell signaling. In primary CD4+ and CD8+ T cells from patients with T1D or healthy control subjects, RAGE- cells showed reduced phosphorylation of Erk. To study T cell receptor signaling in RAGE+ or-T cells, we compared signaling in RAGE+/+ Jurkat cells, Jurkat cells with RAGE eliminated by CRISPR/Cas9, or silenced with siRNA. In RAGE KO Jurkat cells, there was reduced phosphorylation of Zap70, Erk and MEK, but not Lck or CD3ξ. RAGE KO cells produced less IL-2 when activated with anti-CD3 +/- anti-CD28. Stimulation with PMA restored signaling and (with ionomycin) IL-2 production. Silencing RAGE with siRNA also decreased signaling. Our studies show that RAGE expression in human T cells is associated with an activated signaling cascade. These findings suggest a link between inflammatory products that are found in patients with diabetes, other autoimmune diseases, and inflammation that may enhance T cell reactivity.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Diabetes Mellitus, Type 1/metabolism , Receptor for Advanced Glycation End Products/metabolism , Signal Transduction , Adolescent , Adult , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , Child , Female , Glycation End Products, Advanced/metabolism , Humans , Inflammation/metabolism , Jurkat Cells , Male , Young Adult
4.
JCI Insight ; 2(21)2017 11 02.
Article in English | MEDLINE | ID: mdl-29093268

ABSTRACT

The microbiome affects development and activity of the immune system, and may modulate immune therapies, but there is little direct information about this control in vivo. We studied how the microbiome affects regulation of human immune cells in humanized mice. When humanized mice were treated with a cocktail of 4 antibiotics, there was an increase in the frequency of effector T cells in the gut wall, circulating levels of IFN-γ, and appearance of anti-nuclear antibodies. Teplizumab, a non-FcR-binding anti-CD3ε antibody, no longer delayed xenograft rejection. An increase in CD8+ central memory cells and IL-10, markers of efficacy of teplizumab, were not induced. IL-10 levels were only decreased when the mice were treated with all 4 but not individual antibiotics. Antibiotic treatment affected CD11b+CD11c+ cells, which produced less IL-10 and IL-27, and showed increased expression of CD86 and activation of T cells when cocultured with T cells and teplizumab. Soluble products in the pellets appeared to be responsible for the reduced IL-27 expression in DCs. Similar changes in IL-10 induction were seen when human peripheral blood mononuclear cells were cultured with human stool samples. We conclude that changes in the microbiome may impact the efficacy of immunosuppressive medications by altering immune regulatory pathways.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Gastrointestinal Microbiome/immunology , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Adaptive Immunity/immunology , Animals , Antibodies, Antinuclear , Antibodies, Monoclonal, Humanized/pharmacology , Autoimmune Diseases/immunology , Autoimmune Diseases/microbiology , B7-2 Antigen/metabolism , CD11b Antigen , CD11c Antigen , CD3 Complex , CD8-Positive T-Lymphocytes/immunology , Cytokines/blood , Cytokines/metabolism , Disease Models, Animal , Gastrointestinal Tract/microbiology , Graft Rejection/immunology , Humans , Immunosuppressive Agents/pharmacology , Immunotherapy , Interferon-gamma , Interleukin-10/metabolism , Interleukin-27/metabolism , Mice , Mice, Knockout , Mucous Membrane/immunology , STAT5 Transcription Factor/metabolism , Skin Transplantation , T-Lymphocytes/immunology , Transplantation, Heterologous
7.
J Radiol Case Rep ; 9(2): 16-23, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25926924

ABSTRACT

When approaching a case with a situs abnormality, using the proper terminology, making a specific diagnosis, and understanding the other often associated abnormalities that need to be excluded are of great importance. We present a case of situs ambiguous in the presence of intestinal nonrotation and an obstructing duodenal web. Our patient initially presented at two days old with bilious emesis and failure to pass meconium after birth. An abdominal radiograph demonstrated an unusual bowel gas pattern, a reversed "double bubble" sign. A subsequent thorough imaging survey was crucial to further characterize our patient's unique anatomy. Overall, our case demonstrates many of the unusual plain radiographic and sonographic findings associated with our patient's situs abnormality and allows for review of situs abnormalities and their significance.


Subject(s)
Abnormalities, Multiple/diagnostic imaging , Duodenum/abnormalities , Intestines/abnormalities , Levocardia/diagnostic imaging , Stomach/abnormalities , Abnormalities, Multiple/surgery , Diagnosis, Differential , Duodenum/diagnostic imaging , Female , Humans , Infant, Newborn , Intestines/diagnostic imaging , Radiography , Stomach/diagnostic imaging , Ultrasonography
8.
Nat Rev Endocrinol ; 11(5): 308-14, 2015 May.
Article in English | MEDLINE | ID: mdl-25623120

ABSTRACT

Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of ß cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Disease Models, Animal , Animals , Clinical Trials as Topic , Diabetes Mellitus, Type 1/immunology , Disease Progression , Female , Humans , Insulin-Secreting Cells/immunology , Mice , Mice, Inbred NOD/genetics , Treatment Outcome
9.
Radiographics ; 33(6): 1649-50, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24260792
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