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Item 12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes(The American Society for Clinical Investigation, 2021-07-22) Kulkarni, Abhishek; Pineros, Annie R.; Walsh, Melissa A.; Casimiro, Isabel; Ibrahim, Sara; Hernandez-Perez, Marimar; Orr, Kara S.; Glenn, Lindsey; Nadler, Jerry L.; Morris, Margaret A.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of MedicineMacrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.Item 4033 Evaluating the Effect of Prebiotics on the Gut Microbiome Profile and Beta-cell Function in Newly-Diagnosed Type 1 Diabetes(Cambridge University Press, 2020-07-29) Ismail, Heba M.; Evans-Molina, Carmella; DiMeglio, Linda; Pediatrics, School of MedicineOBJECTIVES/GOALS: Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells. Emerging data suggest that differences in intestinal microbiota might be critically involved both in autoimmunity and in glucose homeostasis. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites positively by increasing production of beneficial short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity and secretion in healthy non-diabetic adults. Further, an acetylated and butyrylated form of HAMS (HAMS-AB) that increases beneficial SCFA production, namely acetate and butyrate, has been safe and effective in disease prevention in mouse T1D models. The objective of the proposed study is to assess the effect of administering a prebiotic, such as HAMS-AB, on the gut microbiome profile, SCFA production, glycemia and β-cell function in humans with T1D. METHODS/STUDY POPULATION: We hypothesize that administration of HAMS-AB will (i) improve the gut microbiome profile in humans with T1D, (ii) increase SCFA production, and (iii) improve β-cell health, β-cell function and overall glycemia. We propose a pilot randomized controlled cross-over trial of HAMS-AB in 12 youth with newly-diagnosed T1D. We will use state-of-the-art markers to profile the gut microbiome (using 16S rRNA sequencing), measure stool SCFA levels (using gas chromatography), asses β-cell stress/death (by measuring proinsulin to C-peptide ratios) and glycemia (assessed by continuous glucose monitoring and HbA1c measurements). RESULTS/ANTICIPATED RESULTS: We expect that the use of HAMS-AB in newly diagnosed youth with type 1 diabetes will alter the gut microbiome profile (thus increasing the number of fermenters and SCFA levels), β-cell function and glycemia in humans with T1D. DISCUSSION/SIGNIFICANCE OF IMPACT: Given the unknown long-term effects of immune-modulatory therapy on those at risk for or those diagnosed with T1D, the use of a prebiotic such as HAMS-AB offers a simple, safe, yet inexpensive and tolerated dietary alternative approach to mitigating disease.Item Adjuvants in COVID-19 vaccines: innocent bystanders or culpable abettors for stirring up COVID-heart syndrome(Sage, 2024-02-04) Kanuri, Sri Harsha; Sirrkay, Prapthi Jayesh; Medicine, School of MedicineCOVID-19 infection is a multi-system clinical disorder that was associated with increased morbidity and mortality. Even though antiviral therapies such as Remdesvir offered modest efficacy in reducing the mortality and morbidity, they were not efficacious in reducing the risk of future infections. So, FDA approved COVID-19 vaccines which are widely administered in the general population worldwide. These COVID-19 vaccines offered a safety net against future infections and re-infections. Most of these vaccines contain inactivated virus or spike protein mRNA that are primarily responsible for inducing innate and adaptive immunity. These vaccines were also formulated to contain supplementary adjuvants that are beneficial in boosting the immune response. During the pandemic, clinicians all over the world witnessed an uprise in the incidence and prevalence of cardiovascular diseases (COVID-Heart Syndrome) in patients with and without cardiovascular risk factors. Clinical researchers were not certain about the underlying reason for the upsurge of cardiovascular disorders with some blaming them on COVID-19 infections while others blaming them on COVID-19 vaccines. Based on the literature review, we hypothesize that adjuvants included in the COVID-19 vaccines are the real culprits for causation of cardiovascular disorders. Operation of various pathological signaling events under the influence of these adjuvants including autoimmunity, bystander effect, direct toxicity, anti-phospholipid syndrome (APS), anaphylaxis, hypersensitivity, genetic susceptibility, epitope spreading, and anti-idiotypic antibodies were partially responsible for stirring up the onset of cardiovascular disorders. With these mechanisms in place, a minor contribution from COVID-19 virus itself cannot be ruled out. With that being said, we strongly advocate for careful selection of vaccine adjuvants included in COVID-19 vaccines so that future adverse cardiac disorders can be averted.Item Antiretroviral Therapy Normalizes Autoantibody Profile of HIV Patients by Decreasing CD33⁺CD11b⁺HLA-DR⁺ Cells: A Cross-Sectional Study(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2016-04) Meng, Zhefeng; Du, Ling; Hu, Ningjie; Byrd, Daniel; Amet, Tohti; Desai, Mona; Shepherd, Nicole; Lan, Jie; Han, Renzhi; Yu, Qigui; Department of Microbiology & Immunology, IU School of MedicineAutoimmune manifestations are common in human immunodeficiency virus (HIV) patients. However, the autoantibody spectrum associated with HIV infection and the impact of antiretroviral therapy (ART) remains to be determined. The plasma autoantibody spectrum for HIV patients was characterized by protein microarrays containing 83 autoantigens and confirmed by enzyme-linked immunosorbent assay (ELISA). Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were analyzed by flow cytometry and their effects on autoantibodies production were determined by B cell ELISpot. Higher levels of autoantibody and higher prevalence of elevated autoantibodies were observed in ART-naive HIV patients compared to healthy subjects and HIV patients on ART. The highest frequency of CD33(+)CD11b(+)HLA-DR(+) cells was observed in ART-naive HIV patients and was associated with the quantity of elevated autoantibodies. In addition, CD33(+)CD11b(+)HLA-DR(+) cells other than Tregs or MDSCs boost the B cell response in a dose-dependent manner by in vitro assay. In summary, HIV infection leads to elevation of autoantibodies while ART suppresses the autoimmune manifestation by decreasing CD33(+)CD11b(+)HLA-DR(+) cells in vivo.The roles of CD33(+)CD11b(+)HLA-DR(+) cells on disease progression in HIV patients needs further assessment.Item B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes(MDPI, 2021-01-06) Felton, Jamie L.; Conway, Holly; Bonami, Rachel H.; Pediatrics, School of MedicineIslet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.Item Control of inflammation, helper T cell responses and regulatory T cell function by Bcl6(2014-01-13) Sawant, Deepali Vijay; Dent, Alexander L.; Kaplan, Mark H.; Blum, Janice Sherry, 1957-; Touloukian, Christopher E.Regulatory T (Treg) cells represent an important layer of immune-regulation indispensible for curtailing exuberant inflammatory responses and maintaining self-tolerance. Treg cells have translational potential for autoimmunity, inflammation, transplantation and cancer. Therefore, delineating the molecular underpinnings underlying the development, suppressor function and stability of Tregs is particularly warranted. The transcriptional repressor Bcl6 is a critical arbiter of helper T cell fate, promoting the follicular helper (Tfh) lineage while repressing Th1, Th2 and Th17 differentiation. Bcl6-deficient mice develop a spontaneous and severe Th2-type inflammatory disease including myocarditis and pulmonary vasculitis, suggesting a potential role for Bcl6 in Treg cell function. Bcl6-deficient Treg cells are competent in controlling Th1 responses, but fail to control Th2 inflammation in an airway allergen model. Importantly, mice with Bcl6 deleted specifically in the Treg lineage develop severe myocarditis, thus highlighting a critical role for Bcl6 in Treg-mediated control of Th2 inflammation. Bcl6-deficient Tregs display an intrinsic increase in Th2 genes and microRNA-21 (miR-21) expression. MiR-21 is a novel Bcl6 gene target in T cells and ectopic expression of miR-21 directs Th2 differentiation in non-polarized T cells. MiR-21 is up-regulated in mouse models of airway inflammation and also in human patients with eosinophilic esophagitis and asthma. Thus, miR-21 is a clinically relevant biomarker for Th2-type pathologies. Our results define a key function for Bcl6 in repressing Gata3 function and miR-21 expression in Tregs, and provide greater understanding of the control of Th2 inflammatory responses by Treg cells.Item COVID-19-Induced Graves' Disease(Springer Nature, 2022-02-15) Ghareebian, Hagop; Mariash, Cary; Medicine, School of MedicineCOVID-19, a multi-system disease, could potentially play a role in thyroid dysfunction. New reports show a prevalence of COVID-related thyroiditis. Recent studies suggest that there may be a higher risk of thyroiditis in the setting of SARS-CoV-2, and several cases of Graves’ disease have been reported in individuals with SARS-CoV-2, although the incidence of such findings and their relationship to COVID-19 is unknown. In this report, we present Graves’ hyperthyroidism in a 48-year-old African American male who was admitted to the hospital for complaints of cough, fatigue, and palpitations. He tested positive for SARS-CoV-2 and was found to have suppressed thyroid-stimulating hormone (TSH) and an elevated free T4. The patient had no prior history of thyroid disease. Initially, it was thought to be a case of viral thyroiditis, and he was discharged on prednisone. However, he was found to have positive thyroid-stimulating immunoglobulin (TSI) and a diffuse increase in flow on doppler ultrasound of the thyroid. Subsequently, he was started on anti-thyroid medications with significant improvement. What is unique about this case is that, unlike other described cases in the literature where there was a relapse of a known Graves' disease after COVID-19 disease, our patient did not have a history or symptoms of thyroid disease prior to this event, which should raise the concern about possible activation of Graves' disease after SARS-CoV-2 infection through an autoimmune pathway. In our opinion, physicians, particularly endocrinologists, must be aware of this condition and keep it in mind as a potential differential diagnosis when encountering a similar clinical scenario.Item CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance(Springer Nature, 2019-09-27) Chen, Yuhong; Yu, Mei; Zheng, Yongwei; Fu, Guoping; Xin, Gang; Zhu, Wen; Luo, Lan; Burns, Robert; Li, Quan-Zhen; Dent, Alexander L.; Zhu, Nan; Cui, Weiguo; Malherbe, Laurent; Wen, Renren; Wang, Demin; Microbiology and Immunology, School of MedicineMany autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.Item FOXP3 exon 2 controls Treg stability and autoimmunity(American Association for the Advancement of Science, 2022) Du, Jianguang; Wang, Qun; Yang, Shuangshuang; Chen, Si; Fu, Yongyao; Spath, Sabine; Domeier, Phillip; Hagin, David; Anover-Sombke, Stephanie; Haouili, Maya; Liu, Sheng; Wan, Jun; Han, Lei; Liu, Juli; Yang, Lei; Sangani, Neel; Li, Yujing; Lu, Xiongbin; Janga, Sarath Chandra; Kaplan, Mark H.; Torgerson, Troy R.; Ziegler, Steven F.; Zhou, Baohua; Pediatrics, School of MedicineDiffering from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing-a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Treg stability and immune homeostasis.Item The Influence of Type 2 Diabetes–Associated Factors on Type 1 Diabetes(American Diabetes Association, 2019-08-01) Redondo, Maria J.; Evans-Molina, Carmella; Steck, Andrea K.; Atkinson, Mark A.; Sosenko, Jay; Pediatrics, School of MedicineCurrent efforts to prevent progression from islet autoimmunity to type 1 diabetes largely focus on immunomodulatory approaches. However, emerging data suggest that the development of diabetes in islet autoantibody–positive individuals may also involve factors such as obesity and genetic variants associated with type 2 diabetes, and the influence of these factors increases with age at diagnosis. Although these factors have been linked with metabolic outcomes, particularly through their impact on β-cell function and insulin sensitivity, growing evidence suggests that they might also interact with the immune system to amplify the autoimmune response. The presence of factors shared by both forms of diabetes contributes to disease heterogeneity and thus has important implications. Characteristics that are typically considered to be nonimmune should be incorporated into predictive algorithms that seek to identify at-risk individuals and into the designs of trials for disease prevention. The heterogeneity of diabetes also poses a challenge in diagnostic classification. Finally, after clinically diagnosing type 1 diabetes, addressing nonimmune elements may help to prevent further deterioration of β-cell function and thus improve clinical outcomes. This Perspectives in Care article highlights the role of type 2 diabetes–associated genetic factors (e.g., gene variants at transcription factor 7-like 2 [TCF7L2]) and obesity (via insulin resistance, inflammation, β-cell stress, or all three) in the pathogenesis of type 1 diabetes and their impacts on age at diagnosis. Recognizing that type 1 diabetes might result from the sum of effects from islet autoimmunity and type 2 diabetes–associated factors, their interactions, or both affects disease prediction, prevention, diagnosis, and treatment.