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Item Adult-Onset Type 1 Diabetes: Current Understanding and Challenges(American Diabetes Association, 2021-11) Leslie, R. David; Evans-Molina, Carmella; Freund-Brown, Jacquelyn; Buzzetti, Raffaella; Dabelea, Dana; Gillespie, Kathleen M.; Goland, Robin; Jones, Angus G.; Kacher, Mark; Phillips, Lawrence S.; Rolandsson, Olov; Wardian, Jana L.; Dunne, Jessica L.; Pediatrics, School of MedicineRecent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.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 Bioinformatic analysis identified novel candidate genes with the potentials for diagnostic blood testing of primary biliary cholangitis(Public Library of Science, 2023-10-16) Pham, Hoang Nam; Pham, Linh; Sato, Keisaku; Medicine, School of MedicinePrimary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers.Item Established and emerging biomarkers for the prediction of type 1 diabetes: a systematic review(Elsevier, 2014-08) WATKINS, RENECIA A.; EVANS-MOLINA, CARMELLA; BLUM, JANICE S.; DIMEGLIO, LINDA A.; Department of Pediatrics, IU School of MedicineType 1 diabetes (T1D) is an autoimmune disease with a prolonged and variable latent period that culminates in the destruction of pancreatic β-cells and the development of hyperglycemia. There is a need for diagnostic biomarkers to detect more accurately detect individuals with prediabetes to expedite targeting for prevention and intervention strategies. To assess the current ability to predict the insidious development of T1D, we conducted a comprehensive systematic review for established and prospective predictive markers of T1D using the Medline, OVID, and EMBASE databases. Resulting citations were screened for relevance to subject. Our research generated five major categories of markers that are either currently used or forthcoming: genetic, autoantibodies, risk score quantification, cellular immunity, and β-cell function. The current standard used to assess T1D onset or predisposition focuses on autoimmune pathology and disease-associated autoantibodies. Research studies in general go beyond autoantibody screening and assess genetic predisposition, and quantitate risk of developing disease based on additional factors. However, there are few currently used techniques that assess the root of T1D: β-cell destruction. Thus, novel techniques are discussed with the potential to gauge degrees of β-cell stress and failure via protein, RNA, and DNA analyses.Item Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents(American Diabetes Association, 2020-03) Ferrara-Cook, Christine; Geyer, Susan Michelle; Evans-Molina, Carmella; Libman, Ingrid M.; Becker, Dorothy J.; Gitelman, Stephen E.; Jose Redondo, Maria; Medicine, School of MedicineObjective: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. Research design and methods: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. Results: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. Conclusions: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.Item HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression(American Diabetes Association, 2016-04) Pugliese, Alberto; Boulware, David; Yu, Liping; Babu, Sunanda; Steck, Andrea K.; Becker, Dorothy; Rodriguez, Henry; DiMeglio, Linda; Evans-Molina, Carmella; Harrison, Leonard C.; Schatz, Desmond; Palmer, Jerry P.; Greenbaum, Carla; Eisenbarth, George S.; Sosenko, Jay M.; Medicine, School of MedicineThe HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.Item Immune complications and their management in inherited and acquired bleeding disorders(American Society of Hematolog, 2022) Arruda, Valder R.; Lillicrap, David; Herzog, Roland W.; Pediatrics, School of MedicineDisorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.Item Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes(American Diabetes Association, 2022) Nathan, Brandon M.; Redondo, Maria J.; Ismail, Heba; Jacobsen, Laura; Sims, Emily K.; Palmer, Jerry; Skyler, Jay; Bocchino, Laura; Geyer, Susan; Sosenko, Jay M.; Pediatrics, School of MedicineObjective: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL). Research design and methods: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians. Results: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below. Conclusions: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.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.Item Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease(Society for Neuroscience, 2011-04-13) Dodel, Richard; Balakrishnan, Karthikeyan; Keyvani, Kathy; Deuster, Oliver; Neff, Frauke; Andrei-Selmer, Luminita-Cornelia; Röskam, Stephan; Stüer, Carsten; Al-Abed, Yousef; Noelker, Carmen; Balzer-Geldsetzer, Monika; Oertel, Wolfgang; Du, Yansheng; Bacher, Michael; Neurology, IU School of MedicineAlzheimer's disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against β-amyloid (Aβ) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against Aβ (NAbs-Aβ) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs-Aβ recognized the mid-/C-terminal end of Aβ and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs-Aβ were able to interfere with Aβ peptide toxicity, but NAbs-Aβ did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs-Aβ in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs-Aβ to dispose of proteins or peptides that are prone to forming toxic aggregates.