Browsing by Subject "Autoantibodies"
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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 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 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.Item The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening(Springer Verlag, 2020-03) Jacobsen, Laura M.; Bocchino, Laura; Evans-Molina, Carmella; DiMeglio, Linda; Goland, Robin; Wilson, Darrell M.; Atkinson, Mark A.; Aye, Tandy; Russell, William E.; Wentworth, John M.; Boulware, David; Geyer, Susan; Sosenko, Jay M.; Medicine, School of MedicineAims/hypothesis: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. Methods: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. Results: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%. Conclusions/interpretation: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.Item The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults(Oxford University Press, 2017-12-01) Ferrara, Christine T.; Geyer, Susan M.; Evans-Molina, Carmella; Libman, Ingrid M.; Becker, Dorothy J.; Wentworth, John M.; Moran, Antoinette; Gitelman, Stephen E.; Redondo, Maria J.; Medicine, School of MedicineBackground: Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective: To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods: Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results: In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions: Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.Item Roles of T follicular helper cells and T follicular regulatory cells in Autoantibody Production in IL-2-deficient mice(American Association of Immunologists, 2019-07-12) Xie, Markus M.; Liu, Hong; Corn, Caleb; Koh, Byung-Hee; Kaplan, Mark H.; Turner, Matthew J.; Dent, Alexander L.; Microbiology and Immunology, School of MedicineAutoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.Item Top-down Mass Spectrometry Analysis of Human Serum Autoantibody Antigen-Binding Fragments(Springer Nature, 2019-02-20) Wang, Zhe; Liu, Xiaowen; Muther, Jennifer; James, Judith A.; Smith, Kenneth; Wu, Si; BioHealth Informatics, School of Informatics and ComputingDetecting autoimmune diseases at an early stage is crucial for effective treatment and disease management to slow disease progression and prevent irreversible organ damage. In many autoimmune diseases, disease-specific autoantibodies are produced by B cells in response to soluble autoantigens due to defects in B cell tolerance mechanisms. Autoantibodies accrue early in disease development, and several are so disease-specific they serve as classification criteria. In this study, we established a high-throughput, sensitive, intact serum autoantibody analysis platform based on the optimization of a one dimensional ultra-high-pressure liquid chromatography top-down mass spectrometry platform (1D UPLC-TDMS). This approach has been successfully applied to a 12 standard monoclonal antibody antigen-binding fragment (Fab) mixture, demonstrating the feasibility to separate and sequence intact antibodies with high sequence coverage and high sensitivity. We then applied the optimized platform to characterize total serum antibody Fabs in a systemic lupus erythematosus (SLE) patient sample and compared it to healthy control samples. From this analysis, we show that the SLE sample has many dominant antibody Fab-related mass features unlike the healthy controls. To our knowledge, this is the first top-down demonstration of serum autoantibody pool analysis. Our proposed approach holds great promise for discovering novel serum autoantibody biomarkers that are of interest for diagnosis, prognosis, and tolerance induction, as well as improving our understanding of pathogenic autoimmune processes.