Geographic location determines beta-cell autoimmunity among adult Ghanaians: Findings from the RODAM study.

INTRODUCTION: Beta-cell autoantibodies are established markers of autoimmunity, which we compared between Ghanaian adults with or without diabetes, living in rural and urban Ghana and in three European cities. METHODS: In the multicenter cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study (N = 5898), we quantified autoantibodies against glutamic acid decarboxylase (GAD65Ab) by radioligand binding assay (RBA) and established cut-offs for positivity by displacement analysis. In a subsample, we performed RBA for zinc transporter-8 autoantibodies (ZnT8Ab). Associations of environmental, sociodemographic, and clinical factors with GAD65Ab were calculated. RESULTS: In this study population (age: 46.1 ± 11.9 years; female: 62%; Ghana-rural: 1111; Ghana-urban: 1455; Europe: 3332), 9.2% had diabetes with adult-onset. GAD65Ab concentrations were the highest in Ghana-rural (32.4; 10.8-71.3 U/mL), followed by Ghana-urban (26.0; 12.3-49.1 U/mL) and Europe (11.9; 3.0-22.8 U/mL) with no differences between European cities. These distributions were similar for ZnT8Ab. Current fever, history of fever, and higher concentrations of liver enzymes marginally explained site-specific GAD65Ab concentrations. GAD65Ab positivity was as frequent in diabetes as in nondiabetes (5.4% vs 6.1%; P = .25). This was also true for ZnT8Ab positivity. CONCLUSION: Geographic location determines the occurrence of GAD65Ab and ZnT8Ab more than the diabetes status. Beta-cell autoimmunity may not be feasible to differentiate diabetes subgroups in this population

Novel minor HLA DR associated antigens in type 1 diabetes

Type 1 diabetes is an autoimmune disease leading to insulin deficiency. Autoantibodies to beta cell proteins are already present in the asymptomatic phase of type 1 diabetes. Recent findings have suggested a number of additional minor autoantigens in patients with type 1 diabetes. We have established luciferase immunoprecipitation systems (LIPS) for anti-MTIF3, anti-PPIL2, anti-NUP50 and anti-MLH1 and analyzed samples from 500 patients with type 1 diabetes at onset of clinical disease and 200 healthy individuals who had a family history of type 1 diabetes but no evidence of beta cell autoantibodies. We show significantly higher frequencies of anti-MTIF3, anti-PPIL2 and anti-MLH1 in recent onset type 1 diabetes patients in comparison to controls. In addition, antibodies to NUP50 were associated with HLA-DRB1*03 and antibodies to MLH1 were associated with HLA-DRB1*04 genotypes.:1. Introduction 2. Material and methods 2.1 Participants 2.2. Cloning and expression of antigens 2.3. Luciferase ImmunoPrecipitation (LIPS) assays 2.4. Antinuclear antibodies (ANA) 2.5. Statistics 3. Results 4. Discussion 5. Conclusion Declaration of interest Funding Acknowledgements Appendix A Suplementary data Reference

Geographic location determines beta-cell autoimmunity among adult Ghanaians: Findings from the RODAM study

Introduction: Beta-cell autoantibodies are established markers of autoimmunity, which we compared between Ghanaian adults with or without diabetes, living in rural and urban Ghana and in three European cities. Methods: In the multicenter cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study (N = 5898), we quantified autoantibodies against glutamic acid decarboxylase (GAD65Ab) by radioligand binding assay (RBA) and established cut-offs for positivity by displacement analysis. In a subsample, we performed RBA for zinc transporter-8 autoantibodies (ZnT8Ab). Associations of environmental, sociodemographic, and clinical factors with GAD65Ab were calculated. Results: In this study population (age: 46.1 ± 11.9 years; female: 62%; Ghana-rural: 1111; Ghana-urban: 1455; Europe: 3332), 9.2% had diabetes with adult-onset. GAD65Ab concentrations were the highest in Ghana-rural (32.4; 10.8-71.3 U/mL), followed by Ghana-urban (26.0; 12.3-49.1 U/mL) and Europe (11.9; 3.0-22.8 U/mL) with no differences between European cities. These distributions were similar for ZnT8Ab. Current fever, history of fever, and higher concentrations of liver enzymes marginally explained site-specific GAD65Ab concentrations. GAD65Ab positivity was as frequent in diabetes as in nondiabetes (5.4% vs 6.1%; P =.25). This was also true for ZnT8Ab positivity. Conclusion: Geographic location determines the occurrence of GAD65Ab and ZnT8Ab more than the diabetes status. Beta-cell autoimmunity may not be feasible to differentiate diabetes subgroups in this population

Longitudinal Frequencies of Blood Leukocyte Subpopulations Differ between NOD and NOR Mice but Do Not Predict Diabetes in NOD Mice

Immune phenotyping provides insight into disease pathogenesis and prognostic markers. Trajectories from age of 4 to 36 weeks were modeled for insulin autoantibodies and for leukocyte subpopulations in peripheral blood from female NOD (n=58) and NOR (n=22) mice. NOD mice had higher trajectories of insulin autoantibodies, CD4+ and CD8+ T lymphocytes, B lymphocytes, IgD+IgM− B lymphocytes, and NK cells and lower trajectories of CD4+CD25+ T lymphocytes, IgM+ B lymphocytes, granulocytes, and monocytes than NOR mice (all p<0.001). Of these, only the increased IAA trajectory was observed in NOD mice that developed diabetes as compared to NOD mice that remained diabetes-free. Therefore, the profound differences in peripheral blood leukocyte proportions observed between the diabetes-prone NOD mice and the diabetes-resistant mice do not explain the variation in diabetes development within NOD mice and do not provide markers for diabetes prediction in this model

Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation

The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome–encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array–based genome-wide linkage analysis revealed IL-2–inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment