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The results suggest that changing the early childhood immunization schedule would not affect the risk of developing beta-cell autoimmunity or type 1 diabetes.

Aims-To determine whether Glb1 homologue antibodies are associated with islet autoimmunity (IA) in children at increased risk for type 1 diabetes (T1D), and to investigate their relation with putative environmental correlates of T1D.Methods-We selected a sample from the Diabetes Autoimmunity Study in the Young (DAISY), a prospective study of children at increased risk for T1D. Cases were those who were positive for insulin, glutamic acid decarboxylase (GAD), or insulinoma-associated antigen-2 (IA-2) autoantibodies on two consecutive visits and either diagnosed with diabetes mellitus or still autoantibody positive when selected. Controls were from the same increased risk group, of similar age as the cases but negative for autoantibodies. Sera from 91 IA cases and 82 controls were analyzed in a blinded manner for immunoglobulin G (IgG) antibodies to Glb1 homologue by ELISA.Results-Adjusting for family history of T1D and HLA-DR4 positivity, Glb1 homologue antibodies were not associated with IA case status (OR: 1.01, 95% CI: 0.99 -1.03). Adjusting for age, family history of T1D, and HLA-DR4 positivity, Glb1 homologue antibody levels were inversely associated with breast-feeding duration (beta = −0.08, p = 0.001) and directly associated with current intake of foods containing gluten (beta = 0.24, p = 0.007) in IA cases but not in controls. Zonulin, a biomarker of gut permeability, was directly associated with Glb1 homologue antibody levels in cases (beta = 0.73, p = 0.003) but not in controls.Conclusion-Differences in correlates of Glb1 antibodies in IA cases and controls suggest an underlying difference in mucosal immune response.

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BackgroundPrior data suggest that anti-citrullinated protein/peptide antibodies (ACPA) may originate in the lung prior to the onset of synovitis in rheumatoid arthritis (RA) (1). Neutrophil extracellular trap (NET) formation is one potential mechanism that could trigger or be associated with local ACPA generation because NETs externalize citrullinated proteins and release peptidylarginine deiminase that could citrullinate nearby proteins (2–4).ObjectivesUsing induced sputum, we recently identified a significant correlation between NETs and anti-cyclic citrullinated peptide (CCP) antibodies in subjects at-risk for future RA. Herein, we sought to explore associations of individual ACPAs and NETs in these subjects.MethodsFrom the Studies of the Etiology of RA (SERA) cohort, we included 24 RA-free subjects At-Risk for future RA based on familial (i.e. first-degree relative of RA patient) or serologic (i.e. serum anti-CCP positive identified at health fairs) risk. Induced sputum was tested using a bead-based ACPA array for IgG reactivity to 29 individual citrullinated proteins/peptides. Levels of NET complexes in sputum were measured using a deoxyribonucleic acid (DNA)-myeloperoxidase (MPO) and DNA-neutrophil elastase (NE) sandwich ELISA. Analyses included Spearman's correlation and linear regression. Using Bonferonni's correction, results were considered significant if both DNA-MPO and DNA-NE assays had a p<0.002.ResultsSubjects had a median age of 51 years, were 67% female and 38% ever-smokers. Increasing sputum NET levels significantly correlated with increasing ACPA levels for 27/29 ACPAs, including proteins/peptides of cit-vimentin, cit-fibrinogen, cit-fibronectin, cit-apoliporoteins and cit-alpha-enolase. After adjusting for ever-smoking, sputum NET levels remained significantly associated with 17/29 ACPAs. The strongest associations (p≤0.001 for both NET assays) were cit-H2A/a21–20, cit-vimentin58–77 cyclic, cit-alpha-enolase5–21, cit-fibrinogen27–43, cit-fibrinogen211–230 cyclic, cit-fibrinogen616–635 cyclic, cit-fibrinogenB54–72, and cit-apolipoprotein E277–269 cyclic.ConclusionsIn subjects At-Risk for future RA, we identified a strong correlation between sputum NET complexes and multiple sputum ACPAs that was independent of smoking exposure. These data suggest that in the lung, NET formation may be associated with the production of multiple ACPA reactivities locally. Additional studies are needed to determine if NET-associated cit-proteins are an initial trigger or a self-perpetuating stimulus of sputum ACPA generation as well as contributions of other local mechanisms of citrullination.References Willis VC, Demoruelle MK, Derber LA, Chartier-Logan CJ, Parish MC, Pedraza IF, et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 2013;65(10):2545–54.Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. Disclosure...

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BackgroundRheumatoid arthritis (RA) patients experience higher cardiovascular disease (CVD) risk and CVD-related mortality. MHC class II HLA-DRB1 alleles, or the shared epitope (SE), has also been linked to endothelial dysfunction in RA patients. It is not known whether this association exists in individuals who are RA-free, but who are at higher risk due to being a first-degree relative (FDR) of an RA patient.ObjectivesTo determine the association between HLA-DRB1 alleles (*0401, *0404, *0405, *0408) and markers of endothelial injury in FDRs of RA patients, a population free of RA and RA-related medications.MethodsFrom the Studies of the Etiology of RA, SERA, (a multicenter prospective study of preclinical RA, started in 2002), 113 FDRs who had been positive for any of 5 RA-related autoantibodies (Abs): rheumatoid factor (RF), RF isotypes – IgM, IgG, IgA, or anti-cyclic citrullinated peptide (anti-CCP2) on at least one of their visits, and 100 FDRs who had never been Ab positive were selected, frequency matched on age, sex, and field center site. No FDR met the 1987 ACR Criteria or 2010 EULAR/ACR Criteria for RA. In cross-sectional testing of single samples from baseline, the following were measured: endothelial injury markers: soluble intracellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin; and high resolution HLA-DRB1 typing for the*0401, *0404, *0405, and *0408 alleles using real-time polymerase chain reaction. ANCOVA was used to evaluate associations between HLA-DRB1 alleles, sVCAM, sICAM, and E-selectin, adjusting for age, sex, race, body mass index (BMI), Ab status, ever smoking, and current statin use.ResultsAmong 213 FDRs, age was 50±18 yr, BMI was 27±6, 75% were women, 83% were Caucasian, 35% ever smoked, 11% were currently taking statins, and 38% were SE positive. sVCAM was significantly higher by 135ng/mL in FDRs with the HLA-DRB1*0404 allele (p=0.009) compared to FDRs without the *0404 allele (Table 1). E-selectin was higher by 23ng/mL in FDRs with the HLA-DRB1*0405 allele (p=0.03) compared to FDRs without the *0405 allele. Being positive for the SE was not significantly associated with sICAM, sVCAM, or E-selectin levels.Table 1.Differences in levels of endothelial injury markers by HLA-DRB1 alleles in FDRs of RA patientsn (%)ICAMp-valueVCAMp-valueE-selectinp-value (ng/mL)(ng/mL)(ng/mL) SE Positive81 (38)11.6 (8.8)0.1955.7 (32.5)0.093.7 (2.2)0.0940155 (26)2.6 (10.0)0.80-14.1 (37.0)0.700.4 (2.5)0.8640423 (11)21.1 (13.9)0.13135.4 (50.9)0.0096.4 (3.4)0.064052 (1)55.1 (44.0)0.21186.0 (163.1)0.2622.9 (10.8)0.034086 (3)-6.6 (25.4)0.797.1 (94.1)0.948.1 (6.2)0.19*n=213 (92 Ab+, 121 Ab−).ConclusionsIn RA-free FDRs, having an HLA-DRB1*0404 or HLA-DRB1*0405 allele was associated with markers of endothelial injury. Therefore, the genetic predisposition to RA could contribute to parallel development of atherosclerosis during the preclinical period of RA.References Gonzalez-Juanatey C et al., Am J Med 2003; 114:647–52.Gonzalez-Gay MA et al., Arth Rheum 2007; 57(...