Le diabete de type 1: Une maladie auto-immune heterogene, predictible, evitable, guerissable?

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Increased prevalence of abnormal immunoglobulin M, G, and A concentrations at clinical onset of insulin-dependent diabetes mellitus: A registry-based study

In view of the reported association of insulin-dependent diabetes mellitus (IDDM) with viral infections, (non-) islet-specific immune changes, and partial immunodeficiencies, we used immunonephelometry to measure circulating levels of IgM, IgG, and IgA in a registry-based group of IDDM patients under age 40 years at clinical onset (n = 397) and in age-matched nondiabetic siblings (n = 316) and control subjects (n = 322). Overall, IgM and IgA concentrations were higher, and IgG concentrations lower, in patients than in control subjects or siblings (P < 0.001). In siblings, IgM concentrations were higher than in control subjects (P < 0.001). Using age- adjusted reference intervals, abnormal Ig concentrations were noted in 27% of the patients at onset versus only 10% of the siblings and 7% of the control subjects (P < 0.001). For onset between 20 and 40 years (n = 220), 30% of the patients presented either increased IgM levels (21%) or decreased IgG levels (11%). Both independent phenomena occurred regardless of diabetes-associated immune and genetic markers. In patients and siblings, IgM levels were positively correlated with pancreatic lipase activity. In diabetic children (0-9 years; n = 65), a subgroup presented increased IgA levels (15%) in association with the highest HLA DQ-linked genetic risk and elevated IgM levels. The changes in total Ig concentrations at onset were largely reversed under insulin therapy. They may reflect exposure to environmental triggers, such as viral infections, or to (relative) insulinopenia prior to clinical disease onset. Whatever their cause, different serum Ig levels exist in different age groups of recent-onset IDDM patients.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets

Peroxisome proliferator-activated receptor (PPAR) alpha is a transcription factor controlling lipid and glucose homeostasis. PPAR alpha-deficient (-/-) mice are protected from high-fat diet-induced insulin resistance. However, the impact of PPAR alpha in the pathophysiological setting of obesity-related insulin resistance is unknown. Therefore, PPAR alpha(-/-) mice in an obese (ob/ob) background were generated. PPAR alpha deficiency did not influence the growth curves of the obese mice but surprisingly resulted in a severe, age-dependent hyperglycemia. PPAR alpha deficiency did not aggravate peripheral insulin resistance. By contrast, PPAR alpha(-/-) ob/ob mice developed pancreatic beta-cell dysfunction characterized by reduced mean islet area and decreased insulin secretion in response to glucose in vitro and in vivo. In primary human pancreatic islets, PPAR alpha agonist treatment prevented fatty acid-induced impairment of glucose-stimulated insulin secretion, apoptosis, and triglyceride accumulation. These results indicate that PPAR alpha improves the adaptative response of the pancreatic beta-cell to pathological conditions. PPAR alpha could thus represent a promising target in the prevention of type 2 diabetes

Detection of antisynthetic mannoside antibodies (ASigmaMA) reveals heterogeneity in the ASCA response of Crohn's disease patients and contributes to differential diagnosis, stratification, and prediction.

International audienceOBJECTIVES: Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is a complex and variable repertoire of oligomannoses acting as epitopes, we chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4), and then explored how antisynthetic mannoside antibodies (ASigmaMA) compare with ASCA as markers of CD. METHODS: The study involved different cohorts of CD and ulcerative colitis (UC) patients and healthy controls who had been studied previously in several medical centers in Europe, the United States, and North Africa to determine the clinical value of ASCA in terms of differential diagnosis, evolution of indeterminate colitis (IC), and serotype-phenotype correlations. The comparison of ASigmaMA and ASCA included a total of 1,365 subjects: 772 CD, 261 UC, 43 IC, and 289 controls. RESULTS: The specificity of ASigmaMA was similar to that of ASCA (89% vs 93%), although the sensitivity was lower (38% vs 55%). Unexpectedly, 24% of the CD patients who were negative for ASCA and/or other CD-associated serologic markers were positive for ASigmaMA. ASigmaMA were associated with colonic involvement in CD (odds ratio [OR] 1.609, 95% confidence interval [CI] 1.033-2.506, P = 0.03) and were 100% predictive of CD in patients with IC. CONCLUSIONS: ASigmaMA reveal the heterogeneity of the antioligomannose antibody response in CD patients and increase the sensitivity of CD diagnosis when combined with ASCA. The subset of ASCA-negative CD patients diagnosed by ASigmaMA had preferentially a colonic involvement, which confirms the high predictive value of ASigmaMA for determining IC evolution toward CD

Candida albicans colonization and ASCA in familial Crohn's disease

OBJECTIVES: Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50-60% of patients with Crohn's disease (CD) and in 20-25% of their healthy relatives (HRs). The yeast, Candida albicans, has been shown to generate ASCAs, but the presence of C. albicans in the digestive tract of CD patients and their HRs has never been investigated. Therefore, we studied C. albicans carriage in familial CD and its correlation with ASCAs. METHODS: Study groups consisted of 41 CD families composed of 129 patients and 113 HRs, and 14 control families composed of 76 individuals. Mouth swabs and stool specimens were collected for isolation, identification, and quantification of yeasts. Serum samples were collected for detection of ASCAs and anti-C. albicans mannan antibodies (ACMAs). RESULTS: C. albicans was isolated significantly more frequently from stool samples from CD patients (44%) and their HRs (38%) than from controls (22%) (P < 0.05). The prevalence of ACMAs was similar between CD patients, their HRs, and controls (22, 19, and 21%, respectively, P = 0.845), whereas the prevalence of ASCAs was significantly increased in CD families (72 and 34% in CD and HRs, respectively, in contrast to 4% in controls, P < 0.0001). AMCA levels correlated with C. albicans colonization in all populations. ASCA levels correlated with C. albicans colonization in HRs but not in CD patients. CONCLUSIONS: CD patients and their first-degree HRs are more frequently and more heavily colonized by C. albicans than are controls. ASCAs correlate with C. albicans colonization in HRs but not in CD. In HRs, ASCAs could result from an altered immune response to C. albicans. In CD, a subsequent alteration in sensing C. albicans colonization could occur with disease onset