Anti-CD38 Autoimmunity in Children with Newly Diagnosed Type 1 Diabetes Mellitus
To test for anti-CD38 autoimmunity in children with newly-diagnosed type 1 diabetes mellitus (DM1).
Serum anti-CD38 autoantibodies were detected by Western blot in 270 children (130 girls, 140 boys, mean age 8 +/- 4 years) with newly-diagnosed DM1 and 179 gender- and age-matched non-diabetic children. In 126 diabetic children, another blood sample was obtained 15 +/- 4 months after the diagnosis.
Anti-CD38 autoantibody titers at least 3 SD above the mean value for the control group were found in 4.4% of children with DM1 vs 0.6% of controls (chi2 = 5.8, p <0.016). No statistical differences were observed between anti-CD38 positive and negative patients in terms of phenotype. At follow-up, of six diabetic children who were positive for anti-CD38 antibodies, two were new cases. A positive correlation was found between the antibody titer of diabetic sera at diagnosis and follow up (r = 0.46, p <0.0001).
An autoimmune reaction against CD38, a protein expressed in human islets, is associated with newly-diagnosed DM1. In children with DM1, CD38 autoimmunity increases with time and persists.
Available from: Shin Takasawa
- "This was confirmed by the fact that the over-expression of CD38 recovered GIS from IH-treated β-cells (Fig. 4). Several lines of evidence such as CD38 knockout mice (Kato et al., 1999), CD38 missense mutation (Yagui et al., 1998), and autoantibodies against CD38 (Ikehata et al., 1998; Pupilli et al., 1999; Antonelli et al., 2002; Marchetti et al., 2002; Mallone et al., 2002; Pupilli et al., 2005) indicate that the down-regulation/dysfunction of CD38 in βcells results in attenuation of GIS. Therefore, the association between nocturnal intermittent hypoxia and the risk of developing type 2 diabetes among community-dwelling Japanese participants (Muraki et al., 2010) may be mediated by the down-regulation of CD38 by IH in the participants. "
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ABSTRACT: Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation during sleep, the development of daytime sleepiness, and deterioration in the quality of life. Accumulating evidence suggests the association of intermittent hypoxia (IH), a hallmark of SAS, and type 2 diabetes independently on body mass index and waist circumference. In addition to insulin resistance, the progression to type 2 diabetes is dependent on the impairment of glucose-induced insulin secretion (GIS) from pancreatic β-cells. However, the direct effects of IH on GIS are elusive.
HIT-T15 hamster β-cells and isolated rat islets were exposed to 64 cycles/24 h of IH (5 min hypoxia/10 min normoxia) or normoxia for 24 h. Changes of GIS and gene expression in IH-treated β-cells were analyzed by ELISA and real-time RT-PCR, respectively.
After IH treatment, GIS both from IH-treated HIT-T15 cells and isolated rat islets were significantly attenuated. The level of insulin mRNA was unchanged by IH. The mRNA levels of glucose transporter 2 (Glut2), glucokinase (GK), sulfonylurea receptor1 (SUR1), and L-type Ca2+channel1.2 (Cav1.2) in IH-treated-islets were similar to those in normoxia-treated islets. In contrast, the mRNA level of CD38 in IH-treated islets was significantly lower than that in normoxia-treated islets. The reporter gene assay revealed that the transcription of CD38 was attenuated by IH, and the transfection of CD38 expression vector recovered the attenuation of GIS by IH.
These results indicate that IH stress directly attenuates GIS from β-cells via the down-regulation of CD38.
Available from: jasn.asnjournals.org
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ABSTRACT: Goodpasture disease (GP) is defined by the presence of anti-glomerular basement membrane (anti-GBM) antibodies and rapidly progressive glomerulonephritis. Besides anti-GBM, many patients with GP produce anti-neutrophil cytoplasmic antibodies (ANCA). For elucidation of the pathophysiologic significance of ANCA in this setting, epitope and antigen specificity of the anti-GBM antibodies and antigen specificity of ANCA were studied. Bovine testis alpha(IV)NC1 (tNC1); recombinant human alpha1, alpha3, alpha4, and alpha5(IV)NC1 (ralpha1 through ralpha5); and three chimeric proteins that contain previously defined epitope regions designated E(A), E(B), and S2 were used to examine the anti-GBM antibodies by ELISA in 205 Chinese patients with GP with or without ANCA. In the 205 anti-GBM antibody-positive sera, 63 (30.7%) were also ANCA positive (61 myeloperoxidase-ANCA and six proteinase 3-ANCA, four being triple positive). All 205 sera recognized tNC1 and ralpha3(IV)NC1. In the double-positive group, 54.0, 66.7, 71.4% of the sera could recognize ralpha1, ralpha4, and ralpha5, respectively, compared with 49.3, 60.6, and 55.6% for patients with anti-GBM antibodies alone. The levels of the antibodies to ralpha3, tNC1, and the alpha3/alpha1 ratio were lower in the double-positive group than that in patients with anti-GBM antibody alone (P < 0.05). Most of the sera could recognize the epitope regions E(A), E(B), and S2, but the absorbance values to E(A), E(B), and S2 were lower in double-positive group (P < 0.05). Double-positive patients had a broader spectrum of anti-GBM antibodies and lower levels of antibodies against alpha3(IV)NC1 compared with that of patients with anti-GBM antibodies alone.
Available from: Tiziana Vaisitti
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ABSTRACT: The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. These reaction products are essential for the regulation of intracellular Ca(2+), the most ancient and universal cell signaling system. The entire family of enzymes controls complex processes, including egg fertilization, cell activation and proliferation, muscle contraction, hormone secretion, and immune responses. Over the course of evolution, the molecules have developed the ability to interact laterally and frontally with other surface proteins and have acquired receptor-like features. As detailed in this review, the loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications in mice. CD38 is a powerful disease marker for human leukemias and myelomas, is directly involved in the pathogenesis and outcome of human immunodeficiency virus infection and chronic lymphocytic leukemia, and controls insulin release and the development of diabetes. Here, the data concerning diseases are examined in view of potential clinical applications in diagnosis, prognosis, and therapy. The concluding remarks try to frame all of the currently available information within a unified working model that takes into account both the enzymatic and receptorial functions of the molecules.
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