Type 1 diabetic individuals are known to develop disorders of bone metabolism resulting in osteopenia. Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and susceptibility for type 1 diabetes mellitus. The present study was initiated to investigate the distribution of vitamin D receptor alleles in Caucasian type 1 diabetic patients and their relation to bone turnover parameters. 75 patients were included and compared to 57 healthy controls. Three vitamin D receptor alleles were examined (BsmI, TaqI and FokI); serum levels of intact osteocalcin, parathyroid hormone, bone specific alkaline phosphatase, the carboxy terminal extension peptide of type I procollagen, 25-OH-vitamin D levels, HbA1c and urinary deoxypyridinoline excretion were measured. We observed a higher frequency of the TT genotype in diabetic patients, but no difference in markers of bone turnover between diabetics and non-diabetics in either sex. Bone turnover was different in men and in women without any association with vitamin D receptor genotype. No association was found between diabetes duration, age of onset or metabolic control and bone turnover parameters. In summary, our results show an association between the TT genotype and diabetes in Germans, but no difference in bone turnover markers between diabetics and non-diabetics.

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Background La/SSB is a phosphoprotein that associates with various small RNA molecules. It has been found that the primary phosphorylation site of the molecule during various physiological processes is in Ser366. Objectives To determine whether the phosphorylation state of Ser366 could affect the antigenicity and the recognition of the protein by antibodies from patients with primary Sjögren's syndrome (pSS). Methods Peptides 349-368aa and phos349-368aa (with the Ser366 residue phosphorylated) were synthesized. Sera with anti-La specificity from 30 patients with pSS and sera from 19 normal individuals were examined against the two synthetic peptides in ELISA. The antibody specificity against the epitopes was tested with homologous and heterologous inhibition assays. Results Of pSS sera 23% reacted against the 349-368aa peptide. Sera binding to unphosphorylated peptide reacted also with phos349-368aa. Although the same sera gave a positive reaction against both peptides, the optical density values received from antibodies to phos349-368aa were higher, indicating a higher concentration or stronger affinity. When phos349-368aa was used as soluble inhibitor, in homologous inhibition the reactivity was almost completely abolished (92%). In contrast, when the unphosphorylated peptide was used as inhibitor, the reactivity of sera against phos349-368aa was only partially reduced (35%), indicating that sera from these patients possess two distinct groups of antibodies: one against the unphosphorylated and one against the phosphorylated epitope. Conclusion The phosphorylation of the serine366 residue resulted in a significant increase in antibody binding on epitope 349-368aa of La/SSB. These observations might explain the increased antigenicity of La/SSB autoantigen in various pathological situations in which phosphorylation may occur. 2 Surface-bound immune complexes containing antibodies to collagen type II induce production of TNF-α α, IL-1β β and IL-8 from monocytes via Fcγ γRII

Background La/SSB is a phosphoprotein that associates with various small RNA molecules. It has been found that the primary phosphorylation site of the molecule during various physiological processes is in Ser366. Objectives To determine whether the phosphorylation state of Ser366 could affect the antigenicity and the recognition of the protein by antibodies from patients with primary Sjögren's syndrome (pSS). Methods Peptides 349-368aa and phos349-368aa (with the Ser366 residue phosphorylated) were synthesized. Sera with anti-La specificity from 30 patients with pSS and sera from 19 normal individuals were examined against the two synthetic peptides in ELISA. The antibody specificity against the epitopes was tested with homologous and heterologous inhibition assays. Results Of pSS sera 23% reacted against the 349-368aa peptide. Sera binding to unphosphorylated peptide reacted also with phos349-368aa. Although the same sera gave a positive reaction against both peptides, the optical density values received from antibodies to phos349-368aa were higher, indicating a higher concentration or stronger affinity. When phos349-368aa was used as soluble inhibitor, in homologous inhibition the reactivity was almost completely abolished (92%). In contrast, when the unphosphorylated peptide was used as inhibitor, the reactivity of sera against phos349-368aa was only partially reduced (35%), indicating that sera from these patients possess two distinct groups of antibodies: one against the unphosphorylated and one against the phosphorylated epitope. Conclusion The phosphorylation of the serine366 residue resulted in a significant increase in antibody binding on epitope 349-368aa of La/SSB. These observations might explain the increased antigenicity of La/SSB autoantigen in various pathological situations in which phosphorylation may occur. 2 Surface-bound immune complexes containing antibodies to collagen type II induce production of TNF-α α, IL-1β β and IL-8 from monocytes via Fcγ γRII

Japan Arthritis Res Ther 2003, 5(Suppl 3):1 (DOI 10.1186/ar800) Apoptosis is a principal mechanism in metazoans by which superfluous or potentially harmful cells are eliminated. Deregulation of this process leads to a variety of diseases such as cancer and autoimmune diseases. Stimuli that can induce apoptosis are relatively diverse, and include the death factors (Fas ligand, tumor necrosis factor and TRAIL), DNA damage, and oxidative stress. Regardless of the origin of the apoptotic stimulus, commitment to apoptosis leads to activation of caspases, a family of cysteine proteases. Cleavage of a select group of cellular substrates by caspases is responsible for the morphological and biochemical changes that characterize apoptotic cell death. The degradation of nuclear DNA into nucleosomal units is one of the features of apoptotic cell death, and is mediated by a caspase-activated DNase (CAD). Cells deficient in CAD undergo cell death without the DNA fragmentation, but CAD-null mice did not show any adverse phenotypes. A close examination of the apoptotic cells in these mice indicated that apoptotic cells are always in macrophages. It seems that at an early stage of apoptosis, the dying cells present an 'eat me signal' on their surface. This signal is recognized by macrophages for engulfment, and DNase II in the lysosomes of macrophages degrades DNA of apoptotic cells. Mice deficient in both CAD and DNase II genes were established, and the development of various organs was found to be severely impaired in these mutant mice. The mice accumulated a large amount of undigested DNA in macrophages in various tissues during development. This accumulation of DNA in macrophages activated the innate immunity to induce the expression of the interferon β gene. The interferon thus produced seems to be responsible for the impaired tissue development. These results indicate that the degradation of DNA during apoptotic cell death is an essential step of apoptosis to maintain mammalian homeostasis. Osteoarthritis (OA) has been considered a biomechanically driven, degenerative disease of cartilage. However, the OA disease process affects not only the cartilage, but also the entire joint structure; and within the bone, cartilage and synovium of affected joints, profound metabolic changes transpire, which include the production of growth factors, nitric oxide (NO), prostaglandins (PGs), leukotrienes (LTs), IL-1β, tumor necrosis factor alpha, IL-6, and IL-8. The autocrine production of IL-1β by OA cartilage has been of particular interest, since both ex vivo human and in vivo animal studies indicate that IL-1 antagonists effectively attenuate cartilage degradation. Microarray technology has demonstrated differential expression in OA cartilage of a variety of IL-1-induced, NFβB-dependent genes. Among IL-β-induced products of OA cartilage are various eicosanoids, which include E 2 , PGD 2 , LTB 4 , PGF 1α , PGF 2α and thromboxane. Treatment of OA cartilage with cyclooxygenase (COX) inhibitors increases LTB 4 production threefold to five...