Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases.
A duplication in the fibrillin-1 gene has been implicated as the cause of the tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemic sclerosis (SSc). In addition to the production of abnormal fibrillin-1 protein, the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of Choctaw Native Americans with the highest prevalence of SSc yet described, a chromosome 15q haplotype containing the fibrillin-1 gene has been strongly associated with SSc. With a recombinant human fibrillin-1 protein, autoantibodies to fibrillin-1 were detected in the sera of Native American SSc patients that correlated significantly with disease. Abs to fibrillin-1 also were detected in sera from Japanese, Caucasian, and African-American SSc patients. Compared with other ethnic groups, Japanese and Native American SSc patients had significantly higher frequencies of anti-fibrillin-1 Abs. Sera from patients with diffuse SSc, calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasias syndrome and mixed connective tissue disease also had significantly higher frequencies of anti-fibrillin-1 Abs than sera from controls or patients with other non-SSc connective tissue diseases (lupus, rheumatoid arthritis, and Sjogren's syndrome). Ab specificity for fibrillin-1 was demonstrated by the lack of binding to a panel of other purified autoantigens. The results presented demonstrate for the first time the presence of high levels of anti-fibrillin-1 Abs in a significant portion of patients with SSc. (+info)
Phlebosclerosis of the colon with positive anti-centromere antibody.
A 56-year-old woman with symptoms of chronic bowel disease presented a peculiar calcification of the mesenteric vein of the ascending to transverse colon on barium enema study. The resected colon was hard and black. Histo-pathologic examinations demonstrated fibrous change of the colon with a calcified and hyaline-deposited mesenteric vein. No cell infiltration was observed. These findings were compatible with phlebosclerosis and also with systemic sclerosis. Positive anti-centromere antibody and Raynaud's phenomenon, hallmarks of a variant systemic sclerosis, the CREST syndrome were observed. We therefore speculated that the pathogenesis of the phlebosclerosis of the colon is related to the CREST syndrome. (+info)
The mammalian centromere: structural domains and the attenuation of chromatin modeling.
The centromere-kinetochore complex can be divided into distinct domains based on structure and function. Previous work has used CREST auto-antibodies with various microscopic techniques to map the locations of proteins within the centromere-kinetochore complex and to analyze the maturation of prekinetochores before mitosis. Here we have focused on the centromere-specific histone Centromere Protein (CENP)-A and its spatial relationship to other histones and histone modifications found in condensed chromatin. We demonstrate that the phosphorylation of histone H3 is essentially excluded from a specific region of centromeric chromatin, defined by the presence of CENP-A. Interspersion of CENP-B with phosphorylated H3 in the inner centromere indicates that the exclusion of H3 modification is not a general property of alpha-satellite DNA. We also demonstrate that these regions are functionally distinct by fragmenting mitotic chromatin into motile centromere-kinetochore fragments that contain CENP-A with little or no phosphorylated H3 and nonmotile fragments that contain exclusively phosphorylated H3. The sequence of CENP-A diverges from H3 in a number of key residues involved in chromosome condensation and in transcription, potentially allowing a more specialized chromatin structure within centromeric heterochromatin, on which kinetochore plates may nucleate and mature. This specialized centromere subdomain would be predicted to have a very tight and static nucleosome structure as a result of the absence of H3 phosphorylation and acetylation. (+info)
Clinical, serological and genetic study in patients with CREST syndrome.
OBJECTIVE: To assess the clinical, serological and genetic features of Japanese patients with CREST syndrome. PATIENTS AND METHODS: Clinical features, autoantibodies and human histocompatibility leukocyte antigen (HLA) typing were studied in thirty patients with CREST syndrome, including 29 females and one male, with a mean age of 59.0 years (ranging from 40 to 76 years). RESULTS: Interstitial pneumonia on chest X-ray and renal involvement were rare. Mitral regurgitation and tricuspid regurgitation were present in 56.7% and 76.7%, respectively. Sjoren's syndrome (SS) and primary biliary cirrhosis (PBC) were highly associated, however the positivity of the marker antibodies to those syndromes, such as anti-SSA, anti-SSB, anti-mitochondrial (AMA) and anti-smooth muscle autoantibodies were less frequent than that of primary SS and PBC without the other autoimmune diseases. The histological findings of PBC were all early stages in Scheuer's classification. HLA-Cw6 were associated with CREST-PBC overlap syndrome (p<0.05). However the HLA antigen was not correlated with CREST syndrome, and the frequency of HLA-DR2 between CREST syndrome with or without PBC was significantly different (p<0.01). CONCLUSION: It was suggested that there was a genetic difference between CREST syndrome alone and CREST-PBC overlap syndrome and there were differences (the positivity of AMA and the severity of bile duct lesion) between PBC and CREST-PBC overlap syndrome. (+info)
Autoimmune hepatitis and systemic sclerosis: a new overlap syndrome?
OBJECTIVE: We report the cases of two patients with the complete CREST variant (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) of systemic sclerosis (SSc) who developed autoimmune hepatitis. RESULTS: Our findings suggest that autoimmune hepatitis can be considered to be one of the liver manifestations associated with SSc. Our data also indicate that, because liver involvement may precede skin manifestations, evaluation for SSc is appropriate when autoimmune hepatitis is noted, and that the evaluation should include clinical examination, testing for antinuclear antibodies (especially for anticentromere antibodies) and nailfold capillaroscopy. CONCLUSIONS: From a practical point of view, our two cases emphasize that suspicion of autoimmune hepatitis in SSc patients presenting with cytolytic hepatitis will help to achieve both accurate diagnosis and optimal management. (+info)
Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome.
A 58-year-old woman with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome presented with slowly progressive renal dysfunction. She was normotensive with normal plasma renin activity and lacking symptoms of vasculitis. Mild proteinuria was of tubular origin, but serological tests and an absence of sicca symptoms excluded the possibility of Sjogren's syndrome. Light microscopic study of renal biopsy showed interstitial fibrosis with ectasia and degeneration of proximal tubule and lymphocyte infiltration. There were no remarkable changes in the glomeruli. Chromatographic analysis of the Chinese herbs regimen that she had been taking for several years demonstrated aristolochic acid. She was diagnosed as Chinese herbs nephropathy. Therapy with oral prednisolone was markedly effective in improving renal function and anemia. To our knowledge, this is the first report of Chinese herbs nephropathy complicating connective tissue disease. It is important to consider the possibility of Chinese herbs nephropathy when patients treated with Chinese herbs develop renal dysfunction. (+info)
Induction of kinetochore-positive and kinetochore-negative micronuclei in CHO cells by ELF magnetic fields and/or X-rays.
To test the genotoxic effects of extremely low frequency (ELF) magnetic fields, the induction of micronuclei by exposure to ELF magnetic fields and/or X-rays was investigated in cultured Chinese hamster ovary (CHO) cells, using the cytokinesis block method. Micronuclei derived from acentric fragments or from whole chromosomes were evaluated by immunofluorescent staining using anti-kinetochore antibodies from the serum of scleroderma (CREST syndrome) patients. A 60 Hz ELF magnetic field at 5 mT field strength was applied, either before or after 1 Gy X-ray irradiation or without additional X-ray irradiation. No statistically significant difference in the frequency of micronuclei in CHO cells was observed between a sham exposure (no exposure to an ELF magnetic field) and a 24 h ELF magnetic field exposure. Exposure to an ELF magnetic field for 24 h before X-ray irradiation or for 18 h after X-ray irradiation did not affect the frequency of X-ray-induced micronuclei. However, the number of kinetochore-positive micronuclei was significantly increased in the cells subjected to X-ray irradiation followed by ELF magnetic field exposure, but not in the cells treated with ELF magnetic field exposure before X-ray irradiation, compared with exposure to X-rays alone. The number of spontaneous kinetochore-positive and kinetochore-negative micronuclei was not affected by exposure to an ELF magnetic field alone. Our data suggest that exposure to an ELF magnetic field has no effect on the number of spontaneous and X-ray-induced micronuclei. However, ELF magnetic field exposure after but not before X-ray irradiation may somehow accelerate X-ray-induced lagging of whole chromosomes (or centric fragments) in CHO cells. (+info)
Human ninein is a centrosomal autoantigen recognized by CREST patient sera and plays a regulatory role in microtubule nucleation.
Centrosome is the major microtubule organizing center in mammalian cells that plays a critical role in a variety of cellular events by the microtubule arrays emanating from it. Despite its significance, the molecular mechanisms underlying the structure and function of the centrosome are still not clear. Herein we describe the identification of three isotypes of human ninein by expression library screening with autoimmune sera from CREST patients. All three ninein isotypes exhibit centrosomal localization throughout the cell cycle when GFP-tagged fusion proteins are expressed transiently in mammalian cells. Construction of serial deletions of GFP-tagged ninein reveals that a stretch of three leucine zippers with a flanking sequence is required and sufficient for centrosomal targeting. Overexpression of ninein results in mislocalization of gamma-tubulin, recruiting it to ectopic (noncentrosomal) ninein-containing sites which are not active in nucleating microtubules. In these cells, nucleation of microtubules from the centrosome is also inhibited. These results thus suggest a regulatory role for ninein in microtubule nucleation. (+info)