Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

ZNF397, a new class of interphase to early prophase-specific, SCAN-zinc-finger, mammalian centromere protein.

The centromere is a complex structure required for equal segregation of newly synthesised sister chromatids at mitosis. One of the significant objectives in centromere research is to determine the complete repertoire of protein components that constitute the kinetochore. Here, we identify a novel centromere protein using a centromere-positive autoimmune serum from a patient with watermelon stomach disease. Western blot and screening of a lambda phage expression library revealed a 60-kDa protein, ZNF397. This protein belongs to the classical Cys(2)His(2) group of the zinc-finger protein superfamily and contains two conserved domains: a leucine-rich SCAN domain and nine Cys(2)His(2) zinc fingers. Bioinformatic analysis shows that ZNF397 is conserved in placental mammals. Stable GFP:ZNF397-expressing human cells show co-localisation of ZNF397 with the constitutive centromere protein CENP-A during interphase and early prophase. Deletion and domain-swap constructs indicate that the SCAN domain is necessary but not sufficient for centromere localisation. Gene-knockout studies in mice using the mouse orthologue (Zfp397) reveal that ZNF397 is a non-essential protein. These properties define ZNF397 as a member of a new class of interphase to early prophase-specific and SCAN domain-containing mammalian centromere protein. The possible role of this protein in transcription at the centromere is discussed.

Watermelon stomach: clinical aspects and treatment with argon plasma coagulation.

BACKGROUND: Gastric antral vascular ectasia is a disorder whose pathogenetic mechanism is unknown. The endoscopic treatment with argon plasma coagulation has been considered one of the best endoscopic therapeutic options. AIM: To analyze the endoscopic and clinical features of gastric antral vascular ectasia and its response to the argon plasma coagulation treatment. PATIENTS AND METHODS: Eighteen patients were studied and classified into two groups: group 1--whose endoscopic aspect was striped (watermelon) or of the diffuse confluent type; group 2--diffuse spotty nonconfluent endoscopic aspect. RESULTS: Group 1 with eight patients, all having autoimmune antibodies, but one, whose antibodies were not searched for. Three were cirrhotic and three had hypothyroidism. All had gastric mucosa atrophy. In group 2, with 10 patients, all had non-immune liver disease, with platelet levels below 90,000. Ten patients were submitted to argon plasma coagulation treatment, with 2 to 36 months of follow-up. Lesions recurred in all patients who remained in the follow-up program and one did not respond to treatment for acute bleeding control. CONCLUSION: There seem to be two distinct groups of patients with gastric antral vascular ectasia: one related to immunologic disorders and other to non-immune chronic liver disease and low platelets. The endoscopic treatment using argon plasma coagulation had a high recurrence in the long-term evaluation.

Watermelon stomach: clinical aspects and treatment with argon plasma coagulation / Ectasia vascular do antro gástrico ("watermelon stomach"): aspectos clínicos e tratamento com coagulação com plasma de argônio

BACKGROUND: Gastric antral vascular ectasia is a disorder whose pathogenetic mechanism is unknown. The endoscopic treatment with argon plasma coagulation has been considered one of the best endoscopic therapeutic options. AIM: To analyze the endoscopic and clinical features of gastric antral vascular ectasia and its response to the argon plasma coagulation treatment. PATIENTS AND METHODS: Eighteen patients were studied and classified into two groups: group 1 - whose endoscopic aspect was striped (watermelon) or of the diffuse confluent type; group 2 - diffuse spotty nonconfluent endoscopic aspect. RESULTS: Group 1 with eight patients, all having autoimmune antibodies, but one, whose antibodies were not searched for. Three were cirrhotic and three had hypothyroidism. All had gastric mucosa atrophy. In group 2, with 10 patients, all had non-immune liver disease, with platelet levels below 90.000. Ten patients were submitted to argon plasma coagulation treatment, with 2 to 36 months of follow-up. Lesions recurred in all patients who remained in the follow-up program and one did not respond to treatment for acute bleeding control. CONCLUSION: There seem to be two distinct groups of patients with gastric antral vascular ectasia: one related to immunologic disorders and other to non-immune chronic liver disease and low platelets. The endoscopic treatment using argon plasma coagulation had a high recurrence in the long-term evaluation.

RACIONAL: "Watermelon stomach" ou ectasia vascular do antro gástrico é uma doença de etiopatogenia desconhecida. O tratamento endoscópico através da coagulação com plasma de argônio é considerado uma das melhores opções terapêuticas. OBJETIVO: Analisar os aspectos clínicos e endoscópicos da ectasia vascular do antro gástrico e a resposta ao tratamento com coagulação com plasma de argônio. PACIENTES E MÉTODOS: Dezoito pacientes foram estudados e classificados em dois grupos: grupo I - oito pacientes que exibiam ectasia vascular do antro gástrico de aspecto difuso confluente ou estriado. Grupo II - 10 pacientes que apresentavam aspecto difuso pontilhado não-confluente. RESULTADOS: Todos os pacientes do grupo I apresentavam auto-anticorpos, exceto um paciente no qual não foi pesquisado. Três eram cirróticos, três tinham hipotireoidismo e todos apresentavam gastrite atrófica. No grupo II, todos tinham doença hepática não-autoimune, com plaquetas menores que 90.000. Dez pacientes foram submetidos a tratamento com coagulação com plasma de argônio, com 2 a 36 meses de seguimento. A ectasia vascular do antro gástrico recorreu em todos os pacientes que continuaram em acompanhamento e um paciente não respondeu ao tratamento para controle de sangramento agudo. CONCLUSÃO: Observou-se a existência de dois grupos distintos de pacientes com ectasia vascular do antro gástrico: um grupo associado a distúrbios imunológicos e outro com doença hepática não auto-imune e plaquetopenia. O tratamento com coagulação com plasma de argônio apresentou alta recurrência das ectasias vasculares.

Unique epitopes in RNA helicase II/Gu protein recognized by serum from a watermelon stomach patient.

RNA helicase II/Gu (RH II/Gu) is a nucleolar antigen originally identified using an autoimmune serum from a patient with watermelon stomach. A later report showed that anti-RH II/Gu autoantibodies were also present at low frequency in connective tissue disease (CTD) patients who did not show any symptoms suggestive of a watermelon stomach lesion. In an attempt to understand the relationship between watermelon stomach, also called gastric antral vascular ectasia (GAVE), and autoimmune disorder, we identified the antigenic sites recognized by these autoantibodies. Serum Gu uniquely recognized epitopes at amino acids 646-748 of RH II/Gu and all four CTD patient sera recognized antigenic sites within amino acids 1-173. Anti-RH II/Gu serum produced by immunizing rabbit with recombinant human RH II/Gu protein bound to the same antigenic sites recognized by the CTD patient sera, but it did not recognize the serum Gu epitopes. Results are also presented showing the use of these anti-RH II/Gu antibodies in the analysis of the evolutionary conservation of RH II/Gu in human, monkey and mouse.