Rheumatoid Arthritis: Selmi C

Selmi C, Lleo A, Zuin M, Podda M, Rossaro L, Gershwin ME. · Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 E Health Sciences Drive, Suite 6510, Davis, CA 95616, USA. · Curr Opin Investig Drugs. · Pubmed #16729722 No free full text.

Abstract: It is now well accepted that interferon (IFN)alpha plays a critical role in the pathogenesis and perpetuation of specific autoimmune diseases, including systemic lupus erythematosus (SLE), autoimmune thyroid disease and type 1 diabetes. IFNalpha-based treatments are widely used for the treatment of chronic viral infections, particularly chronic hepatitis C virus infection; however, several case reports have emerged describing autoimmune conditions that have developed during IFNalpha therapy. The data support the pathogenic potential of IFNalpha in autoimmunity, although it is clear that genetic and environmental factors are also key to the development of autoimmune conditions. Several points of interaction between IFNalpha and immune effector cells have been experimentally defined, the functional consequences of many of which remain poorly understood. This review describes the most recent data in support of an important role for IFNalpha in autoimmunity, particularly SLE, and the potential mechanisms by which IFNalpha contributes to immune dysfunction. Future approaches to IFNalpha modulation as a therapeutic strategy for use in the treatment of autoimmune diseases are also discussed.

Borchers AT, Selmi C, Cheema G, Keen CL, Shoenfeld Y, Gershwin ME. · Department of Nutrition, USA. · Autoimmun Rev. · Pubmed #16697970 No free full text.

Abstract: One of the most enigmatic problems in rheumatology has been juvenile idiopathic arthritis (JIA). Firstly, the classification has often depended on clinical features that have variations between patients. Secondly, there are different classification schemes in usage and there are few objective serologic tests that help to resolve the differences between the criteria sets. Thirdly, only recently have significant advances been made in understanding the immunology and immunopathology of JIA and, in particular, new treatment options. In this review, we will define the historical basis of JIA and emphasize not only the clinical features, but also the immunological characteristics, the pathogenesis, and treatment options. We will also discuss, in particular, quality of life, psychosocial functioning, socioeconomic outcomes and the difficult area of mortality. Finally, this review will attempt to bridge genetic observations with clinical presentation. JIA represents a relatively common syndrome of pediatric onset rheumatologic disease and a better understanding of the clinical definition, the relationship to autoimmunity, and novel treatments with biologic agents are critical for improved patient care.

Oertelt S, Selmi C, Invernizzi P, Podda M, Gershwin ME. · Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, California 95616, USA. · Autoimmun Rev. · Pubmed #16137606 No free full text.

Abstract: A significant body of data on gene expression patterns in autoimmune diseases has been generated by microarray analysis. Although results are very promising, there are many factors that have detracted from the data. Indeed, no common methodological directions are available. Similarly, collection techniques, processing methods, and statistical approaches are often different. The impact of future studies will depend on the comparison of large datasets to validate results and must include rigorous statistical analysis. To better illustrate the issue we review herein the gene expression patterns observed in five representative autoimmune diseases, i.e. systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, dermatomyositis, and primary biliary cirrhosis. We also emphasize how, once potential chromosome regions or pathways are identified, specific array design will be a powerful resource when used on large and representative populations.

Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C, Klareskog L, Pulver AE, Qi L, Gregersen PK, Seldin MF. · Rowe Program in Human Genetics, University of California Davis, Davis, California, United States of America. · PLoS Genet. · Pubmed #18208329 links to  free full text

Abstract: European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

Tanaka A, Nezu S, Uegaki S, Mikami M, Okuyama S, Kawamura N, Aiso M, Gershwin ME, Takahashi S, Selmi C, Takikawa H. · Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan. · Ann N Y Acad Sci. · Pubmed #17804554 No free full text.

Abstract: It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA-AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA-AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA-type autoantibodies in sera or saliva and progression of liver diseases. Fifty-three patients with PBC were enrolled, and IgA-AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA-anti-PDC-E2 (P = 0.0124), but neither with IgA-AMA (P = 0.1296) nor anti-IgA-E3BP (P = 0.5973). In saliva, detectable IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA-anti-PDC-E2 was strongly associated with progression of PBC (P = 0.0002), whereas detection of IgA-AMA and IgA-anti-E3BP were not associated (P = 0.2145 and P = 0.5118). The current findings suggest that the presence of IgA-anti-PDC-E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA-anti-PDC-E2 at early stages will be required to conclude the contribution of IgA-anti-PDC-E2 to the progression of PBC.

Seldin MF, Shigeta R, Villoslada P, Selmi C, Tuomilehto J, Silva G, Belmont JW, Klareskog L, Gregersen PK. · Rowe Program in Human Genetics, Departments of Biological Chemistry and Medicine, University of California Davis, Davis, California, United States of America. · PLoS Genet. · Pubmed #17044734 links to  free full text

Abstract: Using a genome-wide single nucleotide polymorphism (SNP) panel, we observed population structure in a diverse group of Europeans and European Americans. Under a variety of conditions and tests, there is a consistent and reproducible distinction between "northern" and "southern" European population groups: most individual participants with southern European ancestry (Italian, Spanish, Portuguese, and Greek) have >85% membership in the "southern" population; and most northern, western, eastern, and central Europeans have >90% in the "northern" population group. Ashkenazi Jewish as well as Sephardic Jewish origin also showed >85% membership in the "southern" population, consistent with a later Mediterranean origin of these ethnic groups. Based on this work, we have developed a core set of informative SNP markers that can control for this partition in European population structure in a variety of clinical and genetic studies.