SummaryGenetic studies have indicated that susceptibility to rheumatoid arthritis (R.A) maps to the HLA-DP, locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DP,. genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA 1"0301 and DQB 1"0302 genes from an RA predisposing haplotype (DQ8/DR.4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab ~ mice, and their susceptibility to experimental collagen-induced arthritis was evaluated. The HLA-DQ8+,H-2Ab ~ mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4 + T cells expressing a normal repertoire of V~ T cell receptors. Immunization of HLA-DQ8+,H-2Ab ~ mice with bovine type II collagen (CII) induced a strong antibody response that was crossreactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8+,H-2Ab ~ mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2Aq) controls. In contrast, HLA-DQ8-,H-2Ab ~ fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also estabhsh a novel animal model for the study of human arthritis.I t is widely accepted that a strong genetic component contributes to the susceptibility or resistance to certain human autoimmune diseases (1). Attempts to identify the particular genes involved in these disorders has been an area of major focus for many laboratories, and inroads have been clearly made. Among the numerous genes studied, one group that has garnered much attention are the genes encoding the class I and class II molecules of the HLA complex. Located on the short arm of chromosome 6, the primary function of HLA class I and II molecules is to bind and present processed antigenic peptides to T cells bearing receptors specific for the peptide-HLA complex. This presentation event plays a pivotal role in shaping the cellular immune repertoire and dictating the nature and scope of the immune response against a given antigen (2).A role for HLA molecules in the etiology of autoimmune disease derives from genetic studies showing a clear association between the presence or absence of certain HLA class I or II alleles, as well as increased or decreased susceptibility to a particular autoimmune disorder. A disease with a strong autoimmune foundation and HLA class II association is rheumatoid arthritis (RA) 1. In Caucasians, genetic studies initially showed a high prevalence of the HLA-DR4Dw4...

Immunocompetence of the Iowa State University S1 White Leghorn chicken line was studied. This line was divided into eight sublines based upon erythrocyte antigen B (Ea-B) allele (B1B1 or B19B19), antibody response to glutamic acid60-alanine30-tyrosine10 (GAT) (high or low), and response to Rous sarcoma virus-induced tumors (progression or regression). Antibody responses to Pasteurella multocida (PM), Mycoplasma gallisepticum (MG), and infectious bursal disease virus vaccines were evaluated by enzyme-linked immunosorbent assay. Phagocytic activity and T cell-mediated response were measured by carbon clearance and phytohemagglutinin (PHA) injection assays, respectively. Significant haplotype (subline) differences and sire family differences were observed in all three measurements. Significant sex differences were observed in phagocytic activity and T cell-mediated responses. Haplotypes with high antibody responses to GAT had significantly higher antibody titers to PM and MG vaccines than haplotypes with low antibody responses. Significant positive correlations were observed between antibody levels to the two vaccines. A significant negative correlation was seen between phagocytic activity and T cell-mediated response of females. The data suggest that the total immunocompetence profile of an individual must be considered to select for optimum immune responsiveness.

Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer.

The SCN5A gene encodes the alpha subunit of the main cardiac sodium channel Nav1.5. This channel predominates inward sodium current (INa) and plays a critical role in regulation of cardiac electrophysiological function. Since 1995, SCN5A variants have been found to be causatively associated with Brugada syndrome, long QT syndrome, cardiac conduction system dysfunction, dilated cardiomyopathy, etc. Previous genetic, electrophysiological, and molecular studies have identified the arrhythmic and cardiac structural characteristics induced by SCN5A variants. However, due to the variation of disease manifestations and genetic background, impact of environmental factors, as well as the presence of mixed phenotypes, the detailed and individualized physiological mechanisms in various SCN5A-related syndromes are not fully elucidated. This review summarizes the current knowledge of SCN5A genetic variations in different SCN5A-related cardiac disorders and the newly developed therapy strategies potentially useful to prevent and treat these disorders in clinical setting.

Certain HLA-DR alleles have been associated with predisposition to human rheumatoid arthritis (RA). There is also evidence that certain HLA-DQ alleles may also be important in determining susceptibility to RA. We have previously demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, develop severe arthritis after type II collagen immunization. To investigate the influence of polymorphic difference at the DQ loci on susceptibility to arthritis, we generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype. The DQ6 mice were found to be resistant to collagen-induced arthritis. We also assessed the combined effect of an RA-susceptible and an RA nonassociated DQ allele by producing double-transgenic mice expressing DQ6 and DQ8 molecules, representing the more prevalent condition found in humans where heterozygosity at the DQ allele is common. The double-transgenic mice developed moderate CIA when immunized with CII when compared with the severe arthritis observed in DQ8 transgenic mice, much like RA patients bearing both susceptible and nonsusceptible HLA haplotypes. These studies support a role for HLA-DQ polymorphism in human RA. (