Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin-1β, and joint damage in pristane- and collagen-induced arthritis.

Objective: Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen- and pristane-induced arthritis (CIA and PIA). This study was undertaken to refine the Cia3 gene-containing interval toward gene identification and obtain insights into its mode of action.

Methods: Five DA.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.

Background: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab.

Methods: In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s).

Streptococcal cell wall arthritis.

Streptococcal cell wall (SCW) arthritis in rats is an experimentally-induced inflammatory model with many features that resemble rheumatoid arthritis (RA) in humans. In this unit, Lewis rats are injected with an aqueous suspension of Group A SCW streptococcal cell wall peptidoglycan-polysaccharide polymers (SCW PG-PS) and observed for the development of arthritis. The resulting arthritis is biphasic.

The non-MHC quantitative trait locus Cia5 contains three major arthritis genes that differentially regulate disease severity, pannus formation, and joint damage in collagen- and pristane-induced arthritis.

Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models.

The non-major histocompatibility complex quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation, and joint damage.

Objective: To construct rats congenic for the chromosome 2 arthritis-regulatory quantitative trait locus Cia10, originally identified in a (DA x ACI)F(2) intercross rat strain that had been assessed for collagen-induced arthritis (CIA), and to determine the effect of this congenic interval on arthritis severity, joint histologic structure, and cytokine transcription in rats with pristane-induced arthritis (PIA).

Methods: A 52.6-MB interval derived from the ACI (CIA- and PIA-resistant) strain and containing the Cia10 interval was introgressed into the DA (arthritis-susceptible) background through genotype-guided congenic breeding.

Identification of two novel female-specific non-major histocompatibility complex loci regulating collagen-induced arthritis severity and chronicity, and evidence of epistasis.

Objective: To identify additional sex-specific and epistatic quantitative trait loci (QTL) regulating collagen-induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex-identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant).

Methods: Arthritic male (DA x ACI)F2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis.

Genomic regions controlling corticosterone levels in rats.

Background: The identification of genetic factors controlling stress-responsiveness should advance the understanding of susceptibility to psychiatric illness.

Methods: Rat strains, F344/NHsd and LEW/NHsd, which differ in measures of stress-responsiveness and behaviors modeling psychiatric disorders, were bred to generate F2 progeny that were used in a quantitative trait loci (QTL) analysis to identify genomic regions influencing late-afternoon corticosterone levels.

Results: Regions on chromosomes 4 and 10 previously identified as influencing autoimmune phenomena were the most significant QTL observed, reaching suggestive significance at the genome-wide level.

Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.

Objective: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings.

Pilot clinical trial of intravenous doxycycline versus placebo for rheumatoid arthritis.

Objective: To screen for potential efficacy and assess the feasibility of intravenous (IV) doxycycline as a treatment for rheumatoid arthritis (RA).

Methods: The study was a (stratified, block) randomized, double blind, 12 week, pilot trial of IV doxycycline 300 mg/day versus identical appearing IV placebo given over 2 h for 14 days. The primary comparison was to a hypothesized placebo rate of 20% as described by Paulus.

Localization of the mutation responsible for osteopetrosis in the op rat to a 1.5-cM genetic interval on rat chromosome 10: identification of positional candidate genes by radiation hybrid mapping.

Osteopetrosis is caused by a heterogenous group of bone diseases that result in an increase in skeletal mass because of inadequate osteoclastic bone resorption. In the op osteopetrotic rat, the disease has been linked to a single genetic locus located at the proximal end of rat chromosome 10. In this study, we identified a 1.

Modulation of multiple experimental arthritis models by collagen-induced arthritis quantitative trait loci isolated in congenic rat lines: different effects of non-major histocompatibility complex quantitative trait loci in males and females.

Objective: Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F(2) offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs.

Neuroimmunoendocrinology of the rheumatic diseases: past, present, and future.

Adaptation to stressful stimuli, maintenance of homeostasis, and ultimately, survival require bidirectional feedback communication among components of the stress response and immune and endocrine systems. Substantial progress has been made in delineating molecular, cellular, and systemic physiologic mechanisms underlying this communication, particularly mechanisms that target the immune system. For example, our understanding of the immunomodulatory activities of numerous neuroendocrine mediators, such as cortisol, estrogen, testosterone, DHEA, catecholamines, corticotropin-releasing hormone, and adenosine, has advanced substantially.

Mutation of macrophage colony stimulating factor (Csf1) causes osteopetrosis in the tl rat.

Osteopetrosis results from a heterogeneous group of congenital bone diseases that display inadequate osteoclastic bone resorption. We recently mapped tl (toothless), a mutation that causes osteopetrosis in rats, to a genetic region predicted to include the rat Csf1 gene. In this study, we sequenced the coding sequence of the rat Csf1 gene to determine if a mutation in Csf1 could be responsible for the tl phenotype.

Evaluation of quantitative trait loci regulating severity of mycobacterial adjuvant-induced arthritis in monocongenic and polycongenic rats: identification of a new regulatory locus on rat chromosome 10 and evidence of overlap with rheumatoid arthritis susceptibility loci.

Objective: To evaluate the regulatory potential of genetic loci controlling Mycobacterium butyricum adjuvant-induced arthritis (Mbt-AIA) using mono- and polycongenic rats.

Methods: Of 4 quantitative trait loci (QTLs) that regulate Mbt-AIA, F344 alleles at 3 of these loci, Aia1, Aia2, and Aia3, are associated with lower arthritis severity, whereas F344 alleles at Aia4 are associated with greater arthritis severity. In this study, we constructed congenic lines by transferring 1 or more of the F344 genomic segments containing Aia1, Aia2, and Aia3 onto the DA genome.