1,25-Dihydroxyvitamin D3 and 20-Hydroxyvitamin D3 Upregulate LAIR-1 and Attenuate Collagen Induced Arthritis.

Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) model to analyze the efficacy of the noncalcemic analog of vitamin D, 20-hydroxyvitamin D3 [20(OH)D3], as well as 1,25(OH)D3, to attenuate arthritis and explore a potential mechanism of action.

Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway.

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1-sufficient and -deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition.

Ameliorating effects of Gö6976, a pharmacological agent that inhibits protein kinase D, on collagen-induced arthritis.

Toll-like receptor (TLR) signaling can contribute to the pathogenesis of arthritis. Disruption of TLR signaling at early stages of arthritis might thereby provide an opportunity to halt the disease progression and ameliorate outcomes. We previously found that Gö6976 inhibits TLR-mediated cytokine production in human and mouse macrophages by inhibiting TLR-dependent activation of protein kinase D1 (PKD1), and that PKD1 is essential for proinflammatory responses mediated by MyD88-dependent TLRs.

The role of Syk in peripheral T cells.

The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk chimeric mice and DR1 Syk CD4 conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Syk T cells but not SykCD4 T cells.

The Role of Leukocyte-Associated Ig-like Receptor-1 in Suppressing Collagen-Induced Arthritis.

Several observations implicate a critical role for T cell dysregulation as a central problem in rheumatoid arthritis. We investigated a mechanism for suppressing T cell activation by stimulating a natural inhibitory receptor called leukocyte-associated Ig-like receptor-1 (LAIR-1). The collagen-induced arthritis (CIA) model and DR-1 transgenic mice were used to study the importance of LAIR-1 in autoimmune arthritis.

Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide.

Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcRγ and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox.

Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease in mice deficiency of IL-1RA.

Background: The mouse strain BALB/c deficient in IL-1 receptor antagonist protein (Il-1ra) develops spontaneous arthritis disease (SAD) while the strain DBA/1 IL1rn (-/-) with the same deficiency does not. Previously, we mapped a QTL on chromosome 1 for SAD and then developed a congenic mouse strain BALB.D1-1(-/-) that contains the QTL genomic fragment associated with resistance from DBA/1(-/-) on a BALB/c(-/-) background.

Non-invasive dual fluorescence in vivo imaging for detection of macrophage infiltration and matrix metalloproteinase (MMP) activity in inflammatory arthritic joints.

Detection and intervention at an early stage is a critical factor to impede arthritis progress. Here we present a non-invasive method to detect inflammatory changes in joints of arthritic mice. Inflammation was monitored by dual fluorescence optical imaging for near-infrared fluorescent (750F) matrix-metalloproteinase activatable agent and allophycocyanin-conjugated anti-mouse CD11b.

Peptide ligand structure and I-Aq binding avidity influence T cell signaling pathway utilization.

Factors that drive T cells to signal through differing pathways remain unclear. We have shown that an altered peptide ligand (A9) activates T cells to utilize an alternate signaling pathway which is dependent upon FcRγ and Syk. However, it remains unknown whether the affinity of peptide binding to MHC drives this selection.

Detection of early cartilage damage using targeted nanosomes in a post-traumatic osteoarthritis mouse model.

Unlabelled: Osteoarthritis (OA) is a major cause of pain and disability in the US. A problem with early intervention is that it is very difficult to detect OA before irreversible damage has already occurred. This study characterizes a novel method of early OA detection in a mouse model of post-traumatic osteoarthritis (PTOA) using fluorescent nanosomes.

Genomic locus on chromosome 1 regulates susceptibility to spontaneous arthritis in mice deficiency of IL-1RA.

Background: To understand the role of genetic factors on chromosome 1 in the regulation of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA), we previously used speed congenic breeding to transfer the QTL region from DBA/1(-/-) mice that are resistant to spontaneous arthritis into BALB/c(-/-) mice which are susceptible. We were able to establish two congenic strains which exhibited a delayed onset and reduced severity of disease. In this study, we asked a different set of questions.

Effect of fluorosis on liver cells of VC deficient and wild type mice.

For decades, mouse and other rodents have been used for the study of oxidative or related studies such as the effect of fluoride. It is known that rodents normally synthesize their own vitamin C (VC) due to the presence of a key enzyme in ascorbic acid synthesis, l-gulono-lactone-γ-oxidase (Gulo), while humans do not have the capacity of VC synthesis due to the deletion of most parts of the GULO gene. The spontaneous fracture (sfx) mouse recently emerged as a model for study of VC deficiency.

Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis.

Introduction: T cells orchestrate joint inflammation in rheumatoid arthritis (RA), yet they are difficult to study due to the small numbers of antigen-specific cells. The goal of this study was to characterize a new humanized model of autoimmune arthritis and to describe the phenotypic and functional changes that occur in autoimmune T cells following the induction of pathological events.

Methods: We developed a double transgenic mouse containing both the HLA-DR1 transgene and an HLA-DR1-restricted collagen-specific TCR in order to obtain large numbers of antigen-specific T cells that can be used for immunologic studies.

Theranostic immunoliposomes for osteoarthritis.

Unlabelled: Although there have been substantial advancements in the treatment of inflammatory arthritis, treatments for osteoarthritis (OA) have lagged and currently are primarily palliative until joints become totally dysfunctional and prosthetic replacement is needed. One obstacle for developing a preventive therapy for OA is the lack of good tools for efficiently diagnosing the disease and monitoring its progression during the early stages when the effect of therapeutic drugs or biologics is most likely to be effective. We have developed near infrared immunoliposomes conjugated with type II collagen antibody for diagnosis and treatment of early OA.

Congenic mice provide evidence for a genetic locus that modulates spontaneous arthritis caused by deficiency of IL-1RA.

To understand the role of genetic factors involved in the development of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA), we have identified a genomic region containing a major quantitative trait locus (QTL) for this disease. The QTL is on chromosome 1 and appears to be the strongest genetic region regulating arthritis. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c(-/-) which are susceptible.

Dual effects of IL-1 overactivity on the immune system in a mouse model of arthritis due to deficiency of IL-1 receptor antagonist.

Previous studies have revealed the significance of cytokine interleukin 1 (IL-1) in the onset and progression of rheumatoid arthritis (RA). The precise molecular mechanisms related to IL-1 underlying RA is still elusive. We conducted a whole genome-wide transcriptomal comparison of wild-type (WT) and arthritis-prone IL-1 receptor antagonist (IL-1rn) deficient BALB/c mice to address this issue.

Genomic dissection and prioritizing of candidate genes of QTL for regulating spontaneous arthritis on chromosome 1 in mice deficient for interleukin-1 receptor antagonist.

Rheumatoid arthritis is a heterogeneous disease with clinical and biological polymorphisms. IL-1RN is a protein that binds to interleukin-1 (IL-1) receptors and inhibits the binding of IL-1-alpha and IL-1-beta. IL-1RN levels are elevated in the blood of patients with a variety of infectious, immune, and traumatic conditions.

Analysis of candidate genes of spontaneous arthritis in mice deficient for interleukin-1 receptor antagonist.

Previously, we identified a major quantitative trait locus (QTL) on mouse chromosome 1 that regulates the susceptibility to arthritis in an F2 population generated from arthritis-prone BALB/c and arthritis-resistant DBA/1 mice deficient for interleukin-1 receptor antagonist. To further select candidate genes for the QTL, we analyzed the expression patterns of arthritis in 38 F2 individuals and compared the expression levels of key candidate genes to the parental strains. Two distinct subpopulations of arthritic mice were identified in the 38 F2 mice.

Characterization of inhibitory T cells induced by an analog of type II collagen in an HLA-DR1 humanized mouse model of autoimmune arthritis.

Introduction: We used DR1 transgenic mice and covalently linked DR1 multimers to characterize analog-specific inhibitory T cells in collagen-induced arthritis (CIA). Because of the low numbers of antigen-specific T cells in wild-type mice, functional T-cell studies in autoimmune arthritis have been challenging. The use of T-cell receptor (TCR) transgenic mice has provided useful information, but such T cells may not represent the heterogeneous T-cell response that occurs in natural settings.

Molecular basis for T cell response induced by altered peptide ligand of type II collagen.

Mounting evidence from animal models has demonstrated that alterations in peptide-MHC interactions with the T cell receptor (TCR) can lead to dramatically different T cell outcomes. We have developed an altered peptide ligand of type II collagen, referred to as A9, which differentially regulates TCR signaling in murine T cells leading to suppression of arthritis in the experimental model of collagen-induced arthritis. This study delineates the T cell signaling pathway used by T cells stimulated by the A9·I-A(q) complex.

T cells stimulated with an analog peptide of type II collagen require the Fc receptor γ-chain to secrete interleukin-4 and suppress autoimmune arthritis in mice.

Objective: To explore the characteristics of the T cell population that responds to an analog peptide (A9) of type II collagen and regulates autoimmunity, using the collagen-induced arthritis (CIA) model.

Methods: Analog peptide A9 is a 26-amino acid peptide analogous to the sequence of a segment of type II collagen (CII245-270) but with substitutions at amino acid positions 260 (alanine for isoleucine), 261 (hydroxyproline for alanine), and 263 (asparagine for phenylalanine). We previously showed that A9 profoundly suppressed CIA and immune responses to type II collagen.

Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II.

Introduction: Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA).

T cell receptor signaling induced by an analog peptide of type II collagen requires activation of Syk.

We have previously described an analog peptide of type II collagen (CII) that can suppress collagen-induced arthritis (CIA). This analog peptide represents CII(245-270), the immunodominant epitope of CII, but with substitutions at 260, 261, and 263 - CII(245-270) (A(260), B(261), and N(263)) (A9). To elucidate the mechanisms responsible for suppression, we used mice transgenic for a collagen-specific T cell receptor (TCR).

Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse.

This is an in silico analysis of data available from genome-wide scans. Through analysis of QTL, genes and polymorphisms that regulate BMD, we identified 82 BMD QTL, 191 BMD-associated (BMDA) genes, and 83 genes containing known BMD-associated polymorphisms (BMDAP). The catalogue of all BMDA/BMDAP genes and relevant literatures are provided.