Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on HLA-B27 and Its Role as an Epistatic Modifier in Experimental Spondyloarthritis.

Objective: We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA).

Methods: ERAP1-knockout rats were created using genome editing and bred with HLA-B27/human β -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses.

mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation and .

Spondyloarthritis (SpA) is characterized by inflammation, articular bone erosions and pathologic new bone formation. Targeting TNFα or IL-17A with current available therapies reduces inflammation in SpA, however, treatment of the bone pathology in SpA remains an unmet clinical need. Activation of the mammalian target Of rapamycin (mTOR) promotes IL-17A expression and osteogenesis.

Three tesla and 3D multiparametric combined imaging evaluation of axial spondyloarthritis and pelvic enthesopathy.

Purpose: Axial spondyloarthritis (SpA) is a group of diseases with temporally disseminated symptoms and clinical signs, which render the diagnosis challenging. Laboratory and MRI findings are used in addition for confirming the diagnosis and evaluation of disease activity. The purpose of this study was to evaluate clinically suspected axial SpA to determine the technical success of a multiparametric and 3D rheumatology lumbosacral MR imaging (MRLI) protocol and to assess the disease distribution, inter-reader reliability, and impact on patient management.

Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis.

Objective: It remains unclear if and how inflammation and new bone formation in spondyloarthritis (SpA) are coupled. We undertook this study to assess the hypothesis that interleukin-17A (IL-17A) is a pivotal driver of both processes.

Methods: The effect of tumor necrosis factor (TNF) and IL-17A on osteogenesis was tested in an osteoblastic differentiation assay using SpA fibroblast-like synoviocytes (FLS) differentiated with dexamethasone, β-glycophosphatase, and ascorbic acid.

The Initiation, but Not the Persistence, of Experimental Spondyloarthritis Is Dependent on Interleukin-23 Signaling.

IL-17A is a central driver of spondyloarthritis (SpA), its production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence suggests, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess the extent to which IL-17A-driven pathology is IL-23 dependent in experimental SpA.

The Peptide Repertoire of HLA-B27 may include Ligands with Lysine at P2 Anchor Position.

The HLA-B*27 peptidome has drawn significant attention due to the genetic association between some of the HLA-B*27 alleles and the inflammatory rheumatic disease ankylosing spondylitis (AS), for which a comprehensive biological explanation is still lacking. This study aims to expand the known limits of the HLA-B*27 peptidome to facilitate selection and testing of new peptides, possibly involved in the disease. The HLA peptidomes of HeLa and C1R cell lines stably transfected with the AS-associated HLA-B*27:05 allele, the nonassociated HLA-B*27:09 allele, or their cysteine 67 to serine mutants (C67S), are analyzed on a very large scale.

Innate Immune Activation Can Trigger Experimental Spondyloarthritis in HLA-B27/Huβ2m Transgenic Rats.

Spondyloarthritis (SpA) does not display the typical features of auto-immune disease. Despite the strong association with MHC class I, CD8 T cells are not required for disease induction in the HLA-B27/Huβ2m transgenic rats. We used Lewis HLA-B27/Huβ2m transgenic rats [21-3 × 283-2]F1, HLA-B7/Huβ2m transgenic rats [120-4 × 283-2]F1, and wild-type rats to test our hypothesis that SpA may be primarily driven by the innate immune response.

The Human Leukocyte Antigen (HLA)-B27 Peptidome , in Spondyloarthritis-susceptible HLA-B27 Transgenic Rats and the Effect of Erap1 Deletion.

HLA-B27 is a class I major histocompatibility (MHC-I) allele that confers susceptibility to the rheumatic disease ankylosing spondylitis (AS) by an unknown mechanism. ERAP1 is an aminopeptidase that trims peptides in the endoplasmic reticulum for binding to MHC-I molecules. ERAP1 shows genetic epistasis with HLA-B27 in conferring susceptibility to AS.

HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats.

The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated.

Role of protein phosphatase magnesium-dependent 1A and anti-protein phosphatase magnesium-dependent 1A autoantibodies in ankylosing spondylitis.

Objective: Although ankylosing spondylitis (AS) is driven by immune-mediated processes, little is known about the presence and role of autoantibodies in this disease. This study was undertaken to investigate whether autoantibodies occur in and are involved in AS.

Methods: We performed human protein microarray analysis of sera derived from patients with AS or other autoimmune disorders to identify autoantibodies associated specifically with AS, and identified autoantibody targeting of protein phosphatase magnesium-dependent 1A (PPM1A) in AS.

Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis.

Objective: In HLA-B27-transgenic rats, the development of a disorder that mimics spondyloarthritis (SpA) is highly correlated with dendritic cell (DC) dysfunction. The present study was undertaken to analyze the underlying mechanisms of this via transcriptome analysis.

Methods: Transcriptome analysis of ex vivo-purified splenic CD103+CD4+ DCs from B27-transgenic rats and control rats was performed.

CD8⁺ T cell help is required for efficient induction of EAE in Lewis rats.

The role of CD8⁺ T cells in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is still unclear. We describe here significantly reduced disease activity of EAE both in Lewis rats depleted of CD8⁺ T cells by monoclonal antibodies and CD8 knockout rats, which was accompanied by reduced leukocyte infiltration into the spinal cord. We detected myelin basic protein (MBP)-specific CD8⁺ T cells in peripheral lymphoid organs of CD8-depleted animals which, however, failed to differentiate into interferon-γ-producing effector cells.

Relationship between inflammation, bone destruction, and osteoproliferation in the HLA-B27/human β2 -microglobulin-transgenic rat model of spondylarthritis.

Objective: Inhibition of inflammation and destruction, but not of osteoproliferation, in patients with spondylarthritis (SpA) treated with anti-tumor necrosis factor raises the question of how these three processes are interrelated. This study was undertaken to analyze this relationship in a rat model of SpA.

Methods: Histologic spine and joint samples from HLA-B27/human β(2) -microglobulin (hβ(2) m)-transgenic rats were analyzed for signs of spondylitis and destructive arthritis and semiquantitatively scored as showing mild, moderate, or severe inflammation.

Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats.

Objective: Male rats transgenic for HLA-B27 and human β(2) -microglobulin (hβ(2) m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hβ(2) m-transgenic rat cross-strain (21-3 × 382-2)F(1) , only the males develop SpA, and neither sex develops gut inflammation. This study was undertaken to determine whether EO and SpA in male (21-3 × 382-2)F(1) rats are causally related.

The role of HLA-B27 in spondyloarthritis.

This article summarizes the proceedings of a one-day international workshop held in July 2009 on the role of HLA-B27 in the pathogenesis of ankylosing spondylitis (AS) and related disorders. HLA-B27 is found in about 90% of patients with AS, with an odds ratio of about 100, but the mechanism underlying this association is not known. There are currently 3 major mechanistic hypotheses for this association: (1) T cell recognition of one or more B27 presented peptides; (2) B27 heavy-chain misfolding that induces an unfolded protein response; and (3) innate immune recognition of cell-surface expressed B27 heavy-chain dimers.

Animal models of spondyloarthritis.

Animal models are available for the study of several different aspects of spondyloarthritis. The models include naturally occurring spontaneous disorders in primates and rodents, spontaneous disorders in transgenic or gene-deleted rodents and induced disorders in rodents. Areas of investigation to which these models contribute include the role HLA-B27, processes of spinal and peripheral joint inflammation and calcification, immune responses to candidate antigens and the role of TNF.

Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8.

Objective: HLA-B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8+ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human beta(2)-microglobulin (Hubeta(2)m)-transgenic rats.

Correlation between dendritic cell functional defect and spondylarthritis phenotypes in HLA-B27/HUMAN beta2-microglobulin-transgenic rat lines.

Objective: To examine the functional capacity of dendritic cells (DCs) from a panel of HLA-B27/human beta2-microglobulin (Hubeta2m)-transgenic rat lines and crosses with varying susceptibilities to spondylarthritis (SpA)-like disease.

Methods: Mature splenic DCs were isolated from HLA-B27-transgenic, HLA-B7-transgenic, and/or Hubeta2m-transgenic rats and tested for support of allogeneic proliferation, compared with nontransgenic controls (all male rats on Lewis background). Graded numbers of DCs were cultured with allogeneic lymph node CD4+ T cells (dark agouti background).