Inflammatory Disease in HLA-B27 Transgenic Rats

Taurog, Joel D.; Hammer, Robert E.

doi:10.1007/978-1-4612-2376-4_5

Cited by 69 publications

(135 citation statements)

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“…However, rat SpA is not a consequence of class I overexpression per se, since HLA-B7-Tg rats expressing comparable amounts of heavy chain remain healthy [24]. There is evidence that the UPR is activated in cells from the synovial fluid of patients with SpA [58].…”

Section: Discussionmentioning

confidence: 99%

“…HLA-B27 is an MHC-encoded class I protein that is linked to the development of spondyloarthritis (SpA) including ankylosing spondylitis [22,23], and when expressed in rats along with human b 2 m (HLA-B27-Tg) results in the development of an inflammatory disease that recapitulates many features of human SpA [24]. A proportion of HLA-B27 misfolds in the ER, resulting in increased degradation by ERAD [25], and formation of disulfide-linked and BiP-bound complexes [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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“…The HLA-B/Hu␤ 2 m-transgenic rat lines used in this study are summarized in Table 1. All of the lines have been previously described (9,10,18), except the 283-2 line, the production of which is described herein. All lines, including 283-2, have been backcrossed to the LEW background for at least 25 generations.…”

Section: Methodsmentioning

confidence: 99%

“…Histologic examination of the colon ( Figure 3L) and stomach ( Figure 3M) from 8 of the (21-3 ϫ 283-2)F 1 rats showed no abnormalities. Ifn␥ mRNA, which is markedly elevated in the intestine of disease-prone B27/Hu␤ 2 m-transgenic lines with high copy numbers (10,12), was assessed by quantitative PCR. Expression of cecal Ifn␥ mRNA normalized to 18S rRNA was a mean Ϯ SEM 188 Ϯ 115 in LEW.33-3 rats (ages 5-7 months; n ϭ 4), compared with 0.5 Ϯ 0.2 in (21-3 ϫ 283-2)F 1 rats (age 8 months; n ϭ 5) and 0.5 Ϯ 0.1 in nontransgenic LEW rats (age 4 months; n ϭ 5).…”

Section: Production Of An Hu␤ 2 M-transgenic Linementioning

confidence: 99%

“…Although some evidence exists for disease-related, B27-specific T cell adaptive immunity (14)(15)(16)(17), other mechanisms have been proposed in recent years, on the basis of the unusual features of B27-specific biologic processes. Part of the impetus for these hypotheses has come from the observation that inflammatory disease in the B27-transgenic rats occurs in only the lines with a relatively high transgene copy number and increased expression level of B27 (10,18). Cell-surface-expressed MHC class I molecules are thought normally to be formed of folded noncovalent complexes consisting of the heavy chain, ␤ 2 m, and peptide that are assembled in the endoplasmic reticulum through association with a series of chaperones (19).…”

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confidence: 99%

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Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Tran¹,

Dorris²,

Satumtira³

et al. 2006

Arthritis & Rheumatism

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158

150

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Objective. Ankylosing spondylitis and related spondylarthritides are associated with HLA-B27, and also with intestinal inflammation, by unknown mechanisms. The folded HLA-B27 molecule is a trimer of heavy chain, ␤ 2 -microglobulin (␤ 2 m), and short peptide. However, B27 heavy chain has an unusual propensity to misfold and trigger the unfolded protein response (UPR). This study was initiated to test the hypothesis that B27 misfolding plays a role in the pathogenesis of spondylarthritis.Methods. Rats with high transgene copy numbers of HLA-B27 heavy chain together with human ␤ 2 m (Hu␤ 2 m) spontaneously develop colitis, peripheral arthritis, and occasional spondylitis, and those with lower transgene copy numbers remain healthy. We crossed disease-prone and healthy HLA-B27/Hu␤ 2 mtransgenic rat lines with a healthy line, 283-2, carrying only the Hu␤ 2 m transgene. HLA-B27 assembly was assessed by pulse-chase analysis of B27 molecules, and UPR triggering was assessed by measuring BiP/Grp78 messenger RNA (mRNA) in splenic concanavalin A blasts. Surface expression of B27 and Hu␤ 2 m was determined by flow cytometry. Disease manifestations were identified by clinical observation, histology, and measurement of cytokine mRNA.Results. The extra Hu␤ 2 m from the 283-2 line significantly reduced B27 misfolding and UPR triggering. Unexpectedly, however, F 1 male offspring of the healthy 21-3 line crossed with the 283-2 line showed a high prevalence, severity, and duration of arthritis and spondylitis, in the absence of colitis. The arthropathy showed many features characteristic of human spondylarthritis.Conclusion. These results suggest that B27 misfolding is associated with intestinal inflammation, but that neither B27 misfolding nor intestinal inflammation is critical to the development of B27-associated arthropathy.The spondylarthritides are a group of inflammatory rheumatic diseases characterized by axial and peripheral arthropathy and a variety of extraarticular lesions (1). In the prototype of these disorders, ankylosing spondylitis (AS), there is inflammation in the spinal and sacroiliac joints and in ligamentous attachments that, in severe cases, leads to bony fusion. The pathogenesis of spondylarthritis is poorly understood. Two factors strongly associated with these conditions are intestinal inflammation and the major histocompatibility complex (MHC) class I gene HLA-B27.With regard to the association with intestinal inflammation, the prevalence of inflammatory bowel disease (IBD) (both Crohn's disease and ulcerative colitis) is increased in individuals with AS. An even higher prevalence of IBD is found in individuals with other forms of spondylarthritis (2), and endoscopic studies with biopsy have shown a prevalence of microscopic inflammatory bowel lesions in 60-70% of patients

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CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice

et al. 2002

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Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal immune response with elevated levels of the Th1 cytokines TNF, IL‐12 and IFN‐γ. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic intestinal inflammation by as yet unknown mechanisms. Bacterial DNA contains unmethylated cytosine‐guanosine dinucleotides (CpG) which strongly activate Th1‐mediated immune responses. To test whether these CpG‐motifs contribute to intestinal inflammation we treated mice with dextran‐sulfate‐sodium (DSS)‐induced acute or chronic colitis for 5 days with CpG‐containing oligodeoxynucleotides (CpG‐ODN). Colonic inflammation was assessed by histological scoring. Colonic cytokine RNA was quantified by reverse transcription‐PCR and cytokine secretion from mesenterial lymph node cells by ELISA. In chronic colitis, CpG‐ODN treatment severely aggravated inflammation by 50%. Colonic expression of IFN‐γ and TNF was elevated (200‐ and 150‐fold, respectively) and IFN‐γ and IL‐12 secretion from lymph node cells was increased 5,000‐ and 8‐fold, respectively, compared to GpG‐ODN‐treated controls. Similar effects were obtained in acute colitis. In conclusion, CpG‐motifs of bacterial DNA have proinflammatory activity by strengthening the Th1 arm of immunity in DSS‐induced colitis, and might therefore play asignificant role in the initiation and perpetuation of inflammation in IBD.

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Inflammatory Disease in HLA-B27 Transgenic Rats

Cited by 69 publications

References 45 publications

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice

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Inflammatory Disease in HLA-B27 Transgenic Rats

Cited by 69 publications

References 45 publications

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice

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Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats