Defective costimulatory function is a striking feature of antigen‐presenting cells in an HLA–B27–transgenic rat model of spondylarthropathy

Hacquard-Bouder, Cécile; Falgarone, Géraldine; Bosquet, A.; Smaoui, Faïza; Monnet, Dominique; Ittah, Marc; Bréban, Maxime

doi:10.1002/art.20211

Cited by 63 publications

(85 citation statements)

References 35 publications

(59 reference statements)

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“…A number of explanations can be considered, including transfer of greater numbers of T cells (Table 1) as well as previously activated T cells from TG compared to non-TG donors that are capable of responding rapidly to stimulatory signals. Nonetheless, the disease we have documented in rnu/rnu TG recipients of rnu/ + non-TG MLN cells closely resembles the disease that develops in the HLA-B27 transgenic rat model of colitis.Several published reports show reduced capacity of accessory cells, such as dendritic cells, from HLA-B27 TG rats to activate allogenic cells in vitro [40,41]. The results of our study, while not directly addressing costimulatory activity, indicate that cells of rnu/rnu TG recipients are potent stimulators of transferred syngeneic donor MLN cells in vivo.…”

Section: Discussioncontrasting

confidence: 68%

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Hoentjen

Tonkonogy

Liu

et al. 2006

Clinical and Experimental Immunology

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SummaryHLA-B27 transgenic (TG) rats develop spontaneous colitis when colonized with intestinal bacteria, whereas athymic nude (rnu/rnu) HLA-B27 TG rats remain disease free. The present study was designed to determine whether or not HLA-B27 expression on T cells is required for development of colitis after transfer of mesenteric lymph node (MLN) cells into rnu/rnu HLA-B27 recipients. Athymic nontransgenic (non-TG) and HLA-B27 TG recipients received MLN cells from either TG or non-TG rnu /+ + + + heterozygous donor rats that contain T cells. HLA-B27 TG rnu/rnu recipients receiving either non-TG or TG MLN cells developed severe colitis and had higher caecal MPO and IL-1β β β β levels, and their MLN cells produced more IFN-γ γ γ γ and less IL-10 after in vitro stimulation with caecal bacterial lysate compared to rnu/rnu non-TG recipients that remained disease free after receiving either TG or non-TG cells. Interestingly, proliferating donor TG T cells were detectable one week after adoptive transfer into rnu/rnu TG recipients but not after transfer into non-TG recipients. T cells from either non-TG or TG donors induce colitis in rnu/ rnu TG but not in non-TG rats, suggesting that activation of effector T cells by other cell types that express HLA-B27 is pivotal for the pathogenesis of colitis in this model.

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Section: Discussioncontrasting

confidence: 68%

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Hoentjen

Tonkonogy

Liu

et al. 2006

Clinical and Experimental Immunology

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“…Defective dendritic cell function has been observed consistently in the disease-prone lines of the transgenic rats (29)(30)(31)(32). Moreover, B27-restricted T cells have been difficult to identify even in the healthy transgenic rat lines (ref.…”

Section: Discussionmentioning

confidence: 99%

Spondylarthritis in HLA–B27/human β₂‐microglobulin–transgenic rats is not prevented by lack of CD8

Taurog¹,

Dorris²,

Satumtira³

et al. 2009

Arthritis & Rheumatism

126

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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 ␤ 2 -microglobulin (Hu␤ 2 m)-transgenic rats.Methods. A missense mutation in the CD8a gene that causes a loss of CD8␣ expression was identified in offspring of a male Sprague-Dawley rat that had been treated with the mutagen N-ethyl-N-nitrosourea. The mutation was crossed into B27/Hu␤ 2 m-transgenic lines on the Lewis background. CD8a -/-and CD8a ؉/-progeny were compared on a mixed SD-LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens.Results. Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/ Hu␤ 2 m-transgenic lines also occurred in the respective CD8a -/--transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a -/-rats and CD8a ؉/-rats. Conclusion. All of the previously described disease manifestations in HLA-B27/Hu␤ 2 m-transgenic rats arise in the absence of any functional CD8؉ T cells. It thus seems unlikely that classic T cell recognition of HLA-B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8-dependent mechanism cannot be entirely excluded.

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“…Our studies have to date focused on macrophages. However, other populations such as dendritic cells that have been shown to be dysfunctional in HLA-B27 transgenic rats (70,71) could also be affected. We do not know as yet the extent to which HLA-B27 misfolding may activate the UPR in individuals with disease, but it is worth noting that BiP overexpression has been reported in adherent synovial fluid mononuclear cells from HLA-B27-positive spondyloarthritis patients (72).…”

Section: Implications For Hla-b27-associated Diseasementioning

confidence: 99%

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

Turner

Sowders

DeLay

et al. 2005

The Journal of Immunology

221

198

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The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human β2-microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-γ increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.

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Defective costimulatory function is a striking feature of antigen‐presenting cells in an HLA–B27–transgenic rat model of spondylarthropathy

Cited by 63 publications

References 35 publications

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Spondylarthritis in HLA–B27/human β₂‐microglobulin–transgenic rats is not prevented by lack of CD8

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

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Defective costimulatory function is a striking feature of antigen‐presenting cells in an HLA–B27–transgenic rat model of spondylarthropathy

Cited by 63 publications

References 35 publications

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

Spondylarthritis in HLA–B27/human β2‐microglobulin–transgenic rats is not prevented by lack of CD8

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

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Spondylarthritis in HLA–B27/human β₂‐microglobulin–transgenic rats is not prevented by lack of CD8