The Genomic Sequence and Comparative Analysis of the Rat Major Histocompatibility Complex

Hurt, Peter; Walter, Lutz; Sudbrak, Ralf; Klages, Sven; Müller, Ines; Shiina, Takashi; Inoko, Hidetoshi; Lehrach, Hans; Günther, Eberhard; Reinhardt, Richard; Himmelbauer, Heinz

doi:10.1101/gr.1987704

Cited by 114 publications

(115 citation statements)

References 41 publications

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“…Furthermore, our combination of rat strains allowed us to study the effect of differences between the donor and host solely within the MHC region, undisturbed by genetic polymorphisms outside the MHC. 29 In our model, fresh bone allografts with a complete MHC mismatch (PVG.RT1.U vs. PVG), showed complete failure of healing and also evoked an antibody response against MHC class I. From this set of data, we infer that host immune responses against MHC antigens are of major importance in determining the fate of a fresh MHC mismatched bone graft.…”

Section: Discussionmentioning

confidence: 79%

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

Reikerås

Shegarfi

Naper³

et al. 2008

Journal Orthopaedic Research

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Cortical bone graft failure develops for poorly defined reasons, and the effects of the immune responses on the incorporation of an allograft are less clear. In a rat model of tibial allotransplantation, we have studied biometric and histological changes of the graft and the humoral immune response against it. We have also compared fresh with prefrozen grafts to study putative effects of freezing on the healing of the graft and the immune response against it. Fresh and frozen cortical bone grafts matched or mismatched for major histocompatibility complex antigens (syngeneic and allogeneic grafts) were implanted in an 8-mm segmental defect in the tibia. The construct was stabilized with intramedullary nailing. Incorporation of the graft was assessed with use of conventional radiography, micro computed tomography (CT), biomechanical testing and histological examination. The immune response was evaluated by monitoring distribution of leukocytes in the blood and by measuring antibodies in a tailor-made fluorescence activating cell scanning (FACS) analysis. We found that the fresh syngeneic grafts were well integrated after 8 weeks with intact bone cells. In the fresh allogeneic grafts, all cells were dead with radiological signs of resorption, and mechanical testing indicated failure of incorporation. The frozen grafts showed poorer overall reconstruction than the fresh syngeneic grafts, but the incorporation was better than the fresh allogeneic grafts. A measurable alloantibody response was only detected after fresh allografting. The combined results suggest that freezing of bone allograft impedes the antibody response against major histocompatibility complex (MHC) antigens and improves incorporation, but frozen allografts still perform poorer than do frozen syngeneic grafts. ß

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Section: Discussionmentioning

confidence: 79%

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

Reikerås

Shegarfi

Naper³

et al. 2008

Journal Orthopaedic Research

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“…Surface expression of Hu␤ 2 m was nearly as abundant in the 283-2 line as in the rats carrying HLA-B27. The rat MHC carries a very large number of class I genes (41), and members of several subclasses of rat MHC class I heavy chains have been shown to be expressed and to bind Hu␤ 2 m efficiently (Lambracht-Washington D: personal communication). Given the complexity of potential interactions, considerable further experimentation may be needed to relate in detail the disease-inducing capacity of the 283-2 locus to its biochemical effects.…”

Section: Discussionmentioning

confidence: 99%

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

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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“…It is analogous to the human leukocyte antigen (HLA) with a general overall similarity in construction of the class II and class III regions, but with varying numbers of MHC class I antigens. 5 Like in humans, the gene region encodes MHC class I and II molecules that provoke strong alloimmune responses to organ transplantation, leading to their rejection. PVG rats promptly reject organ grafts from PVG.1U rats on the basis of differences in the MHC region, and we and others have shown strong immunological reactions after MHC mismatched transplantation of fresh bone.…”

Section: Discussionmentioning

confidence: 99%

Impact of freezing on immunology and incorporation of bone allograft

Reikerås

Sigurdsen

Shegarfi

2010

Journal Orthopaedic Research

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ABSTRACT:With an increasing clinical use of deep frozen allograft for bone reconstruction, it is important to understand the immunological and biological events of allograft incorporation. In this study, we have investigated the impact of deep freezing on immunology and biopotency for incorporation of bone allografts. Deep frozen bone grafts matched or mismatched for major histoscompatibilty complex (MHC) were implanted in an 8-mm segmental defect in the tibia in rats. The construct was stabilized with intramedullary nailing. The immune response was evaluated by determination of serum antibody against the grafts MHC molecules at day 1 and after 2 and 4 months. Incorporation of the graft was compared with fresh syngeneic grafts and assessed with the use of conventional radiography, biomechanical testing and measurement of bone mineral content and density after 4 months. The analyses revealed no antibody responses in the rats that received grafts from donors differing at histocompatibility loci, and at 4 months the frozen grafts showed an overall reconstruction that was not significantly different from the fresh grafts. This study indicates that in the long run there are no significant consequences; either immunological or biomechanical, of the use of deep frozen allogenous bone as compared to fresh autogenous bone grafts in this animal model. ß

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The Genomic Sequence and Comparative Analysis of the Rat Major Histocompatibility Complex

Cited by 114 publications

References 41 publications

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

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

Impact of freezing on immunology and incorporation of bone allograft

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The Genomic Sequence and Comparative Analysis of the Rat Major Histocompatibility Complex

Cited by 114 publications

References 41 publications

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

Impact of MHC mismatch and freezing on bone graft incorporation: An experimental study in rats

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

Impact of freezing on immunology and incorporation of bone allograft

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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