Overview
Spondyloarthritides are spontaneous auto-inflammatory diseases that cause significant morbidity in approximately 0.5-0.9% of individuals, thus rivaling rheumatoid arthritis and systemic lupus erythematosus in terms of prevalence. These disorders involve inflammation in joints throughout the body including the spine and limbs, as well as the lower intestine, eyes and skin. HLA-B27 is a major predisposing factor in human disease, and despite considerable knowledge about the physiological function of HLA-B27, the role of this molecule in the pathogenesis of spondyloarthritis remains unresolved.
When HLA-B27 is expressed in rats, a spontaneous inflammatory disease resembling human spondyloarthritis develops. Thus, the animals serve as a model where we can study how the disease develops. The normal function of HLA-B27 is to display peptides on the surface of the cell, where circulating T-cells can recognize them. However, HLA-B27 also has unique characteristics compared to other HLA class I alleles that may be responsible for its role in this disease, namely its tendency to misfold shortly after its synthesis (Figure 1).
Protein misfolding has been linked to a number of genetic diseases. Our studies test the hypothesis that HLA-B27 misfolding is linked to the pathogenesis of spondyloarthritis via a novel mechanism involving activation of the "unfolded protein response" (UPR). Proteins that misfold and bind an ER chaperone, known as BiP, cause activation of ER signaling pathways that are responsible for initiating the UPR (Figure 2). Preliminary studies indicate that the UPR is activated in cells from HLA-B27 transgenic rats, which has significant immunological implications. These ideas are being investigated using cells from patients with spondyloarthritis as well.
Our ability to effectively treat patients with spondyloarthritis and prevent the development of severe progressive disease is limited. It is our hope that by better understanding pathogenesis, we will be able to devise better therapeutic strategies aimed at the underlying disease mechanism.
Publications
Where applicable, article titles are linked to an abstract of the article. Selected citations may also be linked to PDFs or other full-text versions of the article available on a Journal's site. Depending on the Journal's publishing policy, you may need a subscription to view the full-text version.
Caudill, C.M.; Jayarapu, K.; Elenich, L.; Monaco, J.J.; Colbert, R.A.; Griffin, T.A.: T cells lacking immunoproteasomes subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens. J. Immunol, 2006; 176:4075-4082.
Smith, J.A.; Marker-Hermann, E.; Colbert, R.A.: Pathogenesis of ankylosing spondylitis: current concepts. Best Prac Res Clin Rheumatol, 2006; 20: 571-591.
Turner, M.J.; Sowders, D.P.; DeLay, M.L.; Mohapatra, R.; Bai, S.; Smith, J.A.; Brandewie, J.R.; Taurog, J.D.; Colbert, R.A.: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J. Immunol, 2005; 175:2438-2448.
Duffy, C.M.; Colbert, R.A.; Laxer, R.M.; Schanberg, L.E.; Bowyer, S.L.: Nomenclature and classification in chronic childhood arthritis: Time for a change? Arthritis Rheum, 2005; 52:382-385.
Bukulmez H, Fife M, Tsoras M, Thompson SD, Twine NA, Woo P, Olson JM, Elston RC, Glass DN, Colbert RA. Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: A family based control study. 2004; 7: R285-R290.
Colbert, R.A.: The immunobiology of HLA-B27: Variations on a theme. Curr. Mol. Med., 2004; 4:21-30.
Barnes M, Aronow BJ, Luyrink LK, Moroldo MB, Pavlidis P, Passo MP, Grom AA, Hirsch R, Giannini EH, Colbert RA, Glass DN, Thompson SD. Gene expression in juvenile arthritis and spondyloarthropathy: pro-angiogenic ELR+ chemokine genes relate to course of arthritis. Rheumatology (Oxford) 2004; 43:973-979. [Full Text]
Penttinen MA, Heiskanen KM, Mohapatra R, DeLay ML, Colbert RA, Sistonen L, Granfors K. Enhanced intracellular replication of Salmonella enteritidis in HLA-B27-expressing human monocytic cells is dependent on glutamic acid at the position 45 in the B pocket of HLA-B27. Arth. Rheum. 2004; 50:2255-2263. [Full Text]
De M, Jayarapu K, Elenich L, Monaco JJ, Colbert RA, Griffin TA. b2 subunit propeptides influence cooperative proteasome assembly. J. Biol. Chem. 2003; 278:6153-6159. [Full Text]
Contact Us
The Colbert Laboratory is part of the William S. Rowe Division of Rheumatology at Cincinnati Children's Research Foundation and the University of Cincinnati School of Medicine. Our lab is located in Location R (Research Foundation Building), Room 2447.
Our laboratory participates in pre- and post-doctoral training through the
Molecular and Developmental Biology Graduate Program, the
Immunobiology Graduate Training, and
The Physican Scientist Training Program. The Colbert Laboratory has a range of
postdoctoral research opportunities in basic, translational, and clinical research.
Inquiries from interested trainees are always welcome.
Please contact Bob Colbert at:
Cincinnati Children's Hospital Medical Center
William S. Rowe Division of Rheumatology
3333 Burnet Avenue, MLC 4010
Cincinnati, OH 45229-3039
Phone: 513-636-4934
Fax: 513-636-3328
E-mail: bob.colbert@cchmc.org
Spondyloarthritides are spontaneous auto-inflammatory diseases that cause significant morbidity in approximately 0.5-0.9% of individuals, thus rivaling rheumatoid arthritis and systemic lupus erythematosus in terms of prevalence. These disorders involve inflammation in joints throughout the body including the spine and limbs, as well as the lower intestine, eyes and skin. HLA-B27 is a major predisposing factor in human disease, and despite considerable knowledge about the physiological function of HLA-B27, the role of this molecule in the pathogenesis of spondyloarthritis remains unresolved.
When HLA-B27 is expressed in rats, a spontaneous inflammatory disease resembling human spondyloarthritis develops. Thus, the animals serve as a model where we can study how the disease develops. The normal function of HLA-B27 is to display peptides on the surface of the cell, where circulating T-cells can recognize them. However, HLA-B27 also has unique characteristics compared to other HLA class I alleles that may be responsible for its role in this disease, namely its tendency to misfold shortly after its synthesis (Figure 1).
Protein misfolding has been linked to a number of genetic diseases. Our studies test the hypothesis that HLA-B27 misfolding is linked to the pathogenesis of spondyloarthritis via a novel mechanism involving activation of the 'unfolded protein response' (UPR). Proteins that misfold and bind an ER chaperone, known as BiP, cause activation of ER signaling pathways that are responsible for initiating the UPR (Figure 2). Preliminary studies indicate that the UPR is activated in cells from HLA-B27 transgenic rats, which has significant immunological implications. These ideas are being investigated using cells from patients with spondyloarthritis as well.
Our ability to effectively treat patients with spondyloarthritis and prevent the development of severe progressive disease is limited. It is our hope that by better understanding pathogenesis, we will be able to devise better therapeutic strategies aimed at the underlying disease mechanism.
Publications
Where applicable, article titles are linked to an abstract of the article. Selected citations may also be linked to PDFs or other full-text versions of the article available on a Journal's site. Depending on the Journal's publishing policy, you may need a subscription to view the full-text version.
Caudill, C.M.; Jayarapu, K.; Elenich, L.; Monaco, J.J.; Colbert, R.A.; Griffin, T.A.: T cells lacking immunoproteasomes subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens. J. Immunol, 2006; 176:4075-4082.
Smith, J.A.; Marker-Hermann, E.; Colbert, R.A.: Pathogenesis of ankylosing spondylitis: current concepts. Best Prac Res Clin Rheumatol, 2006; 20: 571-591.
Turner, M.J.; Sowders, D.P.; DeLay, M.L.; Mohapatra, R.; Bai, S.; Smith, J.A.; Brandewie, J.R.; Taurog, J.D.; Colbert, R.A.: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J. Immunol, 2005; 175:2438-2448.
Duffy, C.M.; Colbert, R.A.; Laxer, R.M.; Schanberg, L.E.; Bowyer, S.L.: Nomenclature and classification in chronic childhood arthritis: Time for a change? Arthritis Rheum, 2005; 52:382-385.
Bukulmez H, Fife M, Tsoras M, Thompson SD, Twine NA, Woo P, Olson JM, Elston RC, Glass DN, Colbert RA. Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: A family based control study. 2004; 7: R285-R290.
Colbert, R.A.: The immunobiology of HLA-B27: Variations on a theme. Curr. Mol. Med., 2004; 4:21-30.
Barnes M, Aronow BJ, Luyrink LK, Moroldo MB, Pavlidis P, Passo MP, Grom AA, Hirsch R, Giannini EH, Colbert RA, Glass DN, Thompson SD. Gene expression in juvenile arthritis and spondyloarthropathy: pro-angiogenic ELR+ chemokine genes relate to course of arthritis. Rheumatology (Oxford) 2004; 43:973-979. [Full Text]
Penttinen MA, Heiskanen KM, Mohapatra R, DeLay ML, Colbert RA, Sistonen L, Granfors K. Enhanced intracellular replication of Salmonella enteritidis in HLA-B27-expressing human monocytic cells is dependent on glutamic acid at the position 45 in the B pocket of HLA-B27. Arth. Rheum. 2004; 50:2255-2263. [Full Text]
De M, Jayarapu K, Elenich L, Monaco JJ, Colbert RA, Griffin TA. b2 subunit propeptides influence cooperative proteasome assembly. J. Biol. Chem. 2003; 278:6153-6159. [Full Text]
Contact Us
The Colbert Laboratory is part of the William S. Rowe Division of Rheumatology at Cincinnati Children's Research Foundation and the University of Cincinnati School of Medicine. Our lab is located in Location R (Research Foundation Building), Room 2447.
Our laboratory participates in pre- and post-doctoral training through the
Molecular and Developmental Biology Graduate Program, the
Immunobiology Graduate Training, and
The Physican Scientist Training Program. The Colbert Laboratory has a range of
postdoctoral research opportunities in basic, translational, and clinical research.
Inquiries from interested trainees are always welcome.
Please contact Bob Colbert at:
Cincinnati Children's Hospital Medical Center
William S. Rowe Division of Rheumatology
3333 Burnet Avenue, MLC 4010
Cincinnati, OH 45229-3039
Phone: 513-636-4934
Fax: 513-636-3328
E-mail: bob.colbert@cchmc.org
