Pediatric Translational Research Branch

Proposed model linking HLA-B27 misfolding and the unfolded protein response (UPR) to IL-23 production and Th17 activation.

Robert A. Colbert, M.D., Ph.D.
Chief, Pediatric Translational Research Branch
Phone: (301) 443-8935
Fax: (301) 480-5189
E-mail: colbertr@mail.nih.gov

Research Interests

The long-term goals of the Colbert laboratory are to understand cellular and molecular mechanisms underlying the pathogenesis of spondyloarthritis.  Spondyloarthritis refers to a spectrum of chronic immune-mediated inflammatory diseases that affect an estimated 1% of the population.  They differ from other types of inflammatory arthritis in genetic predisposition, pathogenesis, and long-term outcome.  Spondyloarthritis often begins as an undifferentiated disease that, in many cases, progresses to ankylosing spondylitis (AS).  AS can lead to ankylosis of the spine and significant disability.  Although most people affected by AS are adults, approximately 15-20% are first affected as children.  This juvenile onset AS (JAS) differs from adult onset disease because spinal (axial) symptoms are usually missing, while peripheral arthritis and enthesitis are more prominent.  Most spondyloarthritis in children is classified as a form of juvenile idiopathic arthritis known as enthesitis-related arthritis (ERA) or psoriatic arthritis (PsA).  However, children with ERA or PsA and spinal involvement are not distinguished from those with only peripheral arthritis and enthesitis. Since individuals with axial involvement are most likely to progress to AS, recognizing early spinal involvement in children is paramount.

The development of AS is primarily determined by one’s genetic make-up.  HLA-B (predominantly the B27 allele) plays a major role, accounting for an estimated 30-40% of overall susceptibility, with additional genes, such as ERAP1, IL23R, IL1RII, IL1 (probably IL1A), CARD9, TNFR1, TRADD, STAT3, PTGER2, ANTXR2 and others also contributing.  Our knowledge of how these genes and their variants work together to promote the inflammation and bone formation that occurs in AS is incomplete, although new targets have been identified. As therapeutic options improve, identification of children with spondyloarthritis who have axial involvement will be increasingly important, as they may benefit the most from early aggressive intervention.

Current projects include:

  1. Evaluating the role of HLA-B27 and other genetic factors in disease
    1. Studies employ a transgenic animal model of spondyloarthritis and cells from human subjects including induced pluripotent stem cells (iPSC), to evaluate effects of HLA-B27 expression and misfolding on ER stress and its consequences for cytokine production and cellular function
    2. Effects on osteoclast and osteoblast development and function
  2. Elucidating genes that influence how HLA-B27 causes spondyloarthritis in rats
  3. Determining how ERAP1 affects spondyloarthritis pathogenesis
  4. Understanding how HLA-B27 shapes the immunology and microbiology of the gut
  5. Determining clinical manifestations and biomarkers of early axial spondyloarthritis in children.

These studies will inform us on mechanisms that drive pathogenesis of spondyloarthritis and suggest novel strategies that can be developed to more effectively treat disease.


Selected Publications

Layh-Schmitt G, Yang EY, Kwon G, Colbert RA. HLA-B27 Alters the Response to Tumor Necrosis Factor α and Promotes Osteoclastogenesis in Bone Marrow Monocytes From HLA-B27-Transgenic Rats. Arthritis Rheum. 2013 Aug;65(8):2123-31. doi: 10.1002/art.38001. PubMed Icon

Colbert RA, Tran TM, Layh-Schmitt G. HLA-B27 misfolding and ankylosing spondylitis. Mol Immunol. 2013 Aug 29. pii: S0161-5890(13)00479-3. doi: 10.1016/j.molimm.2013.07.013. [Epub ahead of print] PubMed Icon

Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun HW, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A. 2011 Apr 8 PubMed Icon

Barnes MG, Grom AA, Thompson SD, Griffin TA, Luyrink LK, Colbert RA, Glass DN. Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis. Arthritis Rheum. 2010 Nov;62(11):3249-58. PubMed Icon

Colbert RA. Early axial spondyloarthritis. Curr Opin Rheumatol. 2010 Sep;22(5):603-7. PubMed Icon

Colbert RA. Classification of juvenile spondyloarthritis: Enthesitis-related arthritis and beyond.Nat Rev Rheum. 2010 Aug;6(8):477-85. PubMed Icon

Hinze CH, Fall N, Thornton S, Mo JQ, Aronow BJ, Layh-Schmitt G, Griffin TA, Thompson SD, Colbert RA, Glass DN, Barnes MG, Grom AA. Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis. Arthritis Res Ther. 2010;12(3):R123. PubMed Icon

Colbert RA. Challenges in the classification of pediatric spondyloarthritis. The Rheumatologist. 2010; (in press).

Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev. 2010; 233:1-22. PubMed Icon

Barnes MG, Grom AA, Thompson SD, Griffin TA, Pavlidis P, Itert L, Fall N, Sowders DP, Hinze C, Aronow BJ, Luyrink LK, Srivastava S, Ilowite N, Gottlieb BS, Olson JC, Sherry D, Glass DN, Colbert RA. Subtype-specific peripheral blood gene expression profiles in recent onset juvenile idiopathic arthritis. Arthritis Rheum. 2009; 60: 2102-2112. PubMed Icon

See extended list of publications

 

Reviewed September 24, 2012