Overview

Principal Investigator

Robert A. Colbert, M.D., Ph.D.

Robert Colbert, M.D., Ph.D., leads a team of scientists in the Pediatric Translational Research Branch studying the etiology and pathogenesis of early onset arthritis, including axial disease in juvenile spondyloarthritis.

The long-term goals of the Pediatric Translational Research 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:

  • Evaluating the role of HLA-B27 and other genetic factors in disease.
    • 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.
    • Effects on osteoclast and osteoblast development and function.
  • Elucidating genes that influence how HLA-B27 causes spondyloarthritis in rats.
  • Determining how ERAP1 affects spondyloarthritis pathogenesis.
  • Understanding how HLA-B27 shapes the immunology and microbiology of the gut.
  • 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.

Staff

Clinical Director, Clinical Research @ NIAMS
301-443-8935
Assistant Clinical Investigator, Pediatric Translational Research Branch
301-443-7961
Postbaccalaureate Fellow, Pediatric Translational Research Branch
301-435-0060
301-827-2892
Postdoctoral Fellow (IRTA), Pediatric Translational Research Branch
301-451-1187
Assistant Clinical Investigator, Pediatric Translational Research Branch
Head, Juvenile Myositis Therapeutic and Translational Studies Unit
301-594-6196
301-451-6019
301-402-3838
301-451-1207
301-402-1376

Image & Media Gallery

Scientific Publications

Janus kinase (JAK) inhibition with baricitinib in refractory juvenile dermatomyositis.

Kim H, Dill S, O'Brien M, Vian L, Li X, Manukyan M, Jain M, Adeojo LW, George J, Perez M, Grom AA, Sutter M, Feldman BM, Yao L, Millwood M, Brundidge A, Pichard DC, Cowen EW, Shi Y, Lu S, Tsai WL, Gadina M, Rider LG, Colbert RA
Annals of the rheumatic diseases.
2020 Aug 25;
pii: annrheumdis-2020-218690. doi: 10.1136/annrheumdis-2020-218690
PMID: 32843325

HLA-B27 misfolding and ankylosing spondylitis.

Colbert RA, Tran TM, Layh-Schmitt G
Molecular immunology.
2014 Jan;
57(1).
doi: 10.1016/j.molimm.2013.07.013
PMID: 23993278

HLA-B27 alters the response to tumor necrosis factor α and promotes osteoclastogenesis in bone marrow monocytes from HLA-B27-transgenic rats.

Layh-Schmitt G, Yang EY, Kwon G, Colbert RA
Arthritis and rheumatism.
2013 Aug;
65(8).
doi: 10.1002/art.38001
PMID: 23666508

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade.

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
Proceedings of the National Academy of Sciences of the United States of America.
2011 Apr 26;
108(17).
doi: 10.1073/pnas.1103681108
PMID: 21478439

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Last Updated: September 2020