Translational Genetics and Genomics Unit

Michael Ombrello, M.D.
Head, Translational Genetics and Genomics Unit
Phone: 301-435-4037

Michael Ombrello, M.D., leads the TGGU. Dr. Ombrello is board-certified in both rheumatology and pediatric rheumatology. He is actively involved in a range of organizations, through both membership and leadership roles, including the American College of Rheumatology, the Childhood Arthritis Rheumatology Research Alliance, and the International Childhood Arthritis Genetics Consortium. He has received numerous local and national awards and honors, including NIAMS and NIAID Merit Awards, the American College of Rheumatology's Distinguished Fellow Award, the NIH Fellows' Award for Research Excellence, and the NIH Director's Award.


Research Interests


  • Use genetics, genomics and bioinformatics approaches to identify the genetic basis of complex autoinflammatory and autoimmune diseases
  • Determine mechanisms through which disease-associated variants participate in pathophysiology of autoinflammatory phenotypes
  • Search for novel genetic causes of autoinflammation and autoimmunity

Program Description

The Translational Genetics and Genomics Unit (TGGU) is a research group focused on understanding the mechanisms that underlie inflammatory and autoimmune disease. The unit applies integrated genomic approaches to investigate autoinflammatory and rheumatic diseases, seeking to understand the mechanisms through which disease-associated genetic variants participate in disease pathophysiology. The unit's goal is to advance our knowledge of rheumatic disease pathophysiology and inflammatory biology.

This figure demonstrates a protein bound to a peptide antigen.

Behçet's disease risk residues cluster around MHC class I peptide binding groove. In this model of the HLA-B*51:01:01 protein bound to a peptide antigen (green), risk residues at positions 67, 97, 116, and 152 are displayed in red. These residues collectively define the molecule's peptide binding specificity and tune its interaction with the killer immunoglobulin-like receptor (KIR) family of cytotoxicity receptors. [Ombrello MJ et al. (2014) Proc Natl Acad Sci USA.]

A major focus of the TGGU is on investigating and understanding genetically-complex diseases, such as Still's disease/systemic juvenile arthritis and Behçet's disease. Working with large international collaborations, we are engaged in integrated genomic investigations of well-phenotyped patient collections. We are also seeking to better understand the mechanisms of seemingly unprovoked inflammation through the study of individuals and families with monogenic inflammatory diseases, such as PLCG2 associated antibody deficiency and immune dysregulation (PLAID), together with phenotypically-similar but genetically-complex disorders, such as common variable immune deficiency. Through the biologic knowledge that such studies produce, we hope to identify novel therapeutic targets to ultimately improve the lives of individuals affected by chronic inflammatory and rheumatic diseases.

Another interest of the group is to determine the role of major histocompatibility complex (MHC) proteins in complex autoinflammatory diseases. Because of their role in presenting peptide antigens to T cells, MHC molecules are traditionally considered to be part of the adaptive immune system, a notion supported by their association with numerous autoimmune diseases. In contrast, autoinflammatory diseases are those in which inflammation develops in the absence of overt evidence of autoimmunity. While there is little evidence that autoimmunity is involved in the inflammatory phenotypes of either Behçet's disease or Still's disease, classical MHC alleles have been identified as risk factors in both cases. This has led the unit to consider mechanisms through which these molecules may influence inflammation without triggering autoimmunity.

Selected Publications

Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF. Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2014 May 12. [Epub ahead of print] PubMed Icon

Ombrello MJ, Sikora KA, Kastner DL. Genetics, genomics, and their relevance to pathology and therapy. Best Pract Res Clin Rheumatol. 2014 Apr;28(2):175-89. doi: 10.1016/j.berh.2014.05.001. PubMed Icon

Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, Gutierrez-Cruz G, Kim Y, Wilson AF, Kastner DL, Gül A, Remmers EF. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8134-9. doi: 10.1073/pnas.1306352110. Epub 2013 Apr 30. PubMed Icon

Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Sacli FS, Erer B, Inoko H, Emrence Z, Cakar A, Abaci N, Ustek D, Satorius C, Ueda A, Takeno M, Kim Y, Wood GM, Ombrello MJ, Meguro A, Gül A, Remmers EF, Kastner DL. (2013) Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45: 202-207. Epub 2013 Jan 6. PubMed Icon

Ombrello MJ, Kastner DL, Milner JD. HOIL and water: the two faces of HOIL-1 deficiency. Nat Immunol. 2012 Dec;13(12):1133-5. doi: 10.1038/ni.2471. PubMed Icon

Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Long Priel DA, Ombrello A, Stone D, Ombrello MJ, Khan J, Milner JD, Kastner DL, Aksentijevich I. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012 Oct 5;91(4):713-20. PubMed Icon

Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, Subramanian N, Bunney TD, Baxendale RW, Martins MS, Romberg N, Komarow H, Aksentijevich I, Kim HS, Ho J, Cruse G, Jung MY, Gilfillan AM, Metcalfe DD, Nelson C, O'Brien M, Wisch L, Stone K, Douek DC, Gandhi C, Wanderer AA, Lee H, Nelson SF, Shianna KV, Cirulli ET, Goldstein DB, Long EO, Moir S, Meffre E, Holland SM, Kastner DL, Katan M, Hoffman HM, Milner JD. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med. 2012 Jan 26;366(4):330-8. PubMed Icon

Ombrello MJ, Kastner DL. Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons. Nat Rev Rheumatol. 2011 Feb;7(2):82-4 PubMed Icon

Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakiris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WE, Cho YH, Bang D, O'Shea J, Wallace GR, Gadina M, Kastner DL, Gül A. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nat Genet. 2010 Aug;42(8):698-702. PubMed Icon

Low JM, Chauhan AK, Gibson DS, Zhu M, Chen S, Rooney ME, Ombrello MJ, Moore TL. Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins. Proteomics Clin Appl. 2009 Jul;3(7):829-40. PubMed Icon


Updated September 29, 2014