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.
The goals of the unit are to:
- 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.
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.
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Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still's Disease, and Related Conditions
ClinicalTrials.gov Identifier: NCT03510442
The purpose of this protocol is to study the natural history, genetics and pathophysiology of systemic juvenile idiopathic arthritis (sJIA), adult-onset Still s disease (AOSD) and related inflammatory conditions. One of seven subtypes of juvenile idiopathic arthritis (JIA), sJIA contributes disproportionately to the morbidity and mortality of JIA and is considered by many to be the most severe JIA subtype. sJIA typically presents with fever of unknown origin and arthritis, together with evanescent skin rash, serositis, hepatosplenomegaly and lymphadenopathy. It is strongly associated with macrophage activation syndrome (MAS), which has a high fatality rate when untreated. AOSD is phenotypically similar to sJIA in presentation, progression and association with MAS, however it develops after the 16th birthday. The causes sJIA and AOSD are poorly understood.