Anthony Shum, MD
Background: Our research lies at the intersection of autoimmunity and pulmonary disease and is focused on the study of clinical disorders such as rheumatoid arthritis that affect the lung. Our goal is to understand the basic mechanisms that control how the lung functions both as an important immune target in autoimmune disorders and as a critical factor in precipitating or propagating autoimmune inflammation.
We enroll patients into our research program to perform next generation sequencing studies that are designed to uncover novel insights into the molecular pathogenesis of disease. We developed a whole exome sequencing (WES) analysis pipeline to identify rare genetic variants that cosegregate with disease in Mendelian disorders of autoimmunity. Much of our work involves the study of immune mechanisms in animal models or cellular and molecular investigations that are designed to functionally validate candidate mutations discovered in our sequencing pipeline.
On Going Research
Role of intracellular trafficking in the generation of autoimmunity: ER stress is increasingly recognized as an important mechanism in the pathogenesis of both autoimmunity and interstitial lung disease. We are studying a unique set of families with a rare Mendelian form of autoimmunity characterized by interstitial lung disease and arthritis. In collaboration with investigators at Baylor College of Medicine, we performed whole-exome sequencing and targeted sequencing to identify four unique deleterious variants in the COPA gene (encoding coatomer subunit a) affecting the same functional protein domain. We have shown that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport and demonstrated that expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Our findings have uncovered an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity (now known as the “COPA syndrome”) manifested by lung and joint disease. Using patient cell lines and multiple tools developed in the lab, a major focus of our group seeks to understand the molecular mechanisms by which defective Golgi-ER transport leads to autoimmunity.
Loss of tolerance to lung self-antigens in the generation of autoimmune-associated ILD: We recently discovered novel mouse and human lung antigens (BPIFB1) targeted in autoimmune-mediated ILD through work in the Aire translational model of human autoimmune polyglandular syndrome Type 1 (APS1). Lung autoimmunity in our model is linked to a well-defined breakdown in immune tolerance, as defects in Aire lead to known defects in central tolerance, and more importantly, shows relevance to more common forms of autoimmune-associated ILD. Strikingly, a subset of non-APS1 patients with autoimmune ILD harbor autoantibodies to BPIFB1, the major human antigen we identified in our model. These results strongly suggest that the Aire model is an ideal system for understanding the role of lung-specific autoimmunity in the pathogenesis of ILD. Using Aire-deficient mice, we are investigating the role of Th17 cells in autoimmune lung fibrosis and defining the role of BPIFB1 as a major autoantigen in lung autoimmunity. Other ongoing projects include the development of clinical tools for improved diagnosis and disease monitoring of autoimmune-associated ILD in patients.
The lung as a site of initiation for rheumatoid arthritis: Rheumatoid arthritis (RA) is the most common inflammatory arthritis affecting nearly 0.5-1% of individuals worldwide. RA is a complex disease with multiple environmental and genetic risk factors. A gene-environment interaction between cigarette smoking and the HLA shared epitope (SE) alleles has been well-described. Case-control studies demonstrate that patients who have 2 HLA SE genes, smoke cigarettes and harbor anti-citrullinated protein antibodies (ACPA) have a 20 fold increase for the development of RA compared to nonsmokers carrying no SE alleles. This suggests that bronchiolar inflammation from smoking may lead to citrullination of proteins in the lung that precipitates RA in genetically susceptible patients. Using whole exome sequencing in a family with a rare form of autosomal dominant RA and ILD, we have identified molecular targets that may link defects in the lung with the development of RA. Using a combination of mouse models, patient cell lines and other molecular tools, we are investigating the role of the lung epithelium in the initiation of inflammatory responses and the onset of systemic RA disease.