Weyand Lab  

Current Research Projects

Telomeric Damage in Rheumatoid Arthritis
In the autoimmune syndrome rheumatoid arthritis, telomeres of T cells shorten prematurely, even in naïve T cells that are not involved in previous or ongoing immune responses. Insufficient induction of telomerase contributes to premature telomeric erosion, but telomere-dependent DNA damage responses suggest additional mechanisms inducing structural abnormalities. We are investigating (1) how T cells recognize telomeric damage; (2) which genotoxic events lead to telomeric injury; and (3) how DNA damage responses emanating from uncapped telomeres impact T cell function and the role of T cells in autoimmune responses.

Metabolic Rewiring of T cells in Rheumatoid Arthritis
Upon stimulation, T cells greatly enhance their metabolic activities and upregulate aerobic glycolysis. They shift from a primarily respiratory energetic pathway to a less conservative glycolytic metabolism with lactate production to enable synthesis of the macromolecules required for growth and functional activity. T cells from patients with rheumatoid arthritis are insufficient in glucose utilization, lactate production and ATP generation. The molecular underpinning of this energy deficiency lies in a lack of phosphofructokinase-2 (PFKFB3), a regulatory enzyme that determines glycolytic flux and energy generation. We are investigating (1) mechanisms that lead to PFKFB3 deficiency; (2) the impact of energy deficiency on functional competence of T cells in normal and pathogenic immunity; and (3) the molecular pathways connecting abnormal energetics with the accelerated immune aging phenotype in rheumatoid arthritis T cells.

ATM Deficiency in Rheumatoid Arthritis T cells
In the autoimmune syndrome rheumatoid arthritis, T cells have a higher load of DNA double-strand breaks due to insufficient DNA damage sensing and repair. Molecular defects include reduced activity of Ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase activated by DNA double-strand breaks. ATMlow T cells produce lower amounts of ATM target genes, including p53 and Chk2, have altered cell cycle kinetics and are apoptosis sensitive. Currently, we are investigating how ATM deficiency affects T cell homeostasis, longevity, and differentiation into disease-relevant effector cells.

Abnormal Macrophage Differentiation in Vascular Inflammation
Rupture of the atherosclerotic plaque, giving rise to thrombotic occlusion of the vascular lumen, is the underlying process in acute myocardial infarction, stroke and sudden cardiac death. Pathogenic mechanisms leading to plaque rupture involve chronic tissue-injurious inflammation, regulated by innate and adaptive immune responses. The plaque is a tissue lesion rich in macrophages, which are dependent on their functional polarization, can either enhance inflammation or support reparative mechanism and resolution. We are studying (1) tissue trafficking of diverse macrophage subsets in patients with advanced coronary artery disease; (2) proinflammatory macrophage effector functions in the human atheroma; and (3) molecular mechanisms of abnormal ROS production in proinflammatory macrophages.

Signalling Pathways in Large Vessel Vasculitis
Large vessel vasculitis is a potentially fatal inflammatory disease of the aorta and its major branches. Over the last decade, we have characterized the cellular and molecular processes sustaining granulomatous inflammation within the vessel wall layers. We have identified vessel wall embedded dendritic cells as primary drivers of the disease process and have implicated several independent T cell lineages in promoting maladaptive immunity. Through genomic analysis of inflamed human arteries, we have identified key signalling pathways involved in vascular inflammation and we are currently defining (1) pathway-specific target gene induction in vascular and immune cells and (2) therapeutic effects of signalling inhibitors in human artery-SCID mouse chimeras.

Immuno-stromal Interactions in Large Vessel Vasculitis
Large vessel vasculitides (LVV) are characterized by a stringent tissue tropism, affecting anatomically defined vascular beds while sparing others. Gene expression profiling of arteries affected by LVV has identified receptor-ligand families facilitating communication between tissue infiltrating immune cells and resident vascular cells. Through NOTCH-NOTCH ligand interactions vascular wall cells serve as signal-sending and signal-receiving cells and shape the pathogenic immune responses. We are investigating (1) how immuno-stromal communication determines the tissue tropism of vasculitis; (2) which disease-relevant effector functions are regulated by signals originating from vascular cells; and (3) whether disruption of immune-stromal communication has therapeutic potential in LVV.


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