Inflammatory Blood Vessel Disease

The aorta and its major branches are life-sustaining organs with a breach in the integrity of their walls causing fatal injuries. The host has developed multiple protective mechanisms to secure the intactness of major arteries; including a protective shield that prevents inflammatory attack. This shield has been named the immunoprivilege of the vessel wall. A breakdown of the arterial immunoprivilege results in vasculitis, an inflammatory condition that induces either destruction of the arterial wall (aneurysm formation) or occlusion of the vascular lumen through a maladaptive repair process.

Our research team of investigators and clinicians has examined pathomechanisms in giant cell arteritis (GCA), a vasculitis of the aorta and its 2nd-5th branches. Clinical manifestations include blindness, stroke, occlusion of upper extremity arteries and aneurismal destruction of the aorta. By applying a multitude of techniques and studying tissues and cells of affected patients, we have discovered several defects that threated the privileged state of the arterial walls, predisposing our patients to GCA.

Transfer of NADPH oxidase-containing membrane particles from CD8 T-reg cells to CD4 effector T cells

GCA patients fail to suppress CD4 T cells in central lymphoid organs.

We have identified a highly specialized population of CD8 T regulatory cells (Treg) that functions to suppress the activation and expansion of CD4 T cells. CD8 Tregs reside in lymph nodes, express on their surface the enzyme NADPH oxidase, and inhibit neighboring CD4 T cells by transferring NADPH oxidase-containing membrane particles. Recipient CD4 T cells are transiently unable to proliferate. Through this mechanism, CD8 Tregs control the overall size of the CD4 T cell compartment, thus regulating the propensity of the host to mount T cell responses.

 

Vascular endothelial cells open the flood gates for infiltrating CD4 T cells

Gene expression profiling of aortic tissue and arterial biopsies harvested from patients with GCA lead us to the discovery of high abundance of Jagged1 and NOTCH1, a receptor-ligand pair directing cell fate decisions. We localized Jagged1 on the surface of microvascular endothelial cells and NOTCH1 on circulating and tissue-infiltrating CD4 T cells. Aberrant expression of Jagged1 on microvessels provided a platform for NOTCH1+ T cells to receive activating signals and invade into an otherwise “forbidden” territory.

Aberrant expression of Jagged1 on CD31+ micro-endothelial cells in the aortic wall.

Pathogenic T cells in GCA lesions are functionally diverse and unleashed

Failure of the immuno-protective PD-1 checkpoint in GCA

The intensity and duration of immune responses is regulated by amplifying feedback loops (co-stimulation) but is equally dependent on negative signals that limit immunity and protect tissue from unwanted damage. In cancer patients, negative signals delivered by immune checkpoints are paralyzed and therapeutic interventions have revolutionized cancer immunotherapy by unleashing anti-tumor T cells.  Gene expression profiling of GCA-affected arteries guided us to the immuno-protective PD-1 checkpoint. Antigen-presenting cells in inflamed arteries failed to upregulate the immuno-suppressive ligand PD-L1, building a permissive tissue niche. In the absence of inhibitory signals, vasculitogenic T cells are functionally diverse, persist chronically and produce a vast variety of pro-inflammatory effector molecules.

Tissue-resident memory T cells provide autonomy to vessel wall inflammatory lesion

Until recently it was unclear to which degree the inflammatory lesions in the arteries dependent on local production versus recruitment of inflammatory cells. In a recent study, we have answered this question. Vascular lesions contain a specialized population of tissue-resident memory T cells, which are anchored in the tissue site. They have high proliferative capacity and are sustained by local survival signals. Tissue-resident memory T cells provide autonomy to the disease lesions and necessitate targeted therapeutic interventions. In a patient personalized model system of humanized mice, tissue resident memory T cells are susceptible to select immunosuppressant therapies.

A patient-personalized model system to study GCA in humanized mice