Presenting:

"A Lupus-Associated Variant in MAC-1 Causes Major Impairment on Its “Catch-Bond” Behavior and Deficiency of Adhesion Under Force"

Yunfeng Chen
Cheng Zhu, PhD - Advisor

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects a large population of people. Although substantial studies have been trying to figure out its cause and cure, the pathological mechanism behind it is still unknown and its therapy is nowadays majorly by injection of immunosuppressive drugs. A mutation in the integrin aMb2 (MAC-1), R77H has a strong correlation with SLE, yet its influence to the functionality of the protein is currently under debate. MAC-1 has the ability to dynamically modulate its binding adhesiveness; more importantly, it is featured by the role of negatively regulating TLR, IFNAR and BCR signaling and promoting DC tolerance through proper binding. Here, by applying BFP experiments, we show for the first time that, R77H causes an impairment in the “Catch-Bond” behavior of MAC-1 during its binding to the ligand ICAM-1. This impairment to some extend explains its deficiency in adhesion under external force, which was discovered by our collaborators in Harvard Medical School. Whether and how this binding deficiency would compromise its regulatory signaling and whether this is part of the mechanism of SLE await further investigations.

"Vascular Status Regulates Size-Dependent Molecular Dissemination from Peripheral Tissues"

Nathan Rohner
Susan Thomas, PhD - Advisor

Tissue immune status is established by the concerted influence of tissue-derived antigenic proteins, cytokines and other cell-produced biomolecules that control the infiltrating immune cell milieu. The capacity of these regionally produced biomolecules to influence the signaling processes of immune cells in distant regional (lymph node) versus systemic (spleen) lymphoid tissues has however remained largely overlooked. Since normal blood capillaries are permeable only to low molecular weight (MW) solutes (<5 nm in diameter), lymphatic drainage supports the clearance of solutes of intermediate MW (>40kDa or >5nm diameter but <100 nm) from the intercapillary tissue space, and cell-mediated trafficking clears large particulates (>100 nm), the size characteristics of locally produced biomolecules may directly regulate their capacity to influence cell signaling processes in diverse local versus systemic tissues. Moreover, tissue vascular status may crucially influence the capacity for biomolecules to disseminate systemically and mediate their signaling function. In order to better understand the tissue vasculature's effect on molecular dissemination patterns, the contribution of the developing tumor vasculature on molecular clearance and dissemination patterns was investigated by comparing the transport patterns of fluorescently labeled molecules from healthy versus malignant tissues that display well-documented changes in their complex neo-vascular plexus with tumor progression. We found that progression of B16F10 melanoma in C57Bl6 animals for seven days or more resulted in dramatically reduced (>75%) lymphatic transport relative to that from normal (naïve) skin tissue, which resulted in reduced sentinel (tumor-draining) lymph node molecular accumulation. Advanced tumors also demonstrated disrupted permeability profiles that resulted in altered systemic accumulation of injected molecular beacons relative to healthy tissues. In summary, this work suggests that altered vascular profiles within malignant skin results in molecular clearance and dissemination patterns that are absent from healthy animals and contributes new insight into the role of tissue vascularization and permeability in potentially shaping tissue immune status as well as in establishing the pre-metastatic niche during tumor progression.