Comparative analysis of LAG3 antibodies shows differential binding patterns by flow cytometry.

Background: LAG3 is an immune checkpoint molecule with emerging therapeutic use. Expression of LAG3 is well studied on T cells, but the proportion of LAG3-expressing cells varies greatly by study and its comparative expression between non-T cells is lacking.

Methods/objectives: This study uses flow cytometry to compare surface LAG3 expression between T cells, NK cells, B cells, pDCs and monocytes of healthy donors.

The effect of blocking immune checkpoints LAG-3 and PD-1 on human invariant Natural Killer T cell function.

Invariant Natural Killer T (iNKT) cells undergo immune exhaustion during chronic activation caused by cancer and viral infections, such as HIV. Exhaustion is marked by cell dysfunction and increased expression of immune checkpoint proteins programmed cell-death-1 (PD-1) and lymphocyte-activation-gene-3 (LAG-3). We hypothesize that blockade of PD-1 and/or LAG-3 will enhance iNKT cell function.

Novel in vitro invariant natural killer T cell functional assays.

Background: Invariant Natural Killer T (iNKT) cells are innate lymphocytes bridging the innate and adaptive immune systems and are critical first responders against cancer and infectious diseases. iNKT cell phenotype and functionality are studied using in vitro stimulation assays assessing cytokine response and proliferation capabilities. The most common stimulant is the glycolipid α-Galactosyl Ceramide (α-GalCer), which stimulates iNKT cells when presented by CD1d, an MHC class I-like molecule expressed by antigen-presenting cells (APC).

LAG3's Enigmatic Mechanism of Action.

LAG3 is an important immune checkpoint with relevance in cancer, infectious disease and autoimmunity. However, despite LAG3's role in immune exhaustion and the great potential of LAG3 inhibition as treatment, much remains unknown about its biology, particularly its mechanism of action. This review describes the knowns, unknowns and controversies surrounding LAG3.

Roles, function and relevance of LAG3 in HIV infection.

HIV causes several forms of immune dysfunction that need to be addressed in a functional cure for HIV. Immune exhaustion describes a dysfunctional phenotype caused by chronic cellular activation. Lymphocyte activation gene-3 (LAG3) is one of several negative coreceptors known as immune checkpoints that contribute to this exhaustion phenotype.

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension.

Background: Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure.

Vascular remodeling process in pulmonary arterial hypertension, with focus on miR-204 and miR-126 (2013 Grover Conference series).

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized primarily by increased proliferation and resistance to apoptosis in distal pulmonary arteries. Previous literature has demonstrated that the transcription factors NFAT (nuclear factor of activated T cells) and HIF-1α (hypoxia inducible factor 1α) are extensively involved in the pathogenesis of this disease and, more recently, has implicated STAT3 (signal transducer and activator of transcription 3) in their activation. Novel research shows that miR-204, a microRNA recently found to be notably downregulated through induction of PARP-1 (poly [ADP-ribose] polymerase 1) by excessive DNA damage in PAH, inhibits activation of STAT3.

Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by significant exercise intolerance, which is multifactorial and involves skeletal muscle alterations. There is growing evidence that microRNAs (miRs) are involved in PAH pathogenesis.

Objectives: We hypothesized that miR-126, an endothelial-specific, proangiogenic miR, is down-regulated in the peripheral muscles of patients with PAH, which would account for skeletal muscle microcirculation loss and exercise intolerance.

miRNAs in PAH: biomarker, therapeutic target or both?

Pulmonary arterial hypertension (PAH) is characterized by progressive increase in pulmonary vascular resistance leading to right ventricular hypertrophy and failure. There is a need to find new biomarkers to detect PAH at its early stages and also for new, more effective treatments for this disease. miRNAs have emerged as key players in cardiovascular diseases and cancer development and progression and, more recently, in PAH pathogenesis.

Role for DNA damage signaling in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) is associated with sustained inflammation known to promote DNA damage. Despite these unfavorable environmental conditions, PAH pulmonary arterial smooth muscle cells (PASMCs) exhibit, in contrast to healthy PASMCs, a pro-proliferative and anti-apoptotic phenotype, sustained in time by the activation of miR-204, nuclear factor of activated T cells, and hypoxia-inducible factor 1-α. We hypothesized that PAH-PASMCs have increased the activation of poly(ADP-ribose) polymerase-1 (PARP-1), a critical enzyme implicated in DNA repair, allowing proliferation despite the presence of DNA-damaging insults, eventually leading to PAH.

Granzyme B deficiency exacerbates lung inflammation in mice after acute lung injury.

Granzyme B (GzmB) is a serine protease with intracellular and extracellular activities capable of regulating inflammation through cytokine processing and the apoptosis of effector cells. We tested the hypothesis that GzmB expression in T regulatory cells (Tregs) is required for the control of inflammatory responses and pathology during acute lung injury. To substantiate the clinical relevance of GzmB during lung injury, we performed GzmB immunohistochemistry on lung tissue from patients with acute respiratory distress syndrome (ARDS) and healthy control subjects.