T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6 + and ALCAM + cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.
Pseudomonas aeruginosa keratitis occurs following trauma, in immunocompromised patients, and in otherwise healthy contact lens wearers. Characterized by a light-blocking infiltrate, P. aeruginosa keratitis is the most serious complication associated with contact lens wear and, in severe cases, can lead to vision loss.
The cornea is the clear dome that covers the front portion of the globe. The primary functions of the cornea are to promote the refraction of light and to protect the eye from invading pathogens, both of which are essential for the preservation of vision. Homeostasis of each cellular layer of the cornea requires the orchestration of multiple processes, including the ability to respond to stress. One mechanism whereby cells respond to stress is autophagy, or the process of “self-eating.” Autophagy functions to clear damaged proteins and organelles. During nutrient deprivation, amino acids released from protein breakdown via autophagy are used as a fuel source. Mitophagy, a selective form of autophagy, functions to clear damaged mitochondria. Thus, autophagy and mitophagy are important intracellular degradative processes that sustain tissue homeostasis. Importantly, the inhibition or excessive activation of these processes result in deleterious effects on the cell. In the eye, impairment or inhibition of these mechanisms have been associated with corneal disease, degenerations, and dystrophies. This review summarizes the current body of knowledge on autophagy and mitophagy at all layers in the cornea in both non-infectious and infectious corneal disease, dystrophies, and degenerations. It further highlights the critical gaps in our understanding of mitochondrial dysfunction, with implications for novel therapeutics in clinical practice.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that can affect multiple organ systems, including the kidneys, skin, and brain. T cells are an important mediator in this end organ damage. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, which binds with activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and various epithelial and endothelial tissues. This signaling pathway is vital for T cell activation, proliferation, differentiation and trafficking. We found increased expression of both CD6 and ALCAM in the kidneys of MRL/lpr mice (a spontaneous model of SLE) versus healthy control B6 mice. In a separate experiment, female MRL/lpr mice were aged to 9–10 weeks of age, at which point we began treating with either anti-CD6 antibody (60 ug/dose, intraperitoneally twice per week), isotype control (60 ug/dose, twice per week), or cyclophosphamide (25 mg/kg, once per week). We also included a no treatment group and a group of MRL/MpJ mice, a congenic healthy control strain. Mice treated with anti-CD6 show lower levels of proteinuria and BUN (p<0.05), improved survival rates, and decreased renal pathology compared to isotype control mice. Flow cytometry revealed decreased numbers of activated and effector T cells within the kidneys of anti-CD6 treated mice compared to isotype control mice. While there was no difference in anti-DNA levels, anti-CD6 treatment significant improved the spontaneous skin lesions associated with disease progression. Overall, these results indicate that targeting CD6-ALCAM interactions may have promising therapeutic potential within the context of different end organ pathologies within lupus.
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