The Double-Edged Sword of ROS in Muscle Wasting and COPD: Insights from Aging-Related Sarcopenia.

An elevation in reactive oxygen species (ROS) is widely accepted to be a key mechanism that drives chronic obstructive pulmonary disease (COPD) and its major co-morbidity, skeletal muscle wasting. However, it will be perhaps a surprise to many that an elevation in ROS in skeletal muscle is also a critical process for normal skeletal muscle function and in the adaptations to physical exercise. The key message here is that ROS are not solely detrimental. This duality of ROS suggests that the mere use of a broad-acting antioxidant is destined to fail in alleviating skeletal muscle wasting in COPD because it will also be influencing critical physiological ROS-dependent processes. Here, we take a close look at this duality of ROS in skeletal muscle physiology and pathophysiology pertaining to COPD and will aim to gain critical insights from other skeletal muscle wasting conditions due to aging such as sarcopenia.

Cutaneous lymphocyte antigen and α4ß7 T-lymphocyte responses are associated with peanut allergy and tolerance in children.

BACKGROUND: It is unclear whether the initial route of allergen exposure in early life could influence the subsequent development of allergy, with cutaneous sensitization leading to peanut allergy (PA), and tolerance induced by oral exposure. The skin- and gastrointestinal (GI)-homing markers, cutaneous lymphocyte antigen (CLA) and α4ß7 integrin, are used to determine whether the state of PA correlates with peanut-specific CLA responses, with tolerance associated with predominant α4ß7 responses. METHODS: CLA+ and α4ß7+ memory T cells were isolated and cultured with peanut extract to assess their proliferation. Stimulation indices were compared in peanut allergic and non-allergic (NA) groups, and peanut-specific cytokine production was measured. RESULTS: In peanut allergic patients, peanut-specific proliferation predominates in the skin-homing CLA+ subset, whilst peanut-tolerant groups have a mixed CLA/α4ß7 response (P = 0.008). Comparison with a control food antigen (ovalbumin) showed that these differences are allergen specific. Cytokine responses showed trends towards Th1 skewing in the GI-homing α4ß7+ cells of peanut-tolerant groups and Th2 skewing in the skin-homing CLA+ cells of peanut allergic patients. CONCLUSION: The predominance of the CLA+ response to peanut in peanut allergic patients is consistent with the hypothesis that allergic sensitization occurs through the skin. The predominant α4ß7+ response in peanut-tolerant groups suggests that allergen exposure through the GI tract induces tolerance.

IgE-mediated facilitated antigen presentation underlies higher immune responses in peanut allergy.

BACKGROUND: Peanut allergy poses significant healthcare problems, because its prevalence is increasing in many countries, and it is rarely outgrown. To explore the immunological mechanisms that underlie peanut allergy and tolerance, we compared the peanut-specific responses of peanut-allergic (PA) and nonallergic (NA) individuals. METHODS: We measured peanut-specific peripheral blood mononuclear cells (PBMC) proliferation using tritiated thymidine. The frequency of peanut-specific T cells amongst PBMC was determined by carboxyfluorescein succinimidyl ester labelling. The role of IgE-dependent facilitated antigen presentation (FAP) in modulating proliferation was investigated by depleting IgE from plasma with anti-IgE-coated beads and then assessing PBMC proliferation in the presence of IgE-depleted or nondepleted plasma. RESULTS: We found that peanut-specific PBMC proliferation is higher and peaks earlier in PA than in NA donors. We investigated the immunological mechanisms that could underlie these differences. We found that both PA and NA have memory responses to peanut, but the frequency of peanut-specific T cells is higher in PA than in NA. Facilitated antigen presentation could cause both the higher proliferation and precursor frequency in PA. Facilitated antigen presentation activity in vitro was confirmed by showing that IgE depletion decreases proliferation, while adding IgE back restores it. CONCLUSION: Our results identify FAP as a mechanism that underlies higher responses to peanut in PA. In these individuals, high levels of peanut-specific IgE could furthermore maintain long-term allergic T-cell responses. We raise the question whether, in the future, therapies targeting IgE such as anti-IgE antibodies may be used to suppress these T-cell responses.

Nephro-urological complications of epidermolysis bullosa in paediatric patients.

A small but important proportion of patients with epidermolysis bullosa (EB) may develop significant renal and urological complications which can have a major impact on their morbidity and mortality. During the last 10 years, five of a large group of children with EB under our care, with either dystrophic or junctional types of disease, experienced major nephro-urological complications. Two patients with recessive dystrophic EB (REDB) developed macroscopic haematuria - one had renal failure and underwent a renal biopsy showing IgA nephropathy. A third patient with RDEB also developed renal failure and his biopsy demonstrated postinfectious glomerulonephritis/type III membranoproliferative (mesangiocapillary) glomerulonephritis. Both patients with renal failure underwent peritoneal dialysis. Two patients with junctional EB developed obstructive uropathies, which required bladder reconstruction and the fashioning of a Mitrofanoff channel in one.