Neuroimmunomodulation during exercise: role of catecholamines as 'stress mediator' and/or 'danger signal' for the innate immune response

Exercise-induced neuroimmunomodulation is clearly accepted today. The present article reviews the main literature concerning the immunomodulatory capacity of catecholamines on the innate immune response during physical exercise, and presents our laboratory's latest results on this topic. It is well known that the effects of exercise on the immune system are mediated by the 'stress hormones and mediators'. Although catecholamines have usually been regarded as immunosuppressors, they may stimulate innate immune response mechanisms (such as phagocytic function) during exercise-induced stress, even without previous antigenic stimulation. The exercise-induced stimulation of the phagocytic response in particular and the innate responses in general have been considered as a prevention strategy of the athlete's organism in order to prevent the entry and/or maintenance of antigens in a situation where the adaptive immune response seems to be depressed, and thus it has been suggested that catecholamines participate as a 'stress mediator' of these effects. Given this hypothesis, it is also suggested here that catecholamines may be the first 'danger signal' to the immune system during exercise-induced stress.     

Excessive skeletal muscle recruitment during strenuous exercise in McArdle patients

We compared the cardiorespiratory response and muscle recruitment [as determined by electromyography (EMG)] of 37 McArdle patients [19 males, 37.4 ± 2.8 years, body mass index (BMI): 25.1 ± 4.7 kg m^?2] and 33 healthy controls (18 males, 36.4 ± 10.0 years, BMI: 25.7 ± 3.8 kg m^?2) during cycle-ergometer exercise (an incremental test to exhaustion and a 12-min submaximal constant workload test). We obtained cardiorespiratory [oxygen uptake and heart rate (HR)] and EMG data (rectus femoris and vastus lateralis muscles). During the incremental test, the patients exhibited the expected hyperkinetic cardiovascular response shown by a marked increase in the slope of the HR:Power relationship (p < 0.001). Throughout the incremental test and at the point of fatigue, the patients produced significantly less power than the controls (peak power output: 67 ± 21 vs. 214 ± 56 watts respectively, p < 0.001), yet they demonstrated significantly higher levels of muscle activity for a given absolute power. During the constant workload test, patients displayed higher levels of EMG activity than the controls during the second half of the test, despite a lower power production (34 ± 13 vs. 94 ± 29 watts respectively, p < 0.001). In conclusion, since the McArdle patients required more motor unit recruitment for a given power output, our data suggest that the state of contractility of their muscles is reduced compared with healthy people. Excessive muscle recruitment for a given load could be one of the mechanisms explaining the exercise intolerance of these patients.     

High cardiovascular risk in patients with diabetes and the cardiometabolic syndrome: mandate for statin therapy

Diabetes mellitus confers a high risk of cardiovascular morbidity and mortality and requires aggressive management of all cardiovascular risk factors, including diabetic dyslipidemia. Although levels of low-density lipoprotein cholesterol are often normal or only slightly elevated in persons with diabetes, lipid-altering therapy with statins has been shown in large, randomized, controlled trials to decrease the risk of cardiovascular complications in this patient population. A target low-density lipoprotein cholesterol level of <70 mg/dL is now a therapeutic option in patients at very high risk for coronary heart disease, including patients with diabetes. Diabetes is also a leading cause of end-stage renal disease. In addition to their lipid-modifying effects, statins have been shown to slow the progression of diabetic nephropathy and potentially exert other renoprotective effects; these benefits, however, remain to be confirmed in clinical trials.     

Ex vivo-activated human macrophages kill chronic lymphocytic leukemia cells in the presence of rituximab: mechanism of antibody-dependent cellular cytotoxicity and impact of human serum

Antibody-dependent cellular cytotoxicity (ADCC) is one of the mechanisms of tumor killing during antibody (Ab) immunotherapy, and a role for myeloid cells as effectors has been observed in several models. We are developing immunotherapy approaches based on administration of large numbers of ex vivo interferon-gamma-activated macrophages to cancer patients. With a quantitative assay measuring killing of nonproliferating tumor cells, we evaluated whether, in physiologic conditions, these macrophages synergize with the anti-CD20 Ab rituximab for killing primary B-cell chronic lymphocytic leukemia (B-CLL) cells. ADCC reached levels of 70% to 80% at effector to target ratios as low as 1:1. Macrophage recruitment by Ab-opsonized tumor cells did not result in enhanced cytokine secretion, suggesting that the cytokine shower observed in rituximab-treated patients is not caused by macrophage activation, and that cytokines have no role in CLL killing. We observed that uptake of tumor material by macrophages was not directly correlated to tumor killing. Nonetheless, experiments in the presence of cytochalasin D showed that ADCC occurred mainly by phagocytosis. Tumor killing was largely mediated by Fc gammaRI and inhibited by increasing concentration of serum. Importantly, complement deposition on B-CLL cells did not seem to enhance macrophage ADCC in this model, as complement-depleted and complement-repleted human plasmas exerted comparable inhibition.     

Happle-Tinschert syndrome variable phenotype as part of the mosaic hedgehog spectrum: Report of three cases

Happle-Tinschert syndrome is a rare genodermatosis caused by a postzygotic mutation in SMO gene. The most recognized clinical findings include segmentally arranged basaloid follicular hamartomas, nevoid hypertrichosis, linear atrophoderma, and hypopigmentation or hyperpigmentation following Blaschko lines associated with osseous, dental, and cerebral alterations. We report three additional cases, two of which lacked the pathognomonic basaloid follicular hamartomas, with genetic confirmation and detailed clinical characterization and describe new cutaneous features of this infrequent syndrome.