Skeletal muscle fibers produce B-cell stimulatory factors in chronic myositis.

Introduction: We aimed to identify B-cell-mediated immunomechanisms in inclusion body myositis (IBM) and polymyositis (PM) as part of the complex pathophysiology. Materials and methods: Human primary myotube cultures were derived from orthopedic surgery. Diagnostic biopsy specimens from patients with IBM (n=9) and PM (n=9) were analyzed for markers of B cell activation (BAFF and APRIL) and for chemokines that control the recruitment of B cells (CXCL-12 and CXCL-13). Results were compared to biopsy specimens without myopathic changes (n=9) and hereditary muscular dystrophy (n=9). Results: The mRNA expression of BAFF, APRIL, and CXCL-13 was significantly higher in IBM and PM compared to controls. Patients with IBM displayed the highest number of double positive muscle fibers for BAFF and CXCL-12 (48%) compared to PM (25%), muscular dystrophy (3%), and non-myopathic controls (0%). In vitro, exposure of human myotubes to pro-inflammatory cytokines led to a significant upregulation of BAFF and CXCL-12, but APRIL and CXCL-13 remained unchanged. Conclusion: The results substantiate the hypothesis of an involvement of B cell-associated mechanisms in the pathophysiology of IBM and PM. Muscle fibers themselves seem to contribute to the recruitment of B cells and sustain inflammation.

Evaluation of dysphagia by novel real-time MRI.

OBJECTIVE: To assess safety and feasibility of real-time (RT) MRI for evaluation of dysphagia and to compare this technique to standard assessment by flexible endoscopic evaluation of swallowing (FEES) and videofluoroscopy (VF) in a cohort of patients with inclusion body myositis (IBM). METHODS: Using RT-MRI, FEES, and VF, an unselected cohort of 20 patients with IBM was studied as index disease with a uniform dysphagia. Symptoms of IBM and dysphagia were explored by standardized tools including Swallowing-Related Quality of Life Questionnaire (SWAL-QoL), IBM Functional Rating Scale, Patient-Reported Functional Assessment, and Medical Research Council Scale. RESULTS: Dysphagia was noted in 80% of the patients and SWAL-QoL was impaired in patients with IBM compared to published reference values of healthy elderly. Swallowing in a supine position during RT-MRI was well-tolerated by all patients. RT-MRI equally revealed dysphagia compared to VF and FEES and correlated well with the SWAL-QoL. Only RT-MRI allowed precise time measurements and identification of the respective tissue morphology. The pharyngeal transit times were 2-fold longer compared to published reference values and significantly correlated with morphologic abnormalities. CONCLUSIONS: RT-MRI is safe and equally capable as VF to identify the cause of dysphagia in IBM. Advantages of RT-MRI include visualization of soft tissue, more reliable timing analysis, and lack of X-ray exposure. RT-MRI may become a routine diagnostic tool for detailed assessment of the esophagus and other moving parts of the body, facilitating longitudinal evaluations in daily practice and clinical trials.

Tumor stroma-derived Wnt5a induces differentiation of basal cell carcinoma of Ptch-mutant mice via CaMKII.

Basal cell carcinoma (BCC) is the most common skin tumor in humans. Although BCCs rarely metastasize, they can cause significant morbidity due to local aggressiveness. Approximately 20% of BCCs show signs of spontaneous regression. The understanding of molecular events mediating spontaneous regression has the potential to reduce morbidity of BCC and, potentially, other tumors, if translated into tumor therapies. We show that BCCs induced in conditional Ptch(flox/flox)ERT2(+/-) knockout mice regress with time and show a more differentiated phenotype. Differentiation is accompanied by Wnt5a expression in the tumor stroma, which is first detectable at the fully developed tumor stage. Coculture experiments revealed that Wnt5a is upregulated in tumor-adjacent macrophages by soluble signals derived from BCC cells. In turn, Wnt5a induces the expression of the differentiation marker K10 in tumor cells, which is mediated by Wnt/Ca(2+) signaling in a CaMKII-dependent manner. These data support a role of stromal Wnt5a in BCC differentiation and regression, which may have important implications for development of new treatment strategies for this tumor. Taken together, our results establish BCC as an easily accessible model of tumor regression. The regression of BCC despite sustained Hedgehog signaling activity seems to be mediated by tumor-stromal interactions via Wnt5a signaling.