Elemental signals regulating eosinophil accumulation in the lung

Summary: In this review we identify the elemental signals that regulate eosinophil accumulation in the allergic lung. We show that there are two interwoven mechanisms for the accumulation of eosinophils in pulmonary tissues and that these mechanisms are linked to the development of airways hyperreactivity (AHR). Interleukin-(IL)-5 plays a critical role in the expansion of eosinophil pools in both the bone marrow and blood in response to allergen provocation of the airways. Secondly, IL-4 and IL-13 operate within the allergic lung to control the transmigration of eosinophils across the vascular bed into pulmonary tissues. This process exclusively promotes tissue accumulation of eosinophils. IL-13 and IL-4 probably act by activating eosinophil-specific adhesion pathways and by regulating the production of IL-5 and eotaxin in the lung compartment. IL-5 and eotaxin co-operate locally in pulmonary tissues to selectively and synergistically promote eosinophilia. Thus, IL-5 acts systemically to induce eosinophilia and within tissues to promote local chemotactic signals. Regulation of IL-5 and eotaxin levels within the lung by IL-4 and IL-13 allows Th2 cells to elegantly co-ordinate tissue and peripheral eosinophilia. Whilst the inhibition of either the IL-4/IL-13 or IL-5/ eotaxin pathways resulted in the abolition of tissue eosinophils and AHR, only depletion of IL-5 and eotaxin concurrently results in marked attenuation of pulmonary inflammation. These data highlight the importance of targeting both IL-5 and CCR3 signalling systems for the resolution of inflammation and AHR associated with asthma.
S.M. is a Postdoctoral Fellow funded by a grant from the Human Frontiers Foundation to P.S.F. and M.E.R. J.M. is supported by the German Research Association (grant MA 2241/1-1) and S.P.H by a NH&MRC CJ Martin Postdoctoral Fellowship.     

Ductal eccrine carcinoma with squamous differentiation: apropos a case

Sweat gland carcinomas are rare. Given this, they can pose a diagnostic challenge especially in shave biopsy specimens. We present a case of ductal eccrine carcinoma with extensive squamoid differentiation that was repeatedly misdiagnosed by multiple dermatopathologists as squamous cell carcinoma in the initial few biopsies. As the distinction between these two neoplasms is crucial to patient management, we highlight the histologic features of this uncommon entity to highlight the potential diagnostic pitfalls.     

Genetic profile of naïve untreated primary cutaneous melanomas with a negative sentinel lymph node

Sentinel lymph node (SLN) biopsy is typically offered to patients with primary cutaneous melanomas (PCMs) of ≥ 1 mm depth, but not all SLNs are positive using this cutoff. To ascertain whether positivity is genetically regulated, genetic analysis was performed using an augmented enrichment-based next-generation DNA and RNA sequencing assay in SLN-negative (Group 1, n = 8, mean depth 1.3 mm) and SLN-positive PCMs (controls, Group 2, n = 4, mean depth 1.4 mm). In Group 1, the mean number of mutations was 21 (range 3–48) with the most frequent mutations occurring in NF1 (75%) followed by TP53 (63%), CDKN2A and BRAF (38%), and NRAS (25%), while in Group 2, the ean number of mutations was 9.5 (range 5–18) with mutations in NRAS and BRAF being the most frequent (50%) followed by those in ATM, CDKN2A, CDKN2B, and NOTCH1 (25%). Increased frequency of NF1-inactivating mutations in Group 1 provides provocative early data that the presence of NF1 mutations might confer a less aggressive phenotype.     

Does Apoptosis Play a Role in Varicella Zoster Virus Latency and Reactivation?

Varicella zoster virus (VZV) is an exclusively human highly neurotropic alphaherpesvirus. To date, VZV has been shown to induce apoptosis, primarily through the intrinsic pathway in different cell types, except for neurons in which the virus becomes latent. This review summarizes current studies of varicella-induced apoptosis in non‑neuronal cells. Future studies are proposed to determine whether apoptosis is terminated prematurely or even begins in neurons that are non-productively infected with VZV.