Editors' Picks

        A missing link between skin and lungs

        Paraneoplastic pemphigus (PNP) involves IgG autoantibodies against cell adhesion molecules such as desmoglein 3 (Dsg3) and plakins, as well as a cellular immune response in the skin and mucous membranes. An important difference between PNP and the more common pemphigus vulgaris is that this form often involves fatal pulmonary involvement, although the mechanisms remain unknown. Recently, Hata and colleagues reported a novel PNP mouse model that involved grafting of wild-type skin onto Dsg3-deficient mice. The consequent graft rejection was mediated by generation of anti-Dsg3 IgG and Dsg3-specific T cells, reflecting the humoral and cellular immune reactions that characterize PNP in humans. These mice exhibited bronchial infiltration with a high mortality rate. Interestingly, Dsg3 and other epidermal antigens were expressed in the lungs of mice during squamous metaplasia following pulmonary injuries from naphthalene. Thus, this unexpected ectopic expression, which may redirect both Dsg3-specific CD4+ and CD8+ T cells to the lungs and induce inflammation, represents a missing link between skin and pulmonary involvement in PNP. (J Immunol 191:83–90, 2013) Selected by L. Beck

        Open the floodgates

        Recently, Blaydon and colleagues identified missense mutations in AQP5, the gene that encodes the water channel protein aquaporin-5, from several British and Swedish families affected with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK). These mutated aquaporins appeared to retain their ability to traffic to the cell membrane, where this protein functions to allow the osmotic movement of water across the cell membrane in a solute transport-independent manner. Interestingly, the five AQP5 mutants identified in these patients were clustered in the tertiary structure of the aquaporin monomer. Three of the substituted amino acids in diffuse NEPPK (Ile45, Ile177, and Arg188) are situated in the extracellular end of the water channel, where they probably affect water conductance. On the basis of protein structure modeling, the immunohistochemical data, and the disease phenotype, which involves increased keratinocyte water uptake, the investigators propose that the mutant AQP5 molecules form open channels and serve as gain-of-function alleles that allow water transport. (Am J Hum Genet 93:330–5, 2013) Selected by J. Uitto

        Finding the right balance

        The balance between self-renewal and differentiation in adult stem cells dictates tissue homeostasis. Niessen and colleagues recently inactivated atypical protein kinase C (aPKC)λ in the interfollicular epidermis and its appendages in mice in order to examine whether this protein, which is critical for controlling cell fate via asymmetric cell division (ACD) in lower organisms, is important for epidermal homeostasis. Epidermal loss of aPKCλ resulted in perturbed homeostasis characterized by increased differentiated sebaceous gland cells, altered interfollicular epidermis differentiation, a persistent anagen-like state, and disturbed hair follicle differentiation. Furthermore, this loss caused activation and gradual depletion of quiescent epidermal bulge stem cells, as epidermal compartment cells exhibited a 20% shift toward more ACDs, ultimately leading to loss of these cells in older mice and premature hair loss. Thus, aPKCλ balances the ratio of ACDs versus symmetric cell divisions in order to regulate epidermal cell fate and homeostasis. (J Cell Biol 202:887–900, 2013) Selected by S. Yuspa

        Seventeen strains

        Single-strain probiotics have been shown to exert modest clinical effects, suggesting that a collection of functionally distinct bacterial species rationally selected from the human gut microbiota may be more effective. Atarashi and colleagues recently reported the effects of 17 strains of bacteria—identified within Clostridia clusters XIVa, IV, and XVIII—from a human fecal sample. The strains were identified based on their ability to induce CD4+ FOXP3+ regulatory T cells (Tregs) as well as anti-inflammatory molecules such as IL-10 and inducible T-cell costimulator in Tregs upon inoculation into germ-free mice. These bacterial strains function collectively to provide short-chain fatty acids, bacterial antigens, and other factors that contribute to differentiation, expansion, and colonic homing of Treg cells. Importantly, following oral administration of these 17 bacterial strains, the treated mice exhibited attenuated disease in induced models of colitis and diarrhea, supporting the clinical relevance of these findings for human allergic and inflammatory conditions. (Nature 500:232–6, 2013) Selected by M. Amagai

        Direct effects on neurons

        The cytokine thymic stromal lymphopoietin (TSLP) has been implicated in initiation and maintenance of asthma, allergic rhinitis, and atopic dermatitis (AD), a chronic itch and inflammatory disorder. Wilson and colleagues recently found that TSLP, which is released by keratinocytes in response to signaling via the ORAI1 calcium ion channel, activates sensory neurons and subsequent itch behaviors in mice. Thus, epithelial cells utilize ORAI1-mediated Ca2+ influx to regulate cytokines, indicating that ORAI1 may be a new therapeutic target for atopic disease. In addition, the transient receptor potential cation channel member A1 (TRPA1) is required for this TSLP activity. These findings are particularly interesting because acute TSLP-evoked itch does not require histamine, other pruritogens, or lymphocytes, whereas histamine-dependent itch requires TRPV1, which is also unnecessary for TSLP-evoked itch, suggesting that acute and chronic phases of TSLP-evoked inflammation may rely on different mechanisms. (Cell 155:285–95, 2013) Selected by E. Lerner