Advertisement

Editors' Picks

        Changing of the guard

        Pemphigus is a rare but debilitating blistering disease caused by a pathogenic autoimmune response to the desmosomal proteins desmoglein 1 and 3. Although high doses of corticosteroids are the favored treatment, recent evidence supports use of the B cell–depleting antibody rituximab to treat severe pemphigus. In a subsequent study of the long-term effects of this drug, Colliou and colleagues demonstrated that rituximab induced long-term complete remission in 58% of patients even six years after the initial infusion. In concert, desmoglein-specific B-cell depletion induced by the drug also persisted, and complete responders exhibited loss of anti-desmoglein-specific B cells but not B cells that respond to pathogens. Rituximab appears to induce a prolonged and continuous repopulation with naive B cells and a distinct delay in the reappearance of memory B cells. Thus, in some cases, rituximab actually provides a functional cure for pemphigus via long-term reshaping of the B-cell repertoire in addition to short-term loss of pathogenic autoantibodies. (Sci Transl Med 5:175ra30, 2013) Selected by M. Amagai

        MCC family tree

        Merkel cell carcinoma (MCC) is a highly malignant nonmelanoma skin cancer. It is known to be associated with the Merkel cell polyomavirus, but its cellular ancestry is unclear. Judging by marker expression patterns, MCC is most closely related to Merkel cells; however, mouse models have suggested that epidermal stem cells or other primitive totipotent stem cells are the origin of MCC. Interestingly, MCC has recently been shown to express early B-cell lineage markers such as terminal deoxynucleotidyl transferase (TdT), B cell–specific activating protein (BSAP/PAX5), and immunoglobulin rearrangements. In a recent study, zur Hausen and colleagues reported TdT expression in 76.2% of MCCs and PAX5 expression in all of the samples. Furthermore, strong expression of immunoglobulins or κ/λ was detected in a significant number of MCCs. These findings strongly suggest that pro-/pre- or pre-B cells are the cellular origin of MCCs and will probably impact treatment strategies. (Cancer Res, published online 10 April 2013; doi: 10.1158/0008-5472/CAN-13-0616) Selected by J. Becker

        Port-wine mutation

        A child born with a port-wine stain cutaneous capillary malformation on the face has a 6% chance of having Sturge–Weber syndrome (also known as encephalofacial angiomatosis). These conditions are hypothesized to result from the same underlying mutations, and the clinical phenotype is therefore dependent on where and when the somatic mutations occur during development. In support of this hypothesis, Shirley and colleagues recently identified a specific somatic mosaic activating mutation (p.Arg183Gln) in GNAQ, which encodes a member of the q class of G-protein α subunits (Gαq) that mediate signaling between G-protein-coupled receptors and downstream effectors. This mutation was associated with both Sturge–Weber syndrome and nonsyndromic port-wine stains and was shown to activate downstream mitogen-activated protein kinase signaling. Somatic mutation of GNAQ in melanocytes is also associated with uveal melanoma, suggesting possible oncogenic potential of the identified mutation. (N Engl J Med 368:1971–8, 2013) Selected by K. Reddy

        One a day

        Recurrent cellulitis episodes are particularly damaging to the lymphatic system and result in significant morbidity and health-care costs. In a recent double-blind, randomized, controlled trial—Prophylactic Antibiotics for the Treatment of Cellulitis at Home I—Thomas and colleagues examined the effectiveness of a prophylactic 12-month course of low-dose penicillin for the prevention of recurrent cellulitis of the leg. In 247 patients, low-dose prophylactic penicillin treatment reduced the risk of recurrence of cellulitis by nearly half as compared with placebo treatment. Patients receiving treatment had significantly fewer recurrences over the follow-up period than patients receiving placebo, although the protection was lost by 36 months. In addition, patients with a high body mass index, preexisting edema, or at least three episodes of cellulitis were less likely to reap the benefits of this treatment. Overall, this trial supports the use of prophylactic penicillin to prevent recurrent cellulitis, although the optimal length of prophylactic treatment remains to be determined. (N Engl J Med 368:1695–703, 2013) Selected by B. Gilchrest

        Two hits are worse than one

        Glomuvenous malformations (GVMs), which have been attributed to mutations in glomulin (GLMN) on chromosome 1p, are characterized by autosomal dominant inheritance, incomplete penetrance, and high phenotypic variability, suggesting that an additional genetic event may be responsible for these venous anomalies. Amyere and colleagues investigated the two-hit hypothesis, which proposes that an association between an inherited and a somatic mutation underlies these abnormalities. Identification of a second hit in 16 of 28 lesions indicated that somatic second hits are necessary for the formation of GVMs and explain the variance in phenotype and penetrance. Interestingly, these hits were not typically intragenic but involved an acquired uniparental isodisomy (aUPID) that results in duplication of the mutant allele concomitant with loss of the wild-type allele without loss of other genes on 1p. Taken together, these results suggest that aUPID may even be more commonly involved in other noncancerous diseases, contrary to previous reports. (Am J Hum Genet 92:188–96, 2013) Selected by J. Uitto