April Deng

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

Neutralizing CXCL10 reverses established vitiligo. New Skin in the Game of Vitiligo Therapy The immune system is tasked with protecting the body from invading pathogens. Yet, sometimes, immune cells themselves attack the tissues they are supposed to protect. One such autoimmune disease is vitiligo, where immune cells are thought to attack melanocytes—the pigment-producing cells in the skin. Individuals with vitiligo have depigmented areas in their skin, which is disfiguring and also increases the risk of skin damage. Now, Rashighi et al. suggest that blocking the chemokine CXCL10 may restore pigmentation in patients with vitiligo. The authors examined gene expression in lesional skin from vitiligo patients and found an interferon-γ–specific signature, including differential expression of the chemokine CXCL10. They found that CXCL10 was up-regulated in vitiligo patients; its receptor CXCR3 was up-regulated in T cells from these patients as well. The authors then looked in a mouse model of vitiligo to determine the functional relevance of this observation. Mice with CXCR3-deficient T cells developed a much less severe form of vitiligo, as did mice lacking CXCL10 or treated with a CXCL10-neutralizing antibody. What’s more, this CXCL10-neutralizing antibody resulted in repigmentation in mice with already established vitiligo lesions. These data suggest that CXCL10 neutralization should be considered as a potential treatment for vitiligo. Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no U.S. Food and Drug Administration–approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8+ T cells in the skin and blood, which are directly responsible for melanocyte destruction. We report that gene expression in lesional skin from vitiligo patients revealed an interferon-γ (IFN-γ)–specific signature, including the chemokine CXCL10. CXCL10 was elevated in both vitiligo patient skin and serum, and CXCR3, its receptor, was expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we used a mouse model of disease that also exhibited an IFN-γ–specific gene signature, expression of CXCL10 in the skin, and up-regulation of CXCR3 on antigen-specific T cells. Mice that received Cxcr3−/− T cells developed minimal depigmentation, as did mice lacking Cxcl10 or treated with CXCL10-neutralizing antibody. CXCL9 promoted autoreactive T cell global recruitment to the skin but not effector function, whereas CXCL10 was required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo and thereby support inhibiting CXCL10 as a targeted treatment strategy.

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001

Immediate Type I Hypersensitivity Response Implicated in Worsening Injection Site Reactions to Adalimumab

BACKGROUND Tumor necrosis factor (TNF) inhibitors such as adalimumab, etanercept, and infliximab play an increasingly important role in the management of a variety of chronic inflammatory disorders. With their increasing use, a wide spectrum of dermatological adverse effects, including injection site reactions and the development of dermatitis, have been recognized. Previous studies have implicated the role of the delayed-type hypersensitivity reaction in mediation of injection site reactions to etanercept. To our knowledge, there have been no published studies on immunologic mechanism of injection site reactions to adalimumab to date. OBSERVATIONS We describe 2 patients with a history of worsening injection site reactions to adalimumab. Findings from skin testing in both patients were suggestive of an immediate type I hypersensitivity reaction to adalimumab. A histamine release assay performed on peripheral blood leukocytes from both patients demonstrated significant histamine release on exposure to adalimumab. Furthermore, passive transfer of serum from one of the allergic patients to basophils from a nonatopic, healthy donor sensitized those cells to release significant amounts of histamine with exposure to adalimumab. Conclusion This study demonstrates that an IgE-mediated immediate type I hypersensitivity reaction plays a role in the mediation of worsening injection site reactions in some patients receiving adalimumab.

Mixed versus pure variants of desmoplastic melanoma: a genetic and immunohistochemical appraisal

Desmoplastic melanoma is subclassified into pure and mixed variants with a higher rate of lymph node metastasis in the latter. Given that reasons for these biological differences are not currently known, we investigated these subtypes with techniques that included genetic and immunohistochemical analyses of 43 cases of desmoplastic melanoma (24 pure, 19 mixed). Direct DNA sequencing was performed on BRAFV600E, RET gene (coding region on exon 11) and KIT (exons 11, 13 and 17). Immunohistochemical stains were performed with antibodies to markers of significance with respect to biological potential of nevomelanocytic proliferations and/or desmoplastic melanoma (Ki-67, CD117, nestin, clusterin, SOX10 and CD271/p75NTR). Polymorphism at the RET coding region (RETp) was noted in 33% of pure (8/24 cases) versus 24% of mixed (4/17 cases); BRAFV600E was absent in all cases of pure (0/24 cases) versus 6% of mixed (1/17 cases); no mutations were found in any of the cases on analyses of exons 11, 13 and 17 of the c-KIT gene (P=NS for all). For immunohistochemical analyses of pure versus mixed: mean percentage of Ki-67 nuclear positivity was 5% (s.d.=5.6) versus 28% (s.d.=12.6, P<0.001); CD117 stained 26% (6/23 cases) versus 78% (14/18 cases, P<0.01); nestin stained 83% (n=19/23 cases) versus 89% (16/18 cases, P=NS); clusterin stained 4% (1/23 cases) versus 6% (1/18 cases, P=NS); SOX10 87% (20/23 cases) versus 94% (17/18 cases, P=NS) and CD271 stained 61% (14/23 cases) versus 67% (12/18 cases, P=NS). Increased CD117 staining in the mixed variant suggests that alterations in the KIT protein may be involved in tumor progression. In addition, the proliferative index of the mixed variant was higher than that of the pure variant.

Activation of Keratinocyte Protein Kinase Cζ in Psoriasis Plaques

PKCzeta (protein kinase C-zeta), a member of protein kinase C family, plays an important role in cell proliferation, differentiation, and apoptosis. It acts as a downstream molecule for TNF-alpha (tumor necrosis factor) signal transduction and also regulates the expression of CD1d, an HLA-class I-like molecule. The interaction of CD1d with natural killer T (NKT) cells has been shown to be important in their Th1 cytokine production in psoriasis. In this study, we examined PKCzeta in psoriasis in order to define its role in the pathogenesis of the disease. We found that T-cell receptor (TCR) V alpha24+ V beta11+ NKT cells and CD1d molecules within psoriatic skin were increased. Moreover, there was an associated increase in PKCzeta mRNA and protein expression with membrane translocation in psoriasis lesions compared to uninvolved skin. Furthermore, cultured keratinocytes exhibited increased PKCzeta activity and membrane translocation upon stimulation by TNF-alpha, a cytokine known to play an important role in the pathogenesis of psoriasis. These results implied that PKCzeta is an important transduction molecule downstream of TNF-alpha signaling and is associated with increased expression of CD1d that may enhance CD1d-NKT cell interactions in psoriasis lesions. This makes PKCzeta a tempting target for possible pharmacological intervention in modifying the downstream effects of TNF-alpha in psoriasis.

Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling

Background: Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 1997 and recently renamed as nephrogenic systemic fibrosis (NSF). The etiology and pathogenesis remain uncertain. Characteristic clinical presentation is described as diffuse thickening and hardening of the skin occurring in patients with renal insufficiency. Typical histological features include proliferation of CD34 positive fibrocytes, increased thick collagen bundles and mucin deposition, without significant inflammatory infiltrate. Variations in clinical presentations have been reported, including papular and plaque‐like skin lesions, focal lesion only, as well as systemic involvement. Histological changes can be subtle and non‐specific, overlapping with other disease processes and harboring features including calcification and osteoclast‐like giant cells with osseous metaplasia.

The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis.

Autoimmune progesterone dermatitis is a rare clinical condition in which patients display hypersensitivity to endogenous progesterone. It manifests as a cyclical cutaneous eruption that flares during the luteal phase of the menstrual cycle, when progesterone levels peak, and resolves partially or completely a few days after menses. Its cutaneous manifestations are variable and include urticaria, eczematous eruptions, vesiculopustular eruptions, fixed drug eruptions, stomatitis, erythema multiforme, and anaphylaxis. Autoimmune progesterone dermatitis has been diagnosed previously with intradermal skin testing or intramuscular progesterone challenge. Treatment of progesterone hypersensitivity generally consists of ovulation inhibition with pharmaceutical agents or oophorectomy; other therapies (eg, thalidomide) have also been used with success. We report a case of cyclical erythema multiforme (EM) induced by hypersensitivity to endogenous progesterone in a patient with a history of past oral contraceptive use. After herpes simplex virus was ruled out as an etiologic factor, a diagnosis of progesterone hypersensitivity was confirmed with intradermal skin testing. Results of subsequent patch testing with various progesterone derivatives were negative. The EM outbreaks were suppressed temporarily by continuous administration of Loestrin (ethinyl estradiol plus norethindrone), which also increased the responsiveness of the outbreaks to prednisone tapers.

IL-1 generated subsequent to radiation-induced tissue injury contributes to the pathogenesis of radiodermatitis.

Radiation injury in the skin causes radiodermatitis, a condition in which the skin becomes inflamed and the epidermis can break down. This condition causes significant morbidity and if severe it can be an independent factor that contributes to radiation mortality. Radiodermatitis is seen in some settings of radiotherapy for cancer and is also of concern as a complication post-radiation exposure from accidents or weapons, such as a “dirty bomb”. The pathogenesis of this condition is incompletely understood. Here we have developed a murine model of radiodermatitis wherein the skin is selectively injured by irradiation with high-energy electrons. Using this model we showed that the interleukin-1 (IL-1) pathway plays a significant role in the development of radiodermatitis. Mice that lack either IL-1 or the IL-1 receptor developed less inflammation and less severe pathological changes in their skin, especially at later time-points. These findings suggest that IL-1 pathway may be a potential therapeutic target for reducing the severity of radiodermatitis.

Assessment of T-cell clonality via T-cell receptor-γ rearrangements in cutaneous T-cell-dominant infiltrates using polymerase chain reaction and single-stranded DNA conformational polymorphism assay

Discerning the pathologic significance of cutaneous T-cell infiltrates can pose a diagnostic challenge for dermatopathologists. Reactive conditions such as drug-associated lymphomatoid hypersensitivity and lymphomatoid lupus erythematosus can demonstrate lymphoid atypia and a phenotype resembling cutaneous T-cell lymphoma (CTCL). Further, lymphoid dyscrasias such as pityriasis lichenoides chronica, large plaque parapsoriasis, and atypical pigmentary purpura confuse the picture because they not only mimic CTCL but also represent prelymphomatous states with inherent malignant potential. Although the emergence of a dominant clone has been considered a clue indicative of a T-cell dyscrasia, there are reports concerning the identification of monoclonality in biopsies of reactive lymphoid infiltrates. We have conducted a modified single-stranded DNA conformational polymorphism (SSCP) assay using paraffin-embedded, formalin-fixed tissue on 92 T-cell–rich biopsies to determine the relative specificity and sensitivity of this methodology. In addition, laser capture microdissection (LCM) was performed on 22 of the 92 samples to isolate the area of interest and to compare its specificity and sensitivity with those SSCP assays performed without LCM. We found that monoclonality or oligoclonality is 86% specific for preneoplastic and neoplastic states, whereas the finding of polyclonality appears to be relatively specific for a reactive process. Some cases of reversible T-cell dyscrasia produced a molecular profile mimicking lymphoma or prelymphomatous states by virtue of monoclonality or oligoclonality. Although LCM appears to improve the sensitivity for detecting preneoplastic conditions, the relative specificity appears to be the same as that encountered with routine SSCP.

Umbilical metastasis from prostate carcinoma (Sister Mary Joseph's nodule): a case report and review of literature.

Sister Mary Joseph’s nodule is referred to as metastatic lesion of the umbilicus. Most of the tumors are adenocarcinomas originating from gastroenteric and genital tracts. Only rarely were metastases from other locations reported. We describe here an unusual case of a Sister Mary Joseph’s nodule that was metastasized from prostate carcinoma 3 years after radiation therapy. The lesion was the first sign of metastatic disease, and the diagnosis was made on skin biopsy. The patient died of extensive metastases of prostate carcinoma 4 months later. We report this case to extend the list of differential diagnosis for Sister Mary Joseph’s nodule in male patients and emphasize the importance of Sister Mary Joseph’s nodule as an ominous diagnostic sign.