In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, since in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN + CD16 + macrophages and CD1b + DC-SIGN − dendritic cells. DC-SIGN + phagocytic macrophages were expanded by TLR-mediated upregulation of IL-15/IL-15R. CD1b + dendritic cells were expanded by TLR-mediated upregulation of GM-CSF/ GM-CSFR, promoted T cell activation and secreted proinflammatory cytokines. While DC-SIGN + macrophages were detected in lesions of all leprosy patients, CD1b + dendritic cells were not detected in patients with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by Th1 responses. In T-lep lesions, DC-SIGN + cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells appears critically to influence effective host defenses in human infectious disease.

A key target of many intracellular pathogens is the macrophage. Although macrophages can generate antimicrobial activity, neutrophils have been shown to have a key role in host defense, presumably by their preformed granules containing antimicrobial agents. Yet the mechanism by which neutrophils can mediate antimicrobial activity against intracellular pathogens such as Mycobacterium tuberculosis has been a long-standing enigma. We demonstrate that apoptotic neutrophils and purified granules inhibit the growth of extracellular mycobacteria. Phagocytosis of apoptotic neutrophils by macrophages results in decreased viability of intracellular M. tuberculosis. Concomitant with uptake of apoptotic neutrophils, granule contents traffic to early endosomes, and colocalize with mycobacteria. Uptake of purified granules alone decreased growth of intracellular mycobacteria. Therefore, the transfer of antimicrobial peptides from neutrophils to macrophages provides a cooperative defense strategy between innate immune cells against intracellular pathogens and may complement other pathways that involve delivery of antimicrobial peptides to macrophages.

Background Dermatologists at the University of California, San Francisco recently reported two patients in the online Journal of the American Academy of Dermatology with purpura presumably induced by levamisole in contaminated cocaine. Levamisole-induced vasculitis and neutropenia has been reported elsewhere in the United States and Canada. Up to 70% of cocaine in the United States could be contaminated. Objective We sought to describe similar cases of vasculitis associated with cocaine use. Methods This is a retrospective case series. Results We report 6 remarkably similar patients seen over just the past few months with retiform purpura on the body and tender purpuric eruptions, necrosis, and eschars of the ears after cocaine use in New York and California. All of these patients had positive perinuclear antineutrophil cytoplasmic antibody values and 3 of the 6 also had an associated neutropenia. Direct immunofluorescence studies suggested an immune complex–mediated vasculitis. Limitations This case series is descriptive in nature and, because testing is not easily performed, we did not test for levamisole in the serum or blood to prove this is the causative agent. Conclusion It appears the use of cocaine is associated with the peculiar clinical findings of ear purpura, retiform purpura of the trunk, and neutropenia. We believe this case series may represent the tip of the iceberg as a looming public health problem caused by levamisole. Although the direct causal relationship may be difficult to establish, the astute dermatologist or primary care physician should be able to recognize the characteristic skin lesions and should be wary of the potential development of agranulocytosis. (J Am Acad Dermatol 2011;65:722-5.)

No abstract

Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma (MCC), usually presents as a dermal and/or subcutaneous tumor. Rarely, it is confined to the epidermis or adnexal epithelium [MCC in situ (MCCIS)]. Little is known about the spectrum of features and biology of MCCIS. Herein, we report a case of MCCIS arising on the cheek of a 77-year-old Caucasian male, which was associated with squamous cell carcinoma in situ. The tumor cells of both the neuroendocrine and squamous components prominently involved adnexal structures but did not invade the dermis. The tumor cells with neuroendocrine features were immunoreactive for cytokeratin-20, chromogranin and synaptophysin. They also expressed p53 but were non-reactive with the monoclonal antibody CM2B4. Lack of labeling for CM2B4 is in keeping with prior observations of combined squamous and MCC. Our findings support the concept of a distinct subtype of virus-independent cutaneous neuroendocrine carcinoma that differs from conventional MCC. The observed overexpression of p53 suggests that the development of this tumor type may be related to chronic ultraviolet damage.

BACKGROUND: Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored. METHODS: A retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash in the setting of therapy with the mTOR inhibitors everolimus and temsirolimus was performed. The parameters that were studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results of microbiologic studies, concomitant medications, the need for dose reduction and/or treatment interruption because of rash, and routine histopathology. RESULTS: In total, 13 patients were analyzed. Most rashes were mild (grade 1; 31%) and moderate (grade 2; 54%) in severity, and grade 3 rashes were observed only in 2 patients (15%). The trunk was the most frequently affected region (77%), with the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly involved. Erythematous papules and pustules constituted the predominant primary lesion morphology (62%). No unique or uniform histopathologic reaction pattern was observed. The most common reaction pattern was that of a mixed, spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%). CONCLUSIONS: Although mTOR inhibitors may commonly induce erythematous papules and pustules, they are associated with a spectrum of lesion morphologies and a variety of histopathologic findings. Further clinicohistologic correlation studies are needed. Cancer 2012. © 2012 American Cancer Society.

undergone exponential growth in the past 2 decades. Many technological innovations are becoming available without necessarily undergoing validation studies for specific dermatologic applications.OBJECTIVE To determine whether patient-taken photographs of acne using Network Oriented Research Assistant (NORA) result in similar lesion counts and Investigator's Global Assessment (IGA) findings compared with in-person examination findings. DESIGN, SETTING, AND PARTICIPANTSThis pilot reliability study enrolled consecutive patients with acne vulgaris from a single general dermatology practice in Los Angeles, California, who were able to use NORA on an iPhone 6 to take self-photographs. Patients were enrolled from January 1 through March 31, 2016. Each individual underwent in-person and digital evaluation of his or her acne by the same dermatologist. A period of at least 1 week separated the in-person and digital assessments of acne.INTERVENTIONS All participants were trained on how to use NORA on the iPhone 6 and take photographs of their face with the rear-facing camera. MAIN OUTCOMES AND MEASURESReliability of patient-taken photographs with NORA for acne evaluation compared with in-person examination findings. Acne assessment measures included lesion count (total, inflammatory, noninflammatory, and cystic) and IGA for acne severity.RESULTS A total of 69 patients (37 male [54%] and 32 female [46%]; mean [SD] age, 22.7 [7.7] years) enrolled in the study. The intraclass correlation coefficients of in-person and photograph-based acne evaluations indicated strong agreement. The intraclass correlation coefficient for total lesion count was 0.81; for the IGA, 0.75. Inflammatory lesion count, noninflammatory lesion count, and cyst count had intraclass correlation coefficients of 0.72, 0.72, and 0.82, respectively.CONCLUSIONS AND RELEVANCE This study found agreement between acne evaluations performed in person and from self-photographs with NORA. As a reliable telehealth technology for acne, NORA can be used as a teledermatology platform for dermatology research and can increase access to dermatologic care.