Iron Screening in Alopecia Areata Patients May Catch Hereditary Hemochromatosis Early.

Hereditary hemochromatosis (HHC), a disorder of iron overload, presents with clinical phenotypic heterogeneity. Complications can be mitigated with early intervention. The association between HHC and alopecia areata (AA) is unknown. We report 4 patients with HHC concurrent with AA. In 2 patients, the HHC diagnosis was revealed from the results of laboratory iron studies as part of an alopecia consultation workup. Alopecia areata may be a rare early cutaneous manifestation of HHC in individuals with a predisposition for autoimmunity; however, the genetic relationship between the 2 disorders is currently unknown. Patients at high risk for HHC such as those with a family history and/or those who fit the demographic profile may benefit from laboratory iron screening if they present to the clinic with AA.

Training Physician‒Scientists for Careers in Investigative Dermatology.

Physician‒scientists have made countless discoveries, and their dwindling numbers are a significant concern. Although dermatology has become an increasingly popular destination for physician‒scientist trainees, the proportion of trainees who pursue scientific research careers after training is among the lowest of all medical specialties. To investigate this problem, we surveyed a national cohort of dermatology educators, physician‒scientist track program directors, and National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 directors for opinions regarding physician‒scientist training in dermatology. On the basis of these findings and to help address the issue, we propose a training practicum and provide a resource for funding opportunities to help guide trainees and institutions interested in supporting investigative dermatologists. We also discuss the important roles of department chairs and institutions in fashioning an environment conducive to physician‒scientist training. The information and recommendations provided in this paper may help to improve the recruitment, training, development, and retention of investigative dermatologists and future leaders in this field.

Soluble DC-HIL/Gpnmb Modulates T-Lymphocyte Extravasation to Inflamed Skin.

Previously, we discovered antigen-presenting cells to express DC-HIL receptor and to secrete its soluble form (soluble DC-HIL [sDC-HIL]), both of which bind to syndecan-4 on T cells and endothelial cells (ECs), with the former binding attenuating T-cell function and the latter binding promoting angiogenesis. In this study, we examined the effects of sDC-HIL binding to EC on T-cell extravasation using an allergic contact dermatitis model in mice. The hapten oxazolone applied to ear skin in sensitized mice upregulated cutaneous expression of sDC-HIL, which downregulated the allergic reaction by reducing transendothelial migration of T cells but not other immune cells (neutrophils and mast cells). Moreover, intravenously infused sDC-HIL bound to EC in blood vessels of oxazolone-challenged skin in a scattered and patchy pattern, and intravital microscopic analysis revealed that blood-circulating T cells firmly adhere to DC-HIL-treated endothelia. This regulatory property of sDC-HIL requires syndecan-4 expression by both EC and T cells. Our findings indicate that the DC-HIL/syndecan-4 pathway mediates a cross-talk between T cells and ECs, regulating the cutaneous immune response by preventing extravasation of activated T cells into inflamed skin.

DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness. EXPERIMENTAL DESIGN: Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (n = 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-DC-HIL gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression. RESULTS: Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (n = 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL+MDSC or induction of sDC-HIL expression. CONCLUSIONS: sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.

Blocking Monocytic Myeloid-Derived Suppressor Cell Function via Anti-DC-HIL/GPNMB Antibody Restores the In Vitro Integrity of T Cells from Cancer Patients.

PURPOSE: Blocking the function of myeloid-derived suppressor cells (MDSC) is an attractive approach for cancer immunotherapy. Having shown DC-HIL/GPNMB to be the T-cell-inhibitory receptor mediating the suppressor function of MDSCs, we evaluated the potential of anti-DC-HIL mAb as an MDSC-targeting cancer treatment. EXPERIMENTAL DESIGN: Patients with metastatic cancer (n = 198) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/lo MDSCs. Their suppressor function was assessed by in vitro coculture with autologous T cells, and the ability of anti-DC-HIL or anti-PDL1 mAb to reverse such function was determined. Tumor expression of these receptors was examined histologically, and the antitumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice. RESULTS: Patients with metastatic cancer had high blood levels of DC-HIL+ MDSCs compared with healthy controls. Anti-DC-HIL mAb reversed the in vitro function in ∼80% of cancer patients tested, particularly for colon cancer. Despite very low expression on blood MDSCs, anti-PDL1 mAb was as effective as anti-DC-HIL mAb in reversing MDSC function, a paradoxical phenomenon we found to be due to upregulated expression of PDL1 by T-cell-derived IFNγ in cocultures. DC-HIL is not expressed by colorectal cancer cells but by CD14+ cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of preestablished colon tumors by reducing MDSCs and increasing IFNγ-secreting T cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb. CONCLUSIONS: Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs.See related commentary by Colombo, p. 453.

Photocontact Dermatitis and Its Clinical Mimics: an Overview for the Allergist.

Photo-contact dermatitis (PCD) describes the adverse cutaneous reaction that occurs in some patients as a result of simultaneous exposure to a contactant and to light. PCD can be subdivided into photo-allergic and photo-irritant dermatitis depending on whether the contactant respectively invokes an allergic or irritant reaction. Photo-irritant reactions are commonly caused by plants, psoralens, and medications taken internally, whereas photo-allergic reactions are commonly caused by sunscreens and topical nonsteroidal anti-inflammatory medications. The work-up of photo-contact dermatitis includes a thorough history and physical exam augmented by patch and/or photopatch testing, as the cornerstone of treatment for PCD is identification and avoidance of the irritating or allergenic chemical. Photo-contact dermatitis has the potential to significantly impact quality of life, so an informed approach to diagnosis and management is critical. Clinical mimics of PCD include polymorphic light eruption, solar urticaria, actinic prurigo, hydroa vacciniforme, cutaneous porphyrias, and systemic disorders with photosensitivity such as lupus and dermatomyositis. Herein, we review the clinical presentation, differential diagnosis (including the clinical mimics mentioned above), pathogenic mechanisms, diagnostic testing, and therapeutic considerations for PCD.

Melanoma-Derived Soluble DC-HIL/GPNMB Promotes Metastasis by Excluding T-Lymphocytes from the Pre-Metastatic Niches.

Soluble factors from the primary tumor induce recruitment of bone marrow-derived progenitors to form tumor-supportive microenvironments or pre-metastatic niches in distal organs before metastasis. How tumor-secreted factors condition the sites for tumor progression remains ambiguous. B16 melanoma produces the secreted form of T cell-inhibitory DC-HIL (sDC-HIL) that travels to distal organs and potentiates the metastatic capacity of tumor cells. We studied the molecular mechanisms and found that sDC-HIL binds to select endothelial cells that co-localize with the sites where bone marrow-derived progenitors and tumor cells migrate. sDC-HIL-bound endothelial cells exist at a similar frequency in mice with or without tumors, and they are strongly associated with survival of intravenously injected tumor cells in the lung. sDC-HIL binding conferred T-cell suppressor function on the ECs and awakened the angiogenic property by inducing vascular endothelial growth factor expression, resulting in enhanced transendothelial migration of bone marrow-derived progenitors and tumor cells, but not for T cells. This selectivity is achieved by the T-cell binding of sDC-HIL, which prevents formation of the leading edges required for chemotaxis. Finally, inducing tumor expression of sDC-HIL significantly reduced tumor-infiltrated T cells. Therefore, the highly metastatic attribute of B16 melanoma can be explained by the endothelial gatekeeper function of sDC-HIL that limits lymphocyte transmigration to pre-metastatic niches.

Photodermatitis for the Allergist.

PURPOSE OF REVIEW: The photodermatoses represent a group of disorders of sensitivity to light that continue to pose difficulties in diagnosis and management. Photodermatoses are of interest to allergists because many photosensitive skin disorders have immunologic underpinnings, and patients often present to clinic complaining of "allergy" to the sun. We provide a concise reference for allergists on the clinical recognition and management of photodermatitis. RECENT FINDINGS: New developments in the understanding of immunomodulatory effects of light have demonstrated normally immunosuppressive responses in the skin to light exposure, and a blunted immunosuppressive response in the pathogenesis of many photodermatoses. Vitamin D plays an important role in immunomodulation and itself may be affected by photodermatoses due to the impact of photoprotective treatment strategies on circulating vitamin D levels. The elucidation of the immunological basis of many photodermatoses may provide guidance for developing new treatment modalities. Further research is necessary to determine the optimal management of vitamin D metabolism in patients with photodermatoses.

Myeloid-Derived Suppressor Cells in Psoriasis Are an Expanded Population Exhibiting Diverse T-Cell-Suppressor Mechanisms.

Psoriasis vulgaris is an inflammatory skin disease caused by hyperactivated T cells regulated by positive and negative mechanisms; although the former have been much studied, the latter have not. We studied the regulatory mechanism mediated by myeloid-derived suppressor cells (MDSCs) and showed that MDSCs expanded in melanoma patients express dendritic cell-associated heparan sulfate proteoglycan-dependent integrin ligand, a critical mediator of T-cell suppressor function. We examined expansion of DC-HIL(+) MDSCs in psoriasis and characterized their functional properties. Frequency of DC-HIL(+) monocytic MDSCs (CD14(+)HLA-DR(no/low)) in blood and skin was markedly increased in psoriatic patients versus healthy control subjects, but there was no statistically significant relationship with disease severity (based on Psoriasis Area and Severity Index score). Blood DC-HIL(+) MDSC levels in untreated patients were significantly higher than in treated patients. Compared with melanoma-derived MDSCs, psoriatic MDSCs exhibited significantly reduced suppressor function and were less dependent on DC-HIL, but they were capable of inhibiting proliferation and IFN-γ and IL-17 responses of autologous T cells. Psoriatic MDSCs were functionally diverse among patients in their ability to suppress allogeneic T cells and in the use of either IL-17/arginase I or IFN-γ/inducible nitric oxide synthase axis as suppressor mechanisms. Thus, DC-HIL(+) MDSCs are expanded in psoriasis patients, and their mechanistic heterogeneity and relative functional deficiency may contribute to the development of psoriasis.

Treatment of warts with contact allergens.

Contact immunotherapy is an increasingly used, effective means of treating cutaneous viral warts. Dinitrochlorobenzene, diphencyprone, and squaric acid dibutylester are the most frequently used modalities, showing slight variances in adverse effect profiles and efficacy. All of these agents serve as safe treatment modalities when administered according to the guidelines recommended herein. We review the value of contact immunotherapy in the treatment of cutaneous viral warts.