Takeya Adachi

Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1hi monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome.

Epidermal LCs but not dermal DCs take up skin surface protein through intact tight junctions and mediate IgG1 antibody responses to bacterial antigen, conferring protective immunization.

Hair follicle–derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma

The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4+ and CD8+ skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8+ TRM cells, and IL-7 for CD8+ and CD4+ TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4+ TRM lymphoma cell localization depended on the presence of hair follicle–derived IL-7. These findings implicate hair follicle–derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.

Japan’s initiative on rare and undiagnosed diseases (IRUD): towards an end to the diagnostic odyssey

Japan has been facing challenges relating to specifically defined rare diseases, called Nan-Byo in Japanese (literally ‘difficult’+‘illness’), and has already taken measures for them since 1972. This governmental support has surely benefited Nan-Byo patients; however, those suffering from medically unidentified conditions do not fall into this scheme and thus still confront difficulty in obtaining an examination, a diagnosis, and a treatment. To identify such rare and often undiagnosed diseases, we must integrate systematic diagnosis by medical experts with phenotypic and genetic data matching. Thus, in collaboration with Nan-Byo researchers and the Japanese universal healthcare system, the Japan Agency for Medical Research and Development launched the Initiative on Rare and Undiagnosed Diseases (IRUD) in 2015. IRUD is an ambitious challenge to construct a comprehensive medical network and an internationally compatible data-sharing framework. Synergizing with existing next-generation sequencing capabilities and other infrastructure, the nationwide medical research consortium has successfully grown to accept more than 2000 undiagnosed registrants by December 2016. We also aim at expanding the concept of microattribution throughout the initiative; that is, proper credit as collaborators shall be given to local primary care physicians, nurses and paramedics, patients, their family members, and those supporting the affected individuals whenever appropriate. As it shares many challenges among similar global efforts, IRUD’s future successes and lessons learned will significantly contribute to ongoing international endeavors, involving players in basic research, applied research, and societal implementation.

Comparison of basophil activation test and lymphocyte transformation test as diagnostic assays for drug hypersensitivity

Lymphocyte transformation test (LTT) is a widely used assay to detect drug-specific T cell reaction, but its relatively low sensitivity renders risk for pseudo-negativity. Basophil activation test (BAT) is an emerging assay initially used to diagnose food allergy, but its application to drug hypersensitivity as been reported anecdotally. Although a promising assay, the clinical settings or a particular class of drugs in which BAT is useful has not been well characterized. Herein, we performed a side-by-side comparison of BAT and LTT in detecting culprit drugs in several types of drug hypersensitivities. 248 patients who visited our department from October 2011 to December 2013 were enrolled in this study. Peripheral blood cells drawn from patients were co-cultured with or without relevant drugs. LTT was performed according to a standard protocol with 3H-thymidine uptake and stimulation index of 1.8 and above (CPM value with drug divided by CPM without drug) were defined positive. For BAT, whole blood cells were exposed to drugs for 24hrs and were assessed via flow cytometry for the proportion of cells that had upregulated CD203c (activated state) among total basophils. 9.0% and above were defined positive, based on values from healthy controls (mean value + 5SD). Overall, 14.7% and 28.8% of culprit drugs tested yielded positive results by BAT and LTT, respectively. Analysis of disease phenotype of patients revealed that BAT yielded positive results not only in immediate-type, but also delayed-type hypersensitivity such as drug-induced hypersensitivity syndrome and Stevens-Johnson syndrome. Of note, samples that yielded positive for LTT and BAT did not overlap, suggesting that the two analyses might compensate each other for pseudo-negativity. Furthermore, analysis focusing on the class of antibiotics showed that macrolides were frequently obtained positive via BAT, whereas that for -lactams tended to be positive via LTT. Utilizing both BAT and LTT, we screened antibiotics and NSAIDs for selection of drugs that could be used for challenge tests in patients with histories of multiple drug allergy. The negative indicative value was 96.4%, suggesting the usefulness of these assays in safely identifying drugs for future use. Taken together, different spectrum of drugs can be covered by performing both BAT and LTT, allowing identification of culprit drugs with higher sensitivity than by performing a single assay.

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome

The pathological mechanisms and immunological kinetics of drug‐induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)‐6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti‐IL‐6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL‐6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

Case of isolated epidermolytic acanthoma: Genetic and immunohistochemical analysis.

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Postherpetic Wolf's isotopic response: possible contribution of resident memory T cells to the pathogenesis of lichenoid reaction.

test with raw fish did not result in positive reactions. We performed the additional prick-to-prick test with heated fish to make the collagen soluble, based on the assumption that negative results with raw fish could have been due to its insolubility. Indeed, negative skin reactions with raw fish became positive after heat treatment. It should also be noted that, despite negative results for IgE against Pacific mackerel and horse mackerel as assessed using FEIA methods, we detected positive results for specific IgE against these fish using ELISA. This could be explained by the fact that we used heated fish extracts for ELISA assays. Our results suggest that the prick-to-prick test with raw fish may risk overlooking fish-collagen allergy. Performing the prick-to-prick test with heat-treated fish in addition to raw fish is recommended in patients with suspected fish allergy, although this may present a higher risk of adverse events than an ordinary skin prick test with standardized samples.