Presence of immunoglobulin E-expressing antibody-secreting cells in the dermis close to bullous pemphigoid lesions.

Antibody-secreting cells (ASCs) produce immunoglobulin (Ig) G and IgE autoantibodies in secondary lymphoid organs. Evidence also suggests their existence in the skin in various chronic inflammatory conditions, and in association with CXCL12 and CXCL13, they regulate the recruitment/survival of ASCs and germinal center formation to generate ASCs, respectively. However, the presence of IgG and IgE in bullous pemphigoid (BP) lesions needs to be addressed. Here, we aimed to analyse BP skin for the presence of IgG and IgE and the factors contributing to their generation, recruitment, and persistence. Skin samples from 30 patients with BP were stained to identify ASCs and the immunoglobulin type they expressed. The presence of tertiary lymphoid organ (TLO) elements, which generate ASCs in non-lymphoid tissues, and the chemokines CXCL12 and CXCL13, which regulate the migration/persistence of ASCs in lymphoid tissues and formation of TLOs, respectively, were evaluated in BP skin. BP skin harboured ASCs expressing the two types of antibodies IgG and IgE. ASCs were found in high-grade cellular aggregates containing TLO elements: T cells, B cells, CXCL12+ cells, CXCL13+ cells and high endothelial venules. IgG+ ASCs were detected among these aggregates, whereas IgE+ ASCs were dispersed throughout the dermis. CXCL12+ fibroblast-like cells were located close to ASCs. The inflammatory microenvironment of BP lesions may contribute to the antibody load characteristic of the skin of patients with BP by providing a site for the presence of ASCs. CXCL13 and CXCL12 expression may contribute to the generation and recruitment/survival of ASCs, respectively.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Exploring the role of Janus kinase (JAK) in atopic dermatitis: a review of molecular mechanisms and therapeutic strategies.

Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in inflammatory diseases such as atopic dermatitis (AD). Large-scale clinical trials on AD utilizing JAK inhibitors and biologic reagents, such as dupilumab, which targets the IL-4Rα receptor subunit of the Th2 cytokines IL-4 and IL-13, have yielded highly favorable results in comparison to traditional therapies. This indicates that therapeutic strategies based on molecular biology are efficacious in clinical settings. However, in September 2021, the U.S. Food and Drug Administration (FDA) indicated that tofacitinib, a JAK inhibitor, may carry various risks, including severe heart disease. Similar concerns have been raised for other JAK inhibitors, and further safety evaluations are underway. Thus, human biology involving JAKs appeared more complicated than we expected. In this article, we provide an overview of the molecular mechanisms of AD and examine the molecular targeting drugs for AD from the perspective of JAK-related biology.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Galactosidase-catalyzed fluorescence amplification method (GAFAM): sensitive fluorescent immunohistochemistry using novel fluorogenic ß-galactosidase substrates and its application in multiplex immunostaining.

Multiplex immunohistochemistry/multiplex immunofluorescence (mIHC/mIF) enables the simultaneous detection of multiple markers in a single tissue section by visualizing the markers in different colors. Currently, tyramide signal amplification (TSA) is the most commonly used method because it is heat resistant to multiplexing. SPiDER-ßGal (6'-(diethylamino)-4'-(fluoromethyl)spiro[isobenzofuran-1(3H),9'-[9H]xanthen]-3'-yl ß-D-galactopyranoside), a novel fluorogenic substrate of ß-galactosidase (ß-gal) was reported recently. Its properties are favorable for application in sensitive mIF based on quinone methide chemistry. Combining SPiDER-ßGal with its related substrates, a novel, sensitive fluorescent IHC method for formalin-fixed paraffin-embedded (FFPE) sections was developed, named the galactosidase-catalyzed fluorescence amplification method (GAFAM). Evaluation of GAFAM indicated the following characteristics: (1) the entire GAFAM procedure was complete within a few hours; (2) the optimal working concentration of the substrates was 20 µM; (3) the fluorescent product was heat resistant; (4) the GAFAM exhibited sensitivity comparable with that of TSA, which was higher than that of conventional IF; and (5) the GAFAM was applicable to mIF and multispectral imaging. GAFAM is expected to be applicable to IF (or mIF in combination with TSA), and is a promising tool for facilitating morphological research in various fields of life science.

Waves of layered immunity over innate lymphoid cells.

Innate lymphoid cells (ILCs) harbor tissue-resident properties in border zones, such as the mucosal membranes and the skin. ILCs exert a wide range of biological functions, including inflammatory response, maintenance of tissue homeostasis, and metabolism. Since its discovery, tremendous effort has been made to clarify the nature of ILCs, and scientific progress revealed that progenitor cells of ILC can produce ILC subsets that are functionally reminiscent of T-cell subsets such as Th1, Th2, and Th17. Thus, now it comes to the notion that ILC progenitors are considered an innate version of naïve T cells. Another important discovery was that ILC progenitors in the different tissues undergo different modes of differentiation pathways. Furthermore, during the embryonic phase, progenitor cells in different developmental chronologies give rise to the unique spectra of immune cells and cause a wave to replenish the immune cells in tissues. This observation leads to the concept of layered immunity, which explains the ontology of some cell populations, such as B-1a cells, γδ T cells, and tissue-resident macrophages. Thus, recent reports in ILC biology posed a possibility that the concept of layered immunity might disentangle the complexity of ILC heterogeneity. In this review, we compare ILC ontogeny in the bone marrow with those of embryonic tissues, such as the fetal liver and embryonic thymus, to disentangle ILC heterogeneity in light of layered immunity.

Treatment With Topical Sirolimus for Recurrent Lymphatic Malformation of the External Urethral Meatus.

This case report describes a 17-year-old male patient with frog spawn­like vesicles around the urethra.

CCL2‒CCR2 Signaling in the Skin Drives Surfactant-Induced Irritant Contact Dermatitis through IL-1ß‒Mediated Neutrophil Accumulation.

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1b in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1ß in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2‒CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1ß expression for neutrophil accumulation.

Giant Pilomatrical Tumor With Broad Epidermal Components: An Example of Histological Diversity and a Potential Diagnostic Pitfall of Tumors With Pilomatrical Differentiation.

ABSTRACT: The diagnosis of pilomatricoma, the most common matrical tumor, is generally straightforward; however, it exhibits diverse histology associated with various morphological stages and several clinical variants, and matrical differentiation can occur in various neoplastic diseases. A 56-year-old man was admitted to our hospital to resect an 11.0-cm skin tumor on his right shoulder. Because of its large size and surface irregularities, including multiple erosions and ulcers, cutaneous malignancies were clinically suspected. Histologically, the tumor formed numerous nodules with marked matrical differentiation in the superficial to deep dermis. Although the tumor was macroscopically asymmetrical and irregular, each nodule was microscopically round-shaped and consisted of basaloid cells without marked atypia, atypical mitoses, or lymphovascular invasion. Immunohistochemically, the tumor cells were positive for beta-catenin, LEF-1, and PHLDA-1, consistent with their pilomatrical differentiation. We diagnosed the case as a giant pilomatrical tumor with uncertain malignant potential, considering its "contradictory" features, namely, the worrisome histoarchitecture, such as the asymmetrical silhouette, but bland-looking cytological appearance. Unlike typical pilomatrical tumors, this tumor contained numerous epidermal components with features similar to those of the dermal components, resulting in a unique macroscopic and histological appearance. Our case broadens the known histological diversity of pilomatrical tumors.

Putative Immunological Functions of Inducible Skin-Associated Lymphoid Tissue in the Context of Mucosa-Associated Lymphoid Tissue.

Acquired immunity is orchestrated in various lymphoid organs, including bone marrow, thymus, spleen, and lymph nodes in humans. However, mucosa-associated lymphoid tissue (MALT) is evolutionally known to be emerged in the oldest vertebrates as an immunological tissue for acquired immunity, much earlier than the advent of lymph nodes which appeared in endotherms. Furthermore, the lymphocytes which developed in MALT are known to circulate within the limited anatomical areas. Thus, MALT is comprehended as not the structure but the immune network dedicated to local immunity. As for the skin, skin-associated lymphoid tissue (SALT) was previously postulated; however, its existence has not been proven. Our group recently showed that aggregations of dendritic cells, M2 macrophages, and high endothelial venules (HEVs) are essential components to activate effector T cells in the murine contact hypersensitivity model and termed it as inducible SALT (iSALT) since it was a transient entity that serves for acquired immunity of the skin. Furthermore, in various human skin diseases, we reported that the ectopic formation of lymphoid follicles that immunohistochemically analogous to MALT and regarded them as human counterparts of iSALT. These data raised the possibility that SALT can exist as an inducible form, namely iSALT, which shares the biological significance of MALT. In this article, we revisit the evolution of immunological organs and the related components among vertebrates to discuss the conserved functions of MALT. Furthermore, we also discuss the putative characteristics and functions of iSALT in the context of the MALT concept.

Association of occupational direct radiation exposure to the hands with longitudinal melanonychia and hand eczema in spine surgeons: a survey by the society for minimally invasive spinal treatment (MIST).

PURPOSE: To investigate the association between occupational direct radiation exposure to the hands and longitudinal melanonychia (LM) and hand eczema in spine surgeons. METHODS: A web-based questionnaire survey of the Society for Minimally Invasive Spinal Treatment (MIST) in Japan was conducted. The proportion of LM and hand eczema in hands with high and low-radiation exposure was compared using Fisher's exact test. The odds ratios (ORs) and their 95% confidence intervals (CIs) for the prevalence of LM and hand eczema in the high-radiation exposure hands were calculated using generalized estimating equations for logistic regression as control for the correlation of observations among the same individuals and possible confounders. RESULTS: Among 324 members of the society, responses were received from 229 members (70.7%). A total of 454 hands from 227 participants were analysed. The prevalence of LM and hand eczema was 43% and 29%, respectively. In a hand-by-hand comparison, more hands had LM in the high-radiation exposure group than the low-radiation exposure group (90 [40%] vs. 39 [17%], respectively, p < 0.001). A similar trend was observed for hand eczema (63 [28%] vs. 33 [15%], respectively, p = 0.001). The adjusted OR for high-radiation exposure hands was 3.18 (95% CI: 2.24-4.52). Consistent results were obtained for hand eczema, with an adjusted OR of 2.26 (95% CI: 1.67-3.06). CONCLUSION: The present study suggests that direct radiation exposure to physician's hands is associated with LM and hand eczema. Those with LM and radially biased hand eczema may have had high direct radiation exposure.

Refractory serum immunoglobulin M elevation during anti-interleukin (IL)-1- or IL-6-targeted treatment in four patients with Schnitzler syndrome.

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1ß. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1ß or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.