Prominent dermal accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection.

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin κ and λ light chains. The present case suggests that when inflammatory cell infiltration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection.

Loss of RhoE Function in Dermatofibroma Promotes Disorganized Dermal Fibroblast Extracellular Matrix and Increased Integrin Activation.

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced ß1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of ß1 integrins, and depleting PLOD2 in T231M-RhoE-expressing cells reduced T231M-RhoE-mediated ß1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

COVID-19 infection- and vaccination-related exacerbation of Darier's disease in a single patient.

Darier's disease (DD) is a rare autosomal dominantly inherited disorder. DD patients usually present with widespread keratotic eruptions with itching in the seborrheic regions that are exacerbated by various factors, including heat, sweat, and physical trauma. The SARS-CoV-2 (COVID-19) pandemic has stirred confusion among the medical community, including dermatologists, as this infection has been implicated in various skin conditions. Only a handful of reports have documented DD associated with COVID-19. Here, we report a 30-year-old male with Darier's disease whose symptoms were exacerbated following both COVID-19 vaccination and COVID-19 infection. The patient had noticed slight eruptions 7 years prior, but was not particularly concerned. After COVID-19 vaccination and infection, he had erythematous maculopapular lesions in large areas of the trunk and extremities. The previously reported pathogenic variant c.2255_2257del (p.(Ile752_Tyr753delinsAsn)) in ATP2A2 was detected in the present patient. Oral etretinate greatly improved his DD manifestations. As far as we know, the present patient is the first genetically confirmed DD case who showed both COVID-19 infection- and vaccination-related DD exacerbations independently. We think that the further accumulation of DD cases exacerbated by COVID-19 infection/vaccination is needed to clarify the mechanisms of DD aggravation.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies.

Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Two novel anti-aminoacyl tRNA synthetase antibodies: Autoantibodies against cysteinyl-tRNA synthetase and valyl-tRNA synthetase.

Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with inflammatory myopathies. Since the myositis of anti-ARS-positive patients is characterized by a unique set of non-myopathic manifestations, including interstitial lung disease, mechanic's hands, and arthralgia, the patients are classified as having anti-synthetase syndrome. Autoantibodies have been identified to eight kinds of ARSs. Of the other 12 ARSs, eight are components of the "OJ" multi-synthetase complex. Autoantibodies to the four remaining ARSs (CysARS, ValARS, SerARS, and TrpARS) have not been reported to be present in patients with inflammatory myopathies. In this study, we first screened samples from more than 300 Japanese patients majorly consisting of those with dermatomyositis (DM) by our established in-house ELISA to find autoantibodies against the four ARSs described above. Since sera from two DM patients specifically reacted to CysARS or ValARS, we determined their reactivities by immunoprecipitation (IP) with the corresponding recombinant proteins and IP-Western blotting with cellular extract. One patient had several features found in anti-synthetase syndrome, but the other did not. The clinical differences among the various anti-ARS antibodies should be explored in a future work.

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1ß Antibody.

NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1ß upregulation and IL-1ß-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1ß antibodies before UVB irradiation. UVB irradiation and the IL-1ß pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

Darier disease successfully treated with a topical agent containing vitamin A (retinyl palmitate), vitamin E, and urea.

Darier disease (DD), also called keratosis follicularis, is an autosomal dominant hereditary keratinization disorder that manifests as keratotic papules with plaques in seborrheic areas. There are no validated curative treatments for DD, with the majority of cases treated symptomatically. We report the efficacy of a topical over-the-counter agent which contains retinyl palmitate, vitamin E, and urea for a patient with DD. A 13-year-old girl had brown papules on her scalp, neck, shoulders, and axillae since entering elementary school. A skin biopsy revealed hyperkeratosis, suprabasal acantholysis, and dyskeratosis manifested as corps ronds and grains in the epidermis. Sanger sequencing found the previously reported heterozygous mutation c.1484C>T in ATP2A2. The application of an over-the-counter topical agent containing retinyl palmitate 2750 µg/g (5000 IU/g), tocopheryl acetate 20 mg/g, urea 200 mg/g, and monoammonium glycyrrhizinate 5 mg/g twice daily for 2 months improved the papules without serious adverse events. Oral or topical aromatic vitamin A analogs (retinoids) are often used to treat DD. However, several adverse events are associated with retinoid treatment, and many patients only undergo their intermittent use or discontinue the treatments. Retinyl palmitate is more stable and has a lower irritative profile than other retinoic acids. When applied topically, however, retinyl palmitate cannot penetrate the skin as well as retinol can. Some reports have noted that vitamin E increases the biological availability of vitamin A and that urea helps mechanical percutaneous drug delivery. Our case suggests that retinyl palmitate has a sufficient therapeutic effect when combined with vitamin E and urea. In conclusion, we propose that topical agents containing retinyl palmitate, vitamin E, and urea might have a satisfactory effect on the skin lesions of DD patients, without the serious risks of adverse events.

Differential Pathomechanisms of Desmoglein 1 Transmembrane Domain Mutations in Skin Disease.

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia.

OBJECTIVE: Anti-NOR90 antibodies are usually found in patients with SSc; however, their clinical relevance remains obscure. We developed an ELISA for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. METHODS: Serum samples from 1252 patients with various conditions from Nagoya University Hospital and 244 patients with idiopathic interstitial pneumonia (IIP) from Tosei General Hospital were included. Anti-NOR90 antibodies were assayed by an ELISA using the recombinant protein produced by in vitro transcription/translation. RESULTS: Five (0.4%) patients in the Nagoya University Hospital cohort had anti-NOR90 antibodies. One patient with diffuse cutaneous SSc, three with limited cutaneous SSc, and one with Raynaud's disease were positive for anti-NOR90 antibodies. Anti-NOR90 antibodies were found more frequently in patients with systemic scleroderma-spectrum disorders (SSDs) than without SSDs (5/316 vs 0/936, P <0.00101) and were found more frequently in patients with SSc than without SSc (4/249 vs 0/528, P <0.0104) in the systemic autoimmune rheumatic diseases cohort. Three of the four anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and two of those four had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All three of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and two of those three had cancer or skin lesions observed in SSc. CONCLUSIONS: Although anti-NOR90 antibodies are rarely found in clinics, our ELISA is useful for their detection. Further studies are needed to confirm the association of anti-NOR90 antibodies with ILD and cancer in SSc and IIP patients.