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Abstract: As anti-cytokine therapies were developed for clinical use during the last decade, anti-IL-1 therapies have emerged as a highly effective treatment for cryopyrin-associated periodic syndromes (CAPSs), including the “urticaria-like rash.” Based on clinical observations, we hypothesized that NLPR3 activation and IL-1β production, in particular in mast cells (MCs), are important for the development of this eruption, due to the observation that CAPS patients have gain-of-function mutations in NLRP3 that result in unregulated excess levels of IL-1β. To further address our hypothesis, we employed gene-targeted mice carrying Nlrp3 mutations and found that signaling in MCs following bacterial colonization of skin is essential for IL-1β-dependent inflammation. Intradermal administration of a molecule that induces the release of granule-associated molecules from MCs showed that MCs and TNF-α were necessary for the inflammation in CAPS-mimicking mice. However, adult CAPS mice exhibited a persistent skin phenotype and did not respond to anti-TNF-α antibody, indicating that TNF-α is important only for the onset of the disease and is dispensable during the chronic phase of CAPS. Thus, in this review, we highlight our recent findings on how MCs play an important role, not only in ordinary urticaria, but also in the “urticaria-like rash” associated with NLRP3 mutations. [Copyright &y& Elsevier]

Mast cells are widely distributed throughout the body, being preferentially localized at host–environment interfaces. They have long been known as major effector cells in IgE-mediated allergic responses. However, accumulating evidence has provided many new insights into their functions. They are now known to be involved in diverse pathological processes, for example, innate and adaptive immunity. Utility of mast cell-deficient mice and mast cell-knock-in mice has provided powerful models to demonstrate compelling evidence for their in vivo relevance. Conversely, primary cultures of tissue-derived mast cells provide excellent models for in vitro studies of functions at both cellular and molecular levels. Because mast cells exhibit phenotypical and functional heterogeneity in different anatomical sites, it is important to obtain tissue-specific mast cells to clarify their function in tissue. In this regard, researchers have established several methods to prepare mast cells from different tissues, which are technically difficult to obtain at high purity and yield. To overcome these difficulties, we have developed a primary culture system to obtain large numbers of mast cells at high purity from murine fetal skin. In this review, we describe characteristics of such mast cells and their utility in mast cell biology.Journal of Investigative Dermatology (2009) 129, 1120–1125; doi:10.1038/jid.2009.44; published online 26 February 2009 [ABSTRACT FROM AUTHOR]

Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear. We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples. Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison. Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ–dependent accelerated inflammatory responses. Comparisons of peripheral blood– and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature. IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB–driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS. [ABSTRACT FROM AUTHOR]

Summary: Pattern-recognition receptors are a first line of defense against invading pathogens. Recent advances in the understanding of innate immunity have revealed a novel family of cytosolic pattern-recognition receptors called Nods, which contain an amino-terminal effector-binding domain, a centrally located nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal ligand recognition domain. Hereditary mutations of Nods have been reported in patients with certain inflammatory diseases; for example, Nod2 mutations are associated with the inflammatory granulomatous disorders, Crohn''s disease and Blau syndrome. Missense mutations of Nod2 are also associated with early-onset sarcoidosis, a rare but sporadic disease. Because Nod2 is predominantly expressed in monocytes and recognizes a component of bacterial peptidoglycan, analysis of its function may help in understanding the role of the immune system in granuloma formation. [Copyright &y& Elsevier]

Human cord blood-derived mast cells (HCMC) grown in medium with serum and recombinant human stem cell factor (rhSCF) with or without interleukin (IL)-6 are less mature than human skin mast cells (HSMC). We found that e-kit-positive HCMC cultured for 8-10 weeks with rhSCF in serum-free medium became sensitive to basic secretatogues and expressed the serine protease, chymase, which is preferentially expressed in HSMC. The HCMC release β-hexosaminidase (β-HEX) within 1 min of stimulation with compound 48/80 or substance P, and release was suppressed by pertussis toxin. Approximately 34% of the HCMC in the serum-free culture stained positively with chymase antibody. Chymase and e-kit levels, and responsiveness to basic secretagogues, increased substantially after an additional 2 weeks in a serum-free environment with rhIL-6 and rhSCF. Moreover, FCεRI-dependent activation of the HCMC resulted in induction of cytokines and cyclooxygenase-2. These results show that HCMC can differentiate into a phenotype morphologically and functionally similar to HSMC if exposed to SCF in serum-free medium. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory skin disease arising from a complex interplay of genetic, immune, and environmental factors. The development and successful marketing of the anti-IL-4/IL-13 monoclonal antibody, dupilumab, and the topical nonsteroidal phosphodiesterase 4 (PDE4) inhibitor, crisaborole, as well as the Janus kinase (JAK) inhibitor, delgocitinib, have brought hope for developing new therapeutic agents. The efficacy of these treatments contributes to our understanding of the pathophysiology of AD. Dupilumab modulates the Th2-related immune response, demonstrating that IL-4 and IL-13 contribute to epidermal hyperplasia, skin homeostasis, and innate immune responses on the skin surface in AD. The effectiveness of crisaborole reveals that PDE4 contributes to Th2 and Th17/Th22 inflammation and lesional skin barrier dysfunction, while delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in AD. This review provides a brief overview of recent research on therapeutic monoclonal antibodies and small biologic molecules for AD and what these treatments reveal about AD pathophysiology. [ABSTRACT FROM AUTHOR]

Adult mastocytosis is usually persistent and caused by c-KIT codon 816–activating mutations. Pediatric mastocytosis is often transient, and the molecular mechanism driving mast cell proliferation in pediatric cases remains unclear. In this issue, Bodemer et al. report novel c-KIT mutations in a large percentage of pediatric cases, identifying both similarities and fundamental differences in the mechanisms causing adult and pediatric mastocytosis. [ABSTRACT FROM AUTHOR]

A 27-year-old Japanese man developed multiple lichenoid papules, fusing into scaly erythematous plaques, over his entire body. In infancy he had been diagnosed with atopic dermatitis and juvenile rheumatoid arthritis. Although the skin disease had almost disappeared afterwards, disorder of the joints and associated eyes involvement had progressively worsened. Although hilar lymphoadenopathy was not apparent on a chest roentgenogram, the transbronchial lung biopsy specimen also demonstrated the presence of non-caseating granulomas.