Tsukasa Ugajin

Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks

Ticks are ectoparasitic arthropods that can transmit a variety of microorganisms to humans and animals during blood feeding, causing serious infectious disorders, including Lyme disease. Acaricides are pharmacologic agents that kill ticks. The emergence of acaricide-resistant ticks calls for alternative control strategies for ticks and tick-borne diseases. Many animals develop resistance to ticks after repeated infestations, but the nature of this acquired anti-tick immunity remains poorly understood. Here we investigated the cellular and molecular mechanisms underlying acquired resistance to Haemaphysalis longicornis ticks in mice and found that antibodies were required, as was IgFc receptor expression on basophils but not on mast cells. The infiltration of basophils at tick-feeding sites occurred during the second, but not the first, tick infestation. To assess the requirement for basophil infiltration to acquired tick resistance, mice expressing the human diphtheria toxin receptor under the control of the mast cell protease 8 (Mcpt8) promoter were generated. Diphtheria toxin administration to these mice selectively ablated basophils. Diphtheria toxin-mediated basophil depletion before the second tick infestation resulted in loss of acquired tick resistance. These data provide the first clear evidence, to our knowledge, that basophils play an essential and nonredundant role in antibody-mediated acquired immunity against ticks, which may suggest new strategies for controlling tick-borne diseases.

Basophils preferentially express mouse mast cell protease 11 among the mast cell tryptase family in contrast to mast cells

Tryptases and chymases are the major proteins stored and secreted by mast cells, and they have various biological functions. However, the nature of proteases produced by basophils has been poorly characterized, particularly in mice. mMCP‐11 is the most recently discovered mast cell tryptase in mice and was originally identified as Prss34, which is transcribed in some mast cell‐like cell lines and at the early stage in the culture of BMMC with IL‐3. Curiously, Prss34 is preferentially expressed in the BM and spleen among normal tissues in contrast to other mast cell tryptases. Therefore, it remains elusive what types of cells express mMCP‐11 in vivo. Here, we show that mMCP‐11 is highly expressed by primary basophils and to a much lesser extent, by some mast cells. Prss34 transcripts were detected abundantly in primary and cultured basophils and very weakly in peritoneal mast cells or cultured BMMC. Conversely, transcripts for mMCP‐6 and mMCP‐7 tryptases were preferentially expressed by cultured and peritoneal mast cells but not basophils. We established a mMCP‐11‐specific mAb and showed that mMCP‐11 proteins are indeed expressed by primary basophils and those infiltrating the affected tissues during allergic inflammation and parasitic infections. Some primary mast cells also expressed mMCP‐11 proteins, albeit at a much lower level. Thus, basophils rather than mast cells are the major source of mMCP‐11. This is the first study to demonstrate that mouse basophils produce a trypsin‐like protease.

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitro-cultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE + antigen (Ag), but not to IgG + Ag. Release of PGs was almost completely abrogated in cultured basophils from FcRγ-chain(-/-) mice, indicating the involvement of FcεRI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/PGE2 and may contribute to allergic inflammation and immune responses.

Two siblings with neonatal pemphigus vulgaris associated with mild maternal disease.

ment to < 3Æ0 mg L after the first infusion. Linear psoriasis is a rare phenomenon and its existence has been discussed for some time. Our diagnosis was based on the classic clinical picture of skin lesions with concomitant psoriatic arthritis and nail dystrophy. Skin biopsy was consistent with psoriasis and no typical signs of inflammatory linear verrucous epidermal naevus were present. The onset of guttate psoriasis after a throat infection also confirms the diagnosis. The coincidence of linear psoriasis and psoriatic arthritis has not been reported in the literature to date. Clinical response of our patient to infliximab was dual. The arthritis symptoms completely disappeared under therapy and have not re-occurred but improvement of the skin lesions remains delayed. Tumour necrosis factor (TNF)-a antagonists are a relatively new therapeutic option for the treatment of severe psoriatic arthritis and chronic plaque-type psoriasis. Treatment with these agents is well established for rheumatoid arthritis and Crohn’s disease and in recent years TNF-a inhibitors have also been efficacious in the treatment of juvenile idiopathic arthritis. To date, no clinical studies on the efficacy and safety of infliximab in children with psoriatic arthritis or chronic plaquetype psoriasis have been published. Previous data about the efficacy of TNF-a antagonists in the treatment of children with refractory juvenile idiopathic arthritis showed a significant improvement of articular signs and symptoms and indicate that these drugs might offer an important clinical advance in the treatment of paediatric rheumatoid diseases in the future. It has also been shown that TNF-a inhibitors in combination with methotrexate can arrest the progression of structural damage and even improve radiographic joint damage. Therefore patients with severe forms of arthritis and rapid disease progression should benefit from early treatment with these drugs, which may lead to significant improvements in functional disability and quality of life. Long-term safety and efficacy, however, remain unknown at present and more clinical studies are needed to prove the currently documented low degree of side-effects over a longer period of time.

Zinc-binding metallothioneins are key modulators of IL-4 production by basophils.

Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcɛRI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcɛRI-mediated regulation of basophil IL-4 production are currently unclear. Here, we show that the Zn-binding metallothionein (MT) proteins are essential for the FcɛRI-induced basophil production of IL-4. Basophils from MT-I/II(-/-) mice produced significantly less FcɛRI-induced IL-4 than did wild-type basophils. The MTs were involved in maintaining intracellular Zn levels, thereby regulated the calcineurin activity and nuclear factor of activated T-cell (NFAT)-mediated IL-4 production. These results suggest that the MT-dependent control of Zn homeostasis is a novel mechanism for regulating basophil IL-4 production.

Basophil-derived mouse mast cell protease 11 induces microvascular leakage and tissue edema in a mast cell-independent manner.

Mouse mast cell protease 11 (mMCP-11) is the most recently identified member of the mouse mast cell tryptase family. This tryptase is preferentially produced by basophils in contrast to other members that are expressed by mast cells but not basophils. Although blood-circulating basophils have long been considered as minor and redundant relatives of tissue-resident mast cells, recent studies illustrated that basophils and mast cells play distinct roles in vivo. To explore the in vivo role of basophil-derived mMCP-11, here we prepared recombinant mMCP-11 and its protease-dead mutant. Subcutaneous injection of the wild-type mMCP-11 but not the mutant induced edematous skin swelling with increased microvascular permeability in a dose-dependent manner. No apparent infiltration of proinflammatory cells including neutrophils and eosinophils was detected in the skin lesions. The cutaneous swelling was abolished by the pretreatment of mice with indomethacin, a cyclooxygenase inhibitor, suggesting the major contribution of prostaglandins to the microvascular leakage. Of note, the cutaneous swelling was elicited even in mast cell-deficient mice, indicating that mast cells are dispensable for the mMCP-11-induced cutaneous swelling. Thus, basophil-derived mMCP-11 can induce microvascular leakage via prostaglandins in a mast cell-independent manner, and may contribute to the development of basophil-mediated inflammatory responses.

A case of bullous pemphigoid associated with infiltration and activation of basophils.

DEAR EDITOR, We appreciate the interest from and comments by Dr Naldi about our work recently published in the BJD, which suggested that preservation of the deep fascia in melanomas thicker than 2 mm (excised with a 1-cm excision margin) is safe and results in a similar outcome to fascia excision. Balancing function, morbidity and cosmetics with oncological outcomes in melanoma management requires careful decision making with respect to determining the appropriate method of excision. Inadequate excision might lead residual tumour cells to a local recurrence of metastases, a life-threatening process (60–80% of such patients eventually die as a result of their disease). However, unnecessary tissue excisions are associated with greater morbidity and might lead to bad functional and cosmetic results. Unfortunately, the optimal depth of excision remains unknown, and the current melanoma guidelines do not make direct recommendations on the depth of excision. Therefore, this lack of evidence-based data causes significant heterogeneity among surgeons, even in a single centre, with regard to the removal or preservation of the deep muscular fascia at the time of wide local excision for primary cutaneous thick melanomas. It is obvious that randomized controlled trials (RCTs) are the reference standard to assess efficacy. Furthermore, the establishment of new protocols and dramatic modification of currently approved melanoma guidelines should only be performed carefully after the implementation of prospective randomized multicentric clinical trials. However, despite several limitations (being retrospective, nonrandomized, and having limited statistical power and a relatively short follow-up), the results of our study addressed this neglected issue and highlighted possible hope for the future, and may provoke the melanoma centres to set up new, large-scale RCTs with longer follow-ups in order to overcome the controversial issue of the correct depth of melanoma excision.

Case of psoriasiform and pustular eruptions in addition to alopecia as a paradoxical reaction induced by infliximab

nosis of PPLP. However, we could not find any triggering factor for the development of LP, including drug, viral infection and contact allergy, in our patient. Because our patient had been diagnosed with GVHD before he developed the skin lesions on his palm, we considered PPLP-like GVHD, which has not been reported previously. After 2 months of potent topical steroid ointment, the lesions showed marked improvement. Palmoplantar lichen planus is a rare, localized variant of LP. Although PPLP has a broad spectrum of clinical manifestations, self-limiting, pruritic, desquamative erythematous plaques with well-defined borders are very characteristic. The lesions are usually located on the internal arches of the feet, thenar and hypothenar eminences, and central palm. Because PPLP has various clinical features, including erythematous plaque, punctate keratosis and diffuse keratosis, without the classical features of LP, including polygonal papules and Wickham’s striae, the diagnosis of PPLP is often challenging. Our patient had well-demarcated erythematous scaly plaques on both hypothenar eminences, which is a characteristic clinical feature of PPLP. However, owing to the overlap of the clinical and histological features of LP and lichenoid-type GVHD, differentiation between the two disorders is often impossible. In our patient, the temporal relationship between the haploPBSCT and the development of his rash and preceding chronic GVHD symptoms suggest that the PPLP-like lesions were associated with chronic GVHD. Our case suggests that localized PPLP is a possible clinical presentation of chronic GVHD.

A case of peripheral T-cell lymphoma, not otherwise specified, with rapid progression to erythroderma

EJD, vol. 28, n◦ 2, March-April 2018 external iliac artery to the abdominal aorta, from where a pelvic arteriogram was performed to delineate the arterial anatomy, including the uterine artery and ovarian artery. The catheter was directed down to the left uterine artery, which was embolized with a gelatin sponge. Then, the catheter was directed to the right uterine artery, which was embolized after the left uterine artery. The size of the gelatin sponge was estimated to be 0.5-1 mm. Angiography showed that an anastomosis developed between the left and the right uterine arteries (figure 1E; arrowheads), and the branching points of the left superior gluteal artery and left uterine artery were very close (figure 1F, black arrows). Therefore, when the gelatin sponge passed the right uterine artery, with the left uterine artery clogged, we considered that it flowed into the left uterine artery through the anastomosis, travelled backwards, entered into the left upper gluteal artery, and also flowed into the left lower gluteal artery. For this reason, we considered that the erythema, which appeared on the buttocks, was predominant on the left side. Whereas polyvinyl alcohol is commonly used in other countries for uterine artery embolization, gelatin sponge is used in Japan. Gelatin sponge dissolves in about two to four weeks, therefore this may be the reason why the lesions of our patient disappeared within two weeks. The reported complications of uterine artery embolization include side effects of angiography, infection, fibroid passage, deep venous thrombosis, pulmonary embolism, and permanent amenorrhoea [1]. Although two cases of necrosis on the buttocks and one case of labial necrosis after uterine artery embolization have been reported [24], to our knowledge, this is the first case of erythema nodosum-like eruption after uterine artery embolization. When erythema is observed in the buttocks of a female after uterine artery embolization, careful medical history should be obtained in order to reveal the nature of the embolic substance.

Bilirubin oxidation derived from oxidative stress is associated with disease severity of atopic dermatitis in adults

Bilirubin is an essential antioxidant. Its oxidative metabolites, biopyrrins, are sensitive urinary markers of oxidative stress. Multiple studies suggest that oxidative stress affects the pathogenesis of skin diseases such as atopic dermatitis (AD).