IgG anti-Pentraxin 3 antibodies are a novel biomarker of ANCA-associated vasculitis and better identify patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: To investigate prevalence of anti-Pentraxin 3 (PTX3) antibodies in sera of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. METHODS: Anti-PTX3 and PTX3 levels were analysed by enzyme-linked immunosorbent assays in sera from unselected patients with AAV and compared with patients with systemic lupus erythematosus (SLE, n = 130), other connective tissue diseases (CTDs, n = 97) and matched healthy controls (n = 97). Optical density (OD) cut-off for positive anti-PTX3 antibodies was determined by ROC curve analysis and set as 0.234. Indirect immunofluorescence (IIF) on fixed human granulocytes was used to analyze the fluorescence pattern of anti-PTX3 antibodies. Liquid-phase inhibition tests were conducted to assess potential interferences. RESULTS: We included 101 AAV patients (females 58%, median age 60[51-69] years) affected either with granulomatosis with polyangiitis (GPA, n = 51), microscopic polyangiitis (MPA, n = 12) or eosinophilic granulomatosis with polyangiitis (EGPA, n = 38). Anti-PTX3 antibodies were detected in 29.7% AAV patients, being significantly higher than in healthy controls (p < 0.001) and CTDs (p = 0.030) but lower than in SLE (p = 0.004). Anti-PTX3 antibody prevalence was 44.7% in EGPA, 25% in MPA and 19% in GPA (p = 0.034). Among ANCA negative patients, 35.7% displayed positive anti-PTX3 antibodies. Anti-PTX3 were associated with a lower prevalence of systemic (p = 0.002), ear-nose-throat (p = 0.006) and renal manifestations (p = 0.016). Anti-PTX3 antibodies were characterized by a specific IIF pattern on fixed granulocytes. PTX3 serum levels resulted lower in AAV than healthy controls (p < 0.001). PTX3 inhibited anti-PTX3 binding in a dose-dependent manner. CONCLUSIONS: Anti-PTX3 autoantibodies appear a promising novel biomarker of AAV, especially EGPA.

Histopathologic reaction patterns to differentially cross-linked hyaluronic acid fillers: A retrospective case series.

BACKGROUND: Hyaluronic acid filler reactions have been increasingly observed in recent years. Our study investigates whether the increased number of filler reactions observed since 2014 is associated with a specific histopathologic inflammatory pattern and type of filler. METHODS: The institution's dermatopathology electronic database was retrospectively searched for histopathologic reactions to hyaluronic acid from January 2014 to December 2019. The age, sex, type of filler, procedure, location, and histopathologic patterns were recorded. RESULTS: From 2014 to 2019, there were 15 cases of granulomatous reactions to hyaluronic acid filler. In 10 of these cases, there was a characteristic inflammatory pattern characterized by tightly cuffed palisades of histiocytes with varying numbers of eosinophils. Of the 11 cases in which the type of filler was known, all used Vycross technology, a novel manufacturing process in the production of hyaluronic acid filler. CONCLUSION: A characteristic histopathologic pattern of discrete foci of tightly cuffed palisaded granulomas with eosinophils is associated with fillers manufactured using Vycross technology.

Testicular infarction and pulmonary embolism secondary to nonasthmatic eosinophilic granulomatosis with polyangiitis: a case report

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Production of interleukins 4 and 10 in children with hepatic involvement in the course of Toxocara spp. infection.

Toxocara spp. infestations present with a wide spectrum of symptoms, from general inflammation of internal organs with eosinophilic granuloma formulation through ocular or brain involvement. There is also an asymptomatic form. The known factors that influence the clinical form of the disease are the intensity of the infestation, the localization of the larvae, the age of the patient, the efficiency of the immune system and the history of reinfection. The aim of our study was to evaluate the production of interleukins 4 (IL-4) and 10 (IL-10) in children in the course of Toxocara spp. infections with hepatic involvement. The analysis of peripheral leucocytes, eosinophils, immunoglobulin E, and IL-4 and IL-10 concentrations presented significantly higher values in children with radiologically confirmed liver granuloma than in uncomplicated hepatomegaly. Based on statistical analysis, we confirmed the IL-4/IL-10 ratio variation in the analysed groups: patients with liver lesions showed a ratio of <1, while children without granulomas had a ratio of >2. The relevant analysis confirmed a positive statistical correlation in both seropositive groups for IgE and IL-4, and only in the granuloma group for IgE and IL-10.

An increase of CD83+ dendritic cells ex vivo correlates with increased regulatory T cells in patients with active eosinophilic granulomatosis and polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by the presence of allergic granulomatosis and necrotizing vasculitis with eosinophilic infiltration. The etiology of EGPA is unknown. Dendritic cells (DCs) are not only critical for the induction of primary immune responses; they may also be important for the induction of immunological tolerance and the regulation of the type of T-cell-mediated immune response. To investigate whether DC maturation is associated with EGPA disease status, we examined the relationship between the maturation of DCs and the differentiation of regulatory T (Treg) cells in EGPA patients. We exposed the CD14+ blood monocytes of 19 patients with EGPA in remission or relapse to stimulation with GM-CSF and IL-4 for 6 d and lipopolysaccharide for 24 h to obtain mature CD83+ DCs and immature CD206+ DCs. Using immunohistochemistry, we examined four patients for the presence of CD83+ and CD206+ DCs in the lung at the onset of EGPA. RESULTS: The percentage of CD83+ cells among DCs differentiated from CD14+ monocytes was lower for EGPA patients in relapse than in remission. The percentage of CD83+ DCs was inversely correlated with the percentage of CD206+ DCs and was significantly correlated with the numbers of naturally occurring CD4+ regulatory Treg (nTreg; FOXP3+CD4+) cells and inducible Treg (iTreg; CD4+CD25+ T cells producing IL-10 or TGF-ß) cells but not the number of eosinophils. The percentage of CD206+ DCs was significantly inversely correlated with the percentages of nTreg and iTreg cells but not the number of eosinophils. Immunohistochemistry revealed both CD206+ DCs and CD83+ DCs in alveoli and interstitial spaces at the onset of EGPA. CONCLUSION: The maturation of DCs from monocytes was related to disease activity in patients with EGPA. Increased CD83+ DCs in EGPA patients may induce the differentiation of iTreg and nTreg cells, thereby suppressing inflammation and disease activity.

Increased interleukin-27 production by antigen-presenting cells promotes regulatory T cell differentiation and contributes to inducing a remission in patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: We investigated the cytokine production profiles of antigen-presenting cells (APCs) and the status of patients with eosinophilic granulomatosis with polyangiitis (EGPA) in order to identify the cytokine profile that contributes to inducing differentiation of CD4(+) effector Th cells and regulatory T cells. METHODS: We counted the number of CD4(+)FOXP3(+) T cells, CD4(+)CD25(+)CTLA-4(+) T cells, CD4(+) T cells that predominantly produce IL-10 (Tr1 cells) and IL-17 (Th17 cells) and monocytes and monocyte-derived dendritic cells (mDCs) expressing Toll-like receptor (TLR)2 and TLR4 in the peripheral blood of 47 EGPA patients and 40 bronchial asthma patients (who did not have EGPA) and calculated the percentages of monocytes and mDCs that produced IL-23p19 and IL-27 in response to lipopolysaccharide (LPS) stimulation. RESULTS: Lower TLR4 expression was observed on the monocytes of relapsed EGPA patients and lower expression of both TLR2 and TLR4 on their mDCs than on the cells from EGPA patients in remission or non-EGPA patients. The percentages of monocytes expressing TLR4 were positively correlated with the percentages of regulatory T cells in peripheral blood. In addition, the percentages of monocytes and the percentages of mDCs that produced IL-27 and IL-23p19 in response to LPS stimulation were positively correlated with the percentages of Tr1 cells and Th17 cells in peripheral blood. A positive correlation was also found between the percentages of mDCs that produced IL-27 and the percentages of Tr1 cells. CONCLUSION: Increased dominancy of IL-23p19 and IL-27 production by the APCs of EGPA patients may be linked to differentiation of Th17 cells and Tr1 cells.

High-dose intravenous immunoglobulin treatment increases regulatory T cells in patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: We studied the effects of intravenous immunoglobulin (IVIG) treatment on clinical symptoms and regulatory T (Treg) cell frequency in patients with eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Twenty-two EGPA patients with severe mononeuritis multiplex or cardiac dysfunction received IVIG therapy combined with conventional therapy (corticosteroid, immunosuppressants, or both). As a control, 24 EGPA patients without severe vasculitic symptoms were treated with conventional therapy. Before, during, and after treatment, we determined percentages of Treg cells and other relevant cells in patients' peripheral blood. RESULTS: The frequency of CD25+ among CD4+ T cells was lower at onset in the study group than in controls but increased significantly after IVIG treatment, relative to controls. The frequency of CD25+ among CD4+ T cells correlated with the frequency of FOXP3+ among CD4+ T cells and interleukin 10 produced by CD25+CD4+ T cells. CONCLUSION: The increase in Treg cells seen with the combination of IVIG and conventional therapy may promote remission in EGPA.

Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation?

Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting the tongue. It has been suggested to represent a reactive pattern to several stimuli. We report on a 12-year-old boy who presented with a painless infiltrating ulcer on the gingiva of the lower jaw, which was covered by necrotic yellowish slough. There were no pathologic features of the jawbones or regional lymph nodes. Histopathological, immunohistochemical and gene rearrangement studies were in agreement with eosinophilic ulcer with predominant oligoclonal CD3+ and CD30+ T lymphocytes expressing the Epstein-Barr virus membrane protein. The ulcer resolved within 4 weeks and follow-up for 3 years revealed no evidence of recurrence. Epstein-Barr virus may have played a role in triggering this reactive lymphoproliferative disorder.

Traumatic ulcerative granuloma with stromal eosinophilia of the oral mucosa: histological and immunohistochemical analysis of three cases.

Traumatic ulcerative granuloma with stromal eosinophilia is an ulcerated oral lesion which pathogenesis is still unclear. Clinically, this disease is characterized by the presence of chronic ulcerative lesions with elevated and indurated borders in the oral mucosa. It usually develops rapidly and persists for several weeks or months, it presents mainly on the tongue but other areas such as gingival, cheek and vestibular mucosa may also be involved. We report three cases showing their clinical, histological and immunohistochemical analysis. In this study the authors underline the importance of a correct differential diagnosis and monitoring of these patients in order to prevent the development of possible serious complications.

Increase of mast cells may be associated with infiltration of eosinophils and proliferation of microvessels in gastric eosinophilic granuloma.

BACKGROUND: Gastric eosinophilic granuloma (GEG) is a rare disease. Recently this disease has begun to increase in China. In the present study, the function and the role of mast cells (MC) in the pathogenesis of GEG were investigated. METHODS: Paraffin-embedded tissue sections from 23 GEG patients and 15 gastric ulcer (GU) patients, were stained with antihuman mast cell tryptase for counting the MC and degranulated MC. Antihuman CD34 antibody was used for detecting the microvessel density (MVD) with immunohistochemical technique. Mast cell degranulation was also studied using electron microscopy. RESULTS: The quantity of both MC and degranulated MC were higher in both GEG and GU than in normal gastric mucosa. The proportion of degranulated MC was higher in the GEG but in GU it was similar to normal mucosa. The MVD was higher in both GU and GEG than that in the normal gastric mucosa and it was higher in the high-MC group than in the low-MC group in GEG. The positive correlation between eosinophil and MC was present only in GEG, not in GU. CONCLUSIONS: The infiltration of eosinophils and MVD may be associated with the increase of MC in GEG. This suggests that in addition to eosinophils, MC might be the important cells in the pathogenesis of GEG.

Evaluation of Felis domesticus allergen I as a possible autoallergen in cats with eosinophilic granuloma complex.

OBJECTIVE: To investigate the role of Felis domesticus allergen I (Feld I) in the pathogenesis of eosinophilic granuloma complex (EGC) in cats. ANIMALS: 7 healthy cats and 6 cats with EGC. PROCEDURE: Epidermis was removed from 4 areas. Rubber stoppers filled with Feld I, saline (0.9% NaCl) solution, and PBS solution were glued to the skin lesions and removed 48 hours later. Fluid within each stopper was collected. Biopsy specimens were obtained at each site, snap frozen, and stored at -70 C. Total and differential numbers of cells in fluid were counted. Biopsy specimens were stained by use of monoclonal antibodies against feline CD4, CD8 and CD3. Data were analyzed by use of multivariate repeated-measures analysis. RESULTS: Healthy cats had a significant increase in number of CD3+ cells, compared with number of CD4+ and CD8+ cells, and Feld I caused a significant increase in number of CD3+ cells, compared with PBS or saline solutions. Cats with EGC had a significant increase in number of CD3+ cells, compared with number of CD4+ and CD8+ cells, and Feld I caused a significant increase in number of CD3+ and CD4+ cells, compared with PBS or saline solutions. Cats with EGC had an increased CD4+ response, a significantly decreased CD8+ response, and a significantly increased CD4-to-CD8 ratio compared with healthy cats. CONCLUSIONS AND CLINICAL RELEVANCE: The increased CD4+ response, significantly decreased CD8+ response, and significantly increased CD4-to-CD8 ratio are comparable to results in atopic people and allergic cats. Therefore, Feld I could be an autoallergen responsible for chronic inflammatory reactions in cats with EGC.

Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent.

Experimental Schistosoma mansoni infections of mice lead to a dynamic type 2 cytokine-mediated pathological process. We have used IL-4-deficient, IL-13-deficient, and IL-4/13-deficient mice to dissect the role of these cytokines in the development of immune response and pathology following S. mansoni infection. We demonstrate that while both of these cytokines are necessary to develop a robust Th2 cell-driven, eosinophil-rich granuloma response, they also perform disparate functions that identify novel sites for therapeutic intervention. IL-13-deficient mice demonstrated significantly enhanced survival following infection, which correlated with reduced hepatic fibrosis. In contrast, increased mortality was manifest in IL-4-deficient and IL-4/13-deficient mice, and this correlated with hepatocyte damage and intestinal pathology. Therefore, we demonstrate that during a dynamic type 2 cytokine disease process IL-13 is detrimental to survival following infection, whereas IL-4 is beneficial.

Injection site eosinophilic granulomas and collagenolysis in 3 horses.

Three horses were presented with a history of having developed raised cutaneous nodules, within 24-48 hours, in areas of previous injections using standard silicone-coated hypodermic needles. Skin biopsies were taken from a selected cutaneous nodule from all horses for histopathologic evaluation. Histologically, the nodules were consistent with a diagnosis of equine eosinophilic granuloma. A hypersensitivity reaction to the silicone, or another component of the coating formulation, was hypothesized to be responsible for these lesions. Two horses were experimentally injected using both coated and noncoated stainless steel hypodermic needles and skin biopsies were obtained 14 days after injection. The sites of the coated needle injections were characterized by severe eosinophilic granulomatous inflammation with and without collagenolysis. The eosinophilic granulomas with and without collagenolysis observed in these horses are proposed to represent a complex immunologic response to the silicone-based coating of most hypodermic needles.

Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice.

The spontaneous development of insulin dependent diabetes mellitus in non-obese diabetic (NOD) mice has been shown to be mediated by a Th1 response against beta cell antigens. It is known that in murine models of Schistosoma mansoni infection, egg production is associated with a switch from a Th1 to Th2 response. This subsequent dominance of a Th2 response in S.mansoni infected mice has been shown to influence the response to other infectious agents or antigens. We therefore determined whether infection with S.mansoni could influence the spontaneous incidence of insulin dependent diabetes mellitus (IDDM) in NOD mice. Infection with this helminth significantly reduced the spontaneous incidence of IDDM. IDDM was also prevented by injecting parasite eggs alone. Because until relatively recently humans might expect to succumb to a variety of infectious agents, the current freedom from infection might permit the expression of a genetic predisposition to autoimmune pathology and be responsible for the increased incidence of IDDM.

IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs.

Schistosoma mansoni egg-induced pulmonary granuloma formation is a cell-mediated inflammatory response associated with dominant Th2-type cytokine expression, tissue eosinophilia, and high levels of serum IgE. In the present study, we show that in vivo blockade of the Th2 cytokine IL-13, using soluble IL-13R alpha2-Fc fusion protein, significantly reduced the size of pulmonary granulomas in unsensitized as well as egg-sensitized mice. Blocking IL-13 also significantly reduced total serum IgE levels. Interestingly, however, IL-13 blockade did not affect the evolving egg-induced Th2-type cytokine response. IL-4, IL-5, as well as IL-13 responses were indistinguishable in control-Fc- and soluble IL-13R alpha2-Fc fusion protein-treated animals. The smaller granulomas were also phenotypically like the control Fc-treated mice, displaying a similar eosinophil content. Additional studies in IL-4-deficient mice demonstrated that IL-13 was produced, but at much lower levels than in wild-type mice, while IL-4 expression was completely independent of IL-13. Moreover, while granuloma formation was partially reduced in IL-4-deficient mice, blocking IL-13 in these animals almost completely abrogated granuloma development and the pulmonary eosinophilia, while it simultaneously increased IFN-gamma production. Together, these data demonstrate that IL-13 serves as an important mediator of Th2-mediated inflammation and plays a role in eliciting IgE responses triggered by schistosome eggs.

Activated eosinophils are the major source of Th2-associated cytokines in the schistosome granuloma.

Eosinophils are a numerically dominant cell population within the schistosome granuloma. These granuloma eosinophils can produce a variety of cytokines, including IL-2, IL-4, IL-5, and IFN-gamma. Therefore, eosinophils may play a key role in the determination of the unique cytokine microenvironment within the granuloma milieu. These studies investigated the potential role of eosinophils in the regulation of granuloma immunopathology. We have characterized spleen- and granuloma-derived eosinophils based on cellular activation and cytokine production during the development of murine schistosomiasis. Based on the criteria of hypodensity and CD69 expression, granuloma eosinophils were highly activated and very homogeneous at 7 and 11 wk postinfection. Splenic eosinophils were also activated at 7 wk postinfection, but were much more heterogeneous than their granuloma counterparts. By 11 wk postinfection, few hypodense splenic eosinophils were observed. Eosinophils represented the majority of cytokine-producing cells in the granuloma and were a dominant source of IL-4. Eosinophils also produced IL-2, IL-5, and IFN-gamma, using the criteria of mRNA in situ hybridization and intracellular cytokine staining by FACS. Granuloma eosinophil activation and cytokine production were greatest at the time of maximum granuloma formation, i.e., 10-12 wk after initial cercarial exposure. Therefore, locally activated eosinophils, not Th2 lymphocytes, produce the majority of Th2 cytokines in the granuloma milieu and may be important determinators of immunopathology in schistosomiasis.