Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

Lactose and Fructo-oligosaccharides Increase Visceral Sensitivity in Mice via Glycation Processes, Increasing Mast Cell Density in Colonic Mucosa.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and erratic bowel habits. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can reduce symptoms of IBS, possibly by reducing microbial fermentation products. We investigated whether ingestion of FODMAPs can induce IBS-like visceral hypersensitivity mediated by fermentation products of intestinal microbes in mice. METHODS: C57Bl/6 mice were gavaged with lactose, with or without the antiglycation agent pyridoxamine, or saline (controls) daily for 3 weeks. A separate group of mice were fed a diet containing fructo-oligosaccharides, with or without pyridoxamine in drinking water, or a normal chow diet (controls) for 6 weeks. Feces were collected and analyzed by 16S ribosomal RNA gene sequencing and bacterial community analyses. Abdominal sensitivity was measured by electromyography and mechanical von Frey filament assays. Colon tissues were collected from some mice and analyzed by histology and immunofluorescence to quantify mast cells and expression of advanced glycosylation end-product specific receptor (AGER). RESULTS: Mice gavaged with lactose or fed fructo-oligosaccharides had increased abdominal sensitivity compared with controls, associated with increased numbers of mast cells in colon and expression of the receptor for AGER in proximal colon epithelium. These effects were prevented by administration of pyridoxamine. Lactose and/or pyridoxamine did not induce significant alterations in the composition of the fecal microbiota. Mass spectrometric analysis of carbonyl compounds in fecal samples identified signatures associated with mice given lactose or fructo-oligosaccharides vs controls. CONCLUSIONS: We found that oral administration of lactose or fructo-oligosaccharides to mice increases abdominal sensitivity, associated with increased numbers of mast cells in colon and expression of AGER; these can be prevented with an antiglycation agent. Lactose and/or pyridoxamine did not produce alterations in fecal microbiota of mice. Our findings indicate that preventing glycation reactions might reduce abdominal pain in patients with IBS with sensitivity to FODMAPs.

Potassium bromate (KBrO3) modulates oxidative stress and inflammatory biomarkers in sodium hydroxide (NaOH) - induced Crohn's colitis in Wistar rats.

Potassium bromate (KBrO3) present in consumed ozonised water was recently documented to exacerbate experimental gastric ulcer. Information, however, is vague as regards its effects in the colon where water reabsorption occurs. In this study, we observed the possible effects of KBrO3 on oxidative stress and inflammatory biomarkers in sodium hydroxide (NaOH) - induced Crohn's colitis (CC). Wistar rats (180-200 g) were divided into six groups (n = 10): (i) control; (ii) untreated CC (induced by 1.4% NaOH; intra-rectal administration); and (iii-vi) CC treated with vitamin E, KBrO3, vitamin E+KBrO3, and sulphazalazine, respectively, for 7 days. Body weight and stool score were monitored daily. By day 3 and 7, excised colon was evaluated for ulcer scores and biochemical and histological analysis. Blood samples collected on days 3 and 7 were assayed for haematological indices using standard methods. Data were subjected to analysis of variance (ANOVA) and p ≤ 0.05 considered significant. Platelet/lymphocyte ratio, colonic ulcer score, malondialdehyde, and mast cells were significantly decreased while colonic sulfhydryl, and Ca2+- and Na+/K+-ATPase activities were increased following KBrO3 treatment compared with untreated CC. These findings suggest that KBrO3 may mitigate against NaOH-induced CC via inhibiting mast cell population and oxidative and inflammatory content but stimulating colonic sulfhydryl and Ca2+- and Na+/K+-ATPase activities.

Vascular responses to compound 48/80 in rat mesenteric vascular beds.

A further investigation was performed on the vascular effect of endogenous histamine using the histamine releaser, compound 48/80, in rat mesenteric vascular beds with active tone. In preparations with intact endothelium, low concentrations of compound 48/80 (1.53 × 10(-5) - 3 × 1.53 × 10(-5) mg/mL) perfusion for 1 min only induced a small vasodilation. High concentrations of compound 48/80 (1.53 × 10(-4) - 3 × 1.53 × 10(-2) mg/mL) induced a biphasic vascular responses, an initial vasoconstriction followed a subsequent long-lasting vasodilation. The vasodilation induced by low concentrations of compound 48/80 and the vasoconstriction induced by high concentration of compound 48/80 was inhibited by olopatadine. However, cimetidine did not affect the responses induced by compound 48/80. Endothelium removal enlarged the compound 48/80-induced phase-2 vasoconstriction, while it attenuated the phase-3 vasodilation. Additionally, indomethacin and seratrodast significantly inhibited vasoconstriction but it did not affect the long-lasting vasodilation induced by high concentrations of compound 48/80. Ruthenium red inhibited the vasodilation induced by low concentrations and high concentrations of compound 48/80. These results suggest that the vasoconstriction induce by high concentrations of compound 48/80 is mediated by endogenous histamine released from mast cells. It is also suggested that thromboxane A2 released from mast cells is related to the vasoconstriction.

Spiraeoside inhibits mast cells activation and IgE-mediated allergic responses by suppressing phospholipase C-γ-mediated signaling.

Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-γ2 (PLC-γ2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-α and IL-4. Finally, we found that SP significantly inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-γ2/MAPK signaling in mast cells.

The potential anti-proliferative effect of ß-sitosterol on human mast cell line-1 cells.

Thymic stromal lymphopoietin (TSLP) was reported to induce mast cell proliferation and aggravate allergic reactions through activation of mouse double minute 2 (MDM2). We aimed to ascertain that ß-sitosterol (SI), which is one of the several phytosterols found mostly in foods, would regulate TSLP-induced mast cell proliferation. The results showed that SI significantly decreased the proliferation of human mast cell line (HMC-1) cells promoted by TSLP. SI significantly decreased the mRNA expression of Ki-67 in the TSLP-treated HMC-1 cells. SI significantly suppressed the production and mRNA expression of interleukin-13 in the TSLP-treated HMC-1 cells. Furthermore, SI downregulated the expression of MDM2 and phosphorylation of STAT6, whereas it upregulated the expression of p53, activation of caspase-3, and cleavage of poly ADP-ribose polymerase in the TSLP-treated HMC-1 cells. Results of this study suggest that SI may be a potential therapeutic agent for mast cell-mediated allergic diseases.

[Angioedema and urticaria]. / Les angiœdèmes dans l'urticaire.

Angiœdema (AE) is the clinical expression of urticaria (U) which occurs when urticaria is located within the subcutis. It is a syndrome characterized by a sudden and limited subcutaneous and/or submucous swelling. The updated classification of urticaria distinguishes acute and chronic urticaria. Chronic urticaria is spontaneous (CSU) or inducible (CIU). Angioedema in chronic urticaria is rarely allergic, but most of the time caused by a non-specific histamine release from activated mast-cell (non IgE mediated reaction). Angioedemas are recurrent, concomitant or not with wheals. They appear skin-coloured, sometimes slightly rosy, non-inflammatory, and more painful than itchy. They are transient, ephemeral, migrant, last most of the time a few hours (< 24 or 48h) and disappear without after-effects. They are considered "deep urticaria" and wheals "superficial urticaria". When AE or wheals last more than 6 weeks (with or without free intermission), it is called chronic urticaria. Angioedema can be elicited or worsened by physical factors (cold urticaria, exercise, heat, solar, vibratory, aquagenic, delayed pressure urticaria…) and /or drugs (as aspirin, nonsteroid anti-inflammatory drugs, morphine, antibiotics…). The treatment of histaminergic angioedemas of chronic urticaria is based on modern second generation antihistamines (anti H1). In allergic acute urticaria only, additional treatment for anaphylaxis can be used if needed (grade 2 to 4). In chronic urticaria, steroids should be avoided : they can make symptoms worse and long-lasting because of corticosteroid dependence.

Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment.

Mast cell tumors are a large group of diseases occurring in dogs, cats, mice, as well as in humans. Systemic mastocytosis (SM) is a disease involving the accumulation of mast cells in organs. KIT gene mutations are very often seen in abnormal mast cells. In SM, high KIT/CD117 expression is observed; however, there are usually no KIT gene mutations present. Mastocytoma (MCT)-a form of cutaneous neoplasm-is common in animals but quite rare in humans. KIT/CD117 receptor mutations were studied as the typical changes for human mastocytosis. In 80% of human cases, the KIT gene substitution p.D816H was present. In about 25% of MCTs, metastasis was observed. Changes in the gene expression of certain genes, such as overexpression of the DNAJ3A3 gene, promote metastasis. In contrast, the SNORD93 gene blocks the expression of metastasis genes. The panel of miR-21-5p, miR-379, and miR-885 has a good efficiency in discriminating healthy and MCT-affected dogs, as well as MCT-affected dogs with and without nodal metastasis. Further studies on the pathobiology of mast cells can lead to clinical improvements, such as better MCT diagnosis and treatment. Our paper reviews studies on the topic of mast cells, which have been carried out over the past few years.

Activated Mast Cells Mediate Low-Grade Inflammation in Type 2 Diabetes: Interleukin-37 Could Be Beneficial.

Mast cells (MCs) promote guest immune responses to parasites and play a critical role in allergic and inflammatory reactions. Once they have been activated, MCs release highly inflammatory compounds that can provoke serious pathologic signs that can lead to death. MCs generate a number of preformed, de novo synthesized compounds and inflammatory cytokine/chemokine synthesis in response to the high-affinity (Kd=10-10 M) immunoglobulin E receptor triggering. Circulating MC progenitors migrate into arterial intima and develop lesions, mediating inflammation. They are involved in several disorders, including metabolic diseases, such as type 2 diabetes mellitus, in which endothelial cells release several inflammatory compounds during acute and chronic vascular damage. Certain inflammatory cytokines, such as interleukin (IL)-1 and IL-33, not only are produced by MCs but also may activate them. These effects mediate systemic inflammatory responses in metabolic disorders. Proinflammatory cytokines, such as tumor necrosis factor, IL-33 and IL-6, secreted by MCs and other immune cells, contribute to insulin resistance by activating kinases. IL-37 (IL-1 family member 7), one of the latest cytokines discovered, binds the IL-18 receptor alpha (IL-18Rα) chain and suppresses innate and acquired immunity, with a therapeutic effect. It also inhibits cytokine levels, including IL-6, IL-18, IL-33, tumor necrosis factor and IL-1, and may improve insulin production and, therefore, the pathogenesis of diabetes, stroke and cardiovascular health. This describes a new concept of inhibition of and cure for inflammatory diseases. However, the safety, dosage and tolerability of this novel therapeutic agent, IL-37, still remains to be determined.

The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions.

BACKGROUND: Mast cell diseases include mastocytosis and mast cell activation syndromes, some of which have been shown to involve clonal defects in mast cells that result in abnormal cellular proliferation or activation. Numerous clinical studies of mastocytosis have been published, but no population-based comprehensive surveys of patients in the United States have been identified. Few mast cell disease specialty centers exist in the United States, and awareness of these mast cell disorders is limited among nonspecialists. Accordingly, information concerning the experiences of the overall estimated population of these patients has been lacking. OBJECTIVE: To identify the experiences and perceptions of patients with mastocytosis, mast cell activation syndromes, and related disorders, The Mastocytosis Society (TMS), a US based patient advocacy, research, and education organization, conducted a survey of its members and other people known or suspected to be part of this patient population. METHODS: A Web-based survey was publicized through clinics that treat these patients and through TMS's newsletter, Web site, and online blogs. Both online and paper copies of the questionnaire were provided, together with required statements of consent. RESULTS: The first results are presented for 420 patients. These results include demographics, diagnoses, symptoms, allergies, provoking factors of mast cell symptoms, and disease impact. CONCLUSION: Patients with mastocytosis and mast cell activation syndromes have provided clinical specialists, collaborators, and other patients with information to enable them to explore and deepen their understanding of the experiences and perceptions of people coping with these disorders.

The role of transient receptor potential vanilloid type-2 ion channels in innate and adaptive immune responses.

The transient receptor potential vanilloid type-2 (TRPV2), belonging to the transient receptor potential channel family, is a specialized ion channel expressed in human and other mammalian immune cells. This channel has been found to be expressed in CD34(+) hematopoietic stem cells, where its cytosolic Ca(2) (+) activity is crucial for stem/progenitor cell cycle progression, growth, and differentiation. In innate immune cells, TRPV2 is expressed in granulocytes, macrophages, and monocytes where it stimulates fMet-Leu-Phe migration, zymosan-, immunoglobulin G-, and complement-mediated phagocytosis, and lipopolysaccharide-induced tumor necrosis factor-alpha and interleukin-6 production. In mast cells, activation of TRPV2 allows intracellular Ca(2) (+) ions flux, thus stimulating protein kinase A-dependent degranulation. In addition, TRPV2 is highly expressed in CD56(+) natural killer cells. TRPV2 orchestrates Ca(2) (+) signal in T cell activation, proliferation, and effector functions. Moreover, messenger RNA for TRPV2 are expressed in CD4(+) and CD8(+) T lymphocytes. Finally, TRPV2 is expressed in CD19(+) B lymphocytes where it regulates Ca(2) (+) release during B cell development and activation. Overall, the specific expression of TRPV2 in immune cells suggests a role in immune-mediated diseases and offers new potential targets for immunomodulation.

Mastocitosis local, sistémica y alergia medicamentosa / Local and systemic mastocytosis anddrug allergy

Se exponen datos relacionados con la histología, fisiología y patología de los mastocitos, tanto normales como patológicos, y el papel de la alergia medicamentosa en la mastocitosis, así como las repercusiones psicopatológicas de la enfermedad y las bases neuroquímicas de dichos trastornos.

Data concerning the biological aspects of mastocytes, its pathology and the importance of childhood and adult mastocytosis are described. The role of drug allergy in mastocytosis is discussed. The psychopathological and neurochemical aspects of these conditions are exposed.

Las mastocitosis / Mastocytosis

Las mastocitosis están incluidas dentro del grupo de enfermedades raras debido a su baja frecuencia. Se caracterizan por el crecimiento y acumulación de causa desconocida de mastocitos en piel y otros órganos. Las manifestaciones clínicas se deben a la infiltración por mastocitos y a la liberación de mediadores químicos. El diagnóstico se establece por la clínica y los hallazgos histopatológicos en biopsias de piel y de órganos afectados, como la médula ósea. En la piel se manifiesta como urticaria pigmentosa. Existen varias clasificaciones, pero ninguna ha sido universalmente aceptada. El tratamiento es sintomático y no altera el curso de la enfermedad. La mayoría de los pacientes presentan síntomas relacionados con la liberación de mediadores del mastocito, y la prevención de sus efectos sobre los tejidos constituye la clave del tratamiento(AU)

Mastocytoses are included among the group of "rare diseases" due to their low frequency. They are characterized by the growth and accumulation of mastocytes on the skin and other organs for no known reason. Clinical manifestations are due to infiltration by mastocytes and the release of chemical mediators. The diagnosis is clinical and based on histopathological findings from biopsies of the skin and other organs affected, such as the bone marrow. On the skin, the illness is manifested as urticaria pigmentosa. Several classifications have been made, but none has been universally accepted. Treatment is symptomatic and does not change the course of the illness. Most patients present symptoms related to mastocyte mediator release, and prevention of its effects on tissues is crucial to the treatment(AU)

Las mastocitosis / Mastocytosis

Las mastocitosis están incluidas dentro del grupo de enfermedades raras debido a su baja frecuencia. Se caracterizan por el crecimiento y acumulación de causa desconocida de mastocitos en piel y otros órganos. Las manifestaciones clínicas se deben a la infiltración por mastocitos y a la liberación de mediadores químicos. El diagnóstico se establece por la clínica y los hallazgos histopatológicos en biopsias de piel y de órganos afectados, como la mÚdula ósea. En la piel se manifiesta como urticaria pigmentosa. Existen varias clasificaciones, pero ninguna ha sido universalmente aceptada. El tratamiento es sintomático y no altera el curso de la enfermedad. La mayoría de los pacientes presentan síntomas relacionados con la liberación de mediadores del mastocito, y la prevención de sus efectos sobre los tejidos constituye la clave del tratamiento

Mastocytoses are included among the group of "rare diseases" due to their low frequency. They are characterized by the growth and accumulation of mastocytes on the skin and other organs for no known reason. Clinical manifestations are due to infiltration by mastocytes and the release of chemical mediators. The diagnosis is clinical and based on histopathological findings from biopsies of the skin and other organs affected, such as the bone marrow. On the skin, the illness is manifested as urticaria pigmentosa. Several classifications have been made, but none has been universally accepted. Treatment is symptomatic and does not change the course of the illness. Most patients present symptoms related to mastocyte mediator release, and prevention of its effects on tissues is crucial to the treatment

Urticaria pigmentosa: dos presentaciones clínicas diferentes en pediatría / Urticaria pigmentosa: two different clinical presentations in pediatric patients

La urticaria pigmentosa es la forma más común de mastocitosis cutánea. Suele iniciarse de manera bimodal: un pico de incidencia desde el nacimiento hasta los 3 años de vida y otro entre la 2ª y 6ª décadas de la vida. El signo de Darier es constante sobre el área afectada, sin extenderse a piel vecina. La forma de comienzo precoz tiene buen pronóstico y desaparece hacia la adolescencia, pero la de comienzo tardío suele ser persistente o asociarse a afectación sistémica. Se comunican dos casos de urticaria pigmentosa, uno con la descripción clásica de la enfermedad y otro con presentación clínica infrecuente, por lo cual el pediatra debe incorporar ambas formas como manifestaciones distintas de una misma entidad.

Urticaria pigmentosa (UP) is the most frequent clinical feature of cutaneous mastocytosis. It usually begins in a bimodal way: a peak of incidence from birth to the age of 3 and the other one between 2nd and 6th decades of life. Darier's sign is constant over the affected skin without affecting the surrounding skin. When UP starts early, it has a good prognosis disappearing into adolescence, while late onset is often associated with persistent or systemic involvement. This article reports two cases of UP, one with the classic description of the disease and the other with an unusual clinical presentation, prompting the pediatrician to incorporate both forms as different manifestations of the same entity.

Mastocitosis: Unaafección poco común

La mastocitosis es la proliferación anormal de mastocitos que puede afectar 1 o varios órganos. Esta célula almacena importantes sustancias farmacológicamente activas. Sus manifestaciones más frecuentes son las cutáneas, pero pueden aparecer otras a causa de afectación de órganos como la médula ósea, hígado, bazo, huesos, ganglios linfáticos y tubo digestivo. Existen varios métodos diagnósticos, pero la histología es fundamental. El tratamiento incluye medidas generales y específicas; actualmente el uso del interferón ha cobrado interés.

Mastocytosis is the abnormal proliferation of mastocytes that may affect one or various organs. This cell stores important pharmacologically active substances. Its most frequent manifestations are the cutaneous ones, but other manifestations may appear as a result of the affectation of some organs as the bone marow, the liver, the spleen, the bones, the lymphatic ganglia and the digestive tube. There are different diagnostic methods, but histology is essential. The treatment includes general and specific measures. Interest in using interferon has increased nowadays.