Number Of Tissue Mast Cells Research Articles

Mastocytosis.

Mastocytosis is defined by a pathological increase in mast cell numbers in tissues. Recent clinical observations on rare manifestations highlight the diversity of this disease. The diagnosis is now aided by new surrogate markers. At the molecular level, recent studies have reinforced the role of activating mutations in KIT in the etiology of mastocytosis. These findings provide a conceptual basis for the development for new therapeutic strategies.

Mastocytosis

Mastocytosis is defined by a pathological increase in mast cell numbers in tissues. Recent clinical observations on rare manifestations highlight the diversity of this disease. The diagnosis is now aided by new surrogate markers. At the molecular level, recent studies have reinforced the role of activating mutations in KIT in the etiology of mastocytosis. These findings provide a conceptual basis for the development for new therapeutic strategies.

The Editors’ Choice

The Editors’ Choice

A link between chronic asthma and chronic infection

Background: Asthma is a prevalent disease with marked effects on quality of life and economic societal burden. However, the cause of asthma and its pathophysiology are not completely defined. Recently, the possibility that chronic infection may play a role has been suggested. Objective: We sought to define the association between Mycoplasma and Chlamydia species and chronic asthma. Methods: We performed a comparison study of asthmatic patients and normal control subjects. Fifty-five patients with chronic stable asthma were compared with 11 normal control subjects by using PCR, culture, and serology for Mycoplasma species, Chlamydia species, and viruses from the nasopharynx, lung, and blood. Bronchoalveolar lavage cell count and differential, as well as tissue morphometry, were also evaluated. Computer-generated scoring for the degree of chronic sinusitis in asthmatic patients was additionally evaluated. Results: Thirty-one of 55 asthmatic patients had positive PCR results for Mycoplasma (n = 25) or Chlamydia species (n = 6), which were mainly found on lung biopsy specimens or in lavage fluid. Only 1 of 11 normal control subjects had positive PCR results for Mycoplasma species. The distinguishing phenotype between asthmatic patients with positive and negative PCR results was the significantly greater number of tissue mast cells in the group with positive results. Conclusion: A significant number of patients with chronic stable asthma demonstrate the presence of Mycoplasma species, Chlamydia species, or both in their airways, with the distinguishing feature of increased mast cell number. These findings need further delineation but may help us to understand the pathophysiology of asthma and new treatment options. (J Allergy Clin Immunol 2001;107:595-601.)

PEDIATRIC MASTOCYTOSIS

Pediatric mastocytosis presents with heterogeneous cutaneous lesions and symptoms that are caused by increased numbers of tissue mast cells. In contrast with adult patients with mastocytosis, the course of pediatric patients is usually transient. Therefore, it has long been speculated that pediatric and adult mastocytosis may be based on different pathogenetic mechanisms. Indeed, new genetic findings now indicate differences in the pathogenesis. Adult patients usually express activating mutations of the growth factor receptor c-kit. Most children lack these mutations but sometimes carry other inactivating mutations of c-kit. Only children with progressive mastocytosis seem to express the activating mutations seen in adults. Causal treatment is not yet available, but H1 and H2 antihistamines may provide relief of symptoms. It is important to counsel patients and their parents carefully to avoid triggers that induce systemic mast cell degranulation.

Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses.

The Kit receptor tyrosine kinase functions in hemato- poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include proliferation, survival, adhesion, secretion and differentiation. In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3'-kinase (PI 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical role in mediating cell adhesion and secretion and has contributory roles in mediating cell survival and proliferation. To investigate the consequences in vivo of blocking Kit-mediated PI 3-kinase activation we have mutated the binding site for the p85 subunit of PI 3-kinase in the Kit gene, using a knock-in strategy. Mutant mice have no pigment deficiency or impairment of steady-state hematopoiesis. However, gametogenesis is affected in several ways and tissue mast cell numbers are affected differentially. While primordial germ cells during embryonic development are not affected, Kit(Y719F)/Kit(Y719F) males are sterile due to a block at the premeiotic stages in spermatogenesis. Furthermore, adult males develop Leydig cell hyperplasia. The Leydig cell hyperplasia implies a role for Kit in Leydig cell differentiation and/or steroidogenesis. In mutant females follicle development is impaired at the cuboidal stages resulting in reduced fertility. Also, adult mutant females develop ovarian cysts and ovarian tubular hyperplasia. Therefore, a block in Kit receptor-mediated PI 3-kinase signaling may be compensated for in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.

Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites.

The cytokine interleukin-3 (IL-3), which can be derived from T cells and other sources, is a potentially important link between the immune and haematopoietic systems. IL-3 may be particularly critical for the development, survival and function of tissue mast cells and blood basophils, which are thought to be important effector cells in immunity to parasites and other immunological responses, such as allergic reactions. Here we show, using IL-3-deficient mice, that IL-3 is not essential for the generation of mast cells or basophils under physiological conditions, but that it does contribute to increased numbers of tissue mast cells, enhanced basophil production, and immunity in mice infected with the nematode Stronglyoides venezuelensis. Parasite expulsion and mast-cell development are impaired even more severely in IL-3-deficient mice that also show a marked reduction in signalling by c-kit. These findings establish a role for IL-3 in immunity to parasites and indicate that one of the functions of IL-3 in host defence against infection is to expand populations of haematopoietic effector cells.

Glucocorticoids decrease tissue mast cell number by reducing the production of the c-kit ligand, stem cell factor, by resident cells: in vitro and in vivo evidence in murine systems.

The local delivery of glucocorticoids to tissues significantly decreases mast cell number. This pharmacologic effect of glucocorticoids is believed to be one of the mechanisms by which glucocorticoids regulate allergic inflammation. To determine the mechanism by which glucocorticoids are able to exert this effect, we first applied the glucocorticoid fluocinonide to mouse dermis and observed that the decrease in mast cell number was associated with an increase in mast cell apoptosis. This did not appear to be due to a direct effect of the glucocorticoid on mast cells, as the addition of 0.01-1.0 microM of the glucocorticoid dexamethasone into stem cell factor (SCF)-dependent mast cell cultures did not enhance mast cell death. However, addition of dexamethasone to cultured fibroblasts did result in a downregulation of SCF mRNA and a significant decrease in SCF protein production. Similarly, immunohistochemistry performed on fluocinonide-treated mouse dermis revealed a decrease in immunoreactive SCF. Administration of SCF at sites of fluocinonide administration to the dermis abolished the mast cell-depleting effect of this glucocorticoid. Thus, glucocorticoids decrease tissue mast cell number by downregulating tissue SCF production required for the survival of local mast cells. This observation may be applicable to the design of improved strategies to treat mast cell-mediated disorders.

Mast cell ontogeny and apoptosis.

The regulation of tissue mast cell number depends both on the rate of production of mast cell precursors from bone marrow and the length of survival of mature mast cells within tissues. Mast cells develop from bone marrow under the influence of both interleukin-3 (IL-3) and the c-kit ligand, also known as stem cell factor (SCF). In humans, the mast cell precursor is CD34+, FcERI-. Mast cell precursors with time become less responsive to IL-3 and more responsive to SCF. Mast cell proliferation directed by SCF is enhanced by other cytokines including both IL-4 and IL-10. Once mast cell precursors target to tissues, their survival may largely be dependent upon the local production of SCF. Withdrawal of IL-3 or SCF results in mast cell apoptosis; SCF rescues mast cells following IL-3 withdrawal. TGF-beta prevents this SCF rescue. Engagement of extracellular matrix by integrin receptors may also effect mast cell numbers. Thus, in the final analysis, mast cell numbers, while relatively constant in the normal state, may be up-regulated by altering the rate of their production centrally or length of survival in the periphery.

The role of c-Kit and its ligand, stem cell factor, in mast cell apoptosis.

The regulation of tissue mast cell number depends both on the rate of production of mast cell precursors and the length of survival of mature mast cells within tissues. Once mast cell precursors target to tissues, their survival may largely be dependent upon the local production of stem cell factor (SCF). Withdrawal of interleukin (IL)-3 results in mast cell apoptosis. The apoptotic changes following IL-3 deprivation are prevented by the addition of SCF which exerts its rescue effect upon interaction with its c-Kit tyrosine kinase receptor. Mast cells undergo apoptosis on withdrawal of IL-3 coincident with a decrease in endogenous bcl-2 mRNA; however, SCF does not induce expression of bcl-2 when added to these cells. When overexpressed, bcl-2 prolongs survival of bcl-2-transfected mast cells following IL-3 deprivation. Transforming growth factor-beta was found to specifically prevent this SCF-mediated rescue from apoptosis, probably by down-regulating the expression of c-Kit. Thus, microenvironmental factors play an important role in regulating mast cell numbers by effecting survival in the periphery.

Repeated antigen challenge in rats induces a mucosal mast cell hyperplasia

Background: A link between mast cells and a number of intestinal diseases has been suggested. Treatment of adult rats with connective tissue mast cell degranulating agents has been shown to induce an intestinal mucosal mast cell hyperplasia. We have examined the hypothesis that repeated systemic antigen challenge would similarly up-regulate the mucosal mast cell population. Methods: Animals were primed with 10 μg of albumin and challenged twice weekly with 3, 30, or 300 μg of ovalbumin, subcutaneously, for 4 weeks. The mast cell numbers were assessed histologically. In addition, measurements were made of tissue/mast cell-mediator content. Results: Repeatedly challenged animals that received 30-μg doses of soluble ovalbumin developed a mucosal mast cell hyperplasia in the duodenum 2 weeks after the cessation of treatment. No change in connective tissue mast cell numbers was observed. Repeated administration of 300 μg of antigen did not induce a mucosal mast cell hyperplasia. No significant difference between the mucosal mast cell numbers in antigen-challenged and control animals was observed when animals were treated concurrently with the mast cell-stabilizing agent disodium cromoglycate. Conclusions: Repeated antigen challenge at doses that induce mast cell activation is associated with an increase in the number of mucosal mast cells.

Ectopic expression of a c-kitW42 minigene in transgenic mice: recapitulation of W phenotypes and evidence for c-kit function in melanoblast progenitors.

The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor that is allelic with the murine white-spotting locus (W). W mutations affect melanogenesis, gametogenesis, and hematopoiesis during development and adult life, and they result from the partial or complete loss of c-kit function. The W42 allele is a W mutation with severe effects in both the homozygous and the heterozygous states. Previous analysis of the W42 allele identified a missense mutation in an essential amino acid of the c-kitW42 kinase domain that abolishes the in vitro kinase activity of the c-kitW42 protein but does not affect its normal expression. These results suggested that the c-kitW42 allele was a dominant negative mutation within the context of c-kit-mediated signal transduction. To further explore the dominant negative characteristics of the W42 mutation, we have generated transgenic mice in which ectopic expression is driven by the human beta-actin promoter (hAP). Two mouse lines carrying the hAP-c-kitW42 transgene show an effect on pigmentation and the number of tissue mast cells. The patchy coat color pattern of the line 695 mice may reflect variable expression of the transgene in melanoblast progenitors and their descendants and, consequently, is indicative of a function for c-kit in early melanoblasts. Germ cell development and erythropoiesis, however, do not appear to be affected by the transgene. Mice expressing the c-kitW42 transgene therefore recapitulate some of the phenotypes of mice with W mutations. These results are therefore in agreement with the molecular basis of the W42 mutation and the dominant-negative characteristics of the c-kitW42 protein product.

Urticaria pigmentosa in monozygotic twins

To the Editor.— The hallmark of mastocytosis is an increased number of tissue mast cells. In the pediatric age group, the most frequent forms are urticaria pigmentosa and diffuse cutaneous mastocytosis. In the systemic form, mast cell infiltration of bone marrow, liver, spleen, small intestine, and skin is common. We describe two monozygotic twins presenting simultaneously with urticaria pigmentosa. To the best of our knowledge, this is the tenth pair with the disease described in the literature. 1,2 Report of Case.— We examined our patients at the age of 8 months, with a follow-up to the age of 4 years. No evidence of consanguinity or a family history of mastocytosis were disclosed. At 3 months of age, reddish-brown, slightly elevated papules were noted. The papules were 1 to 5 cm in diameter, with an irregular shape and generalized distribution, although the face, palms, and soles were initially spared. Some lesions

Reduction of ethanol-induced gastric damage by sodium cromoglycate and FPL-52694. Role of leukotrienes, prostaglandins, and mast cells in the protective mechanism

The mechanism of action of the "mast cell stabilizers" sodium cromoglycate and FPL-52694 as protective agents against ethanol-induced gastric mucosal damage was investigated in the rat. Using an ex vivo gastric chamber model, various concentrations (10-80 mg/mL) of the two agents were applied to the gastric mucosa prior to exposure to 40% ethanol. Both agents significantly reduced ethanol-induced damage in a dose-dependent manner. When given orally (80 mg/kg) both agents significantly reduced gastric damage induced by subsequent oral administration of absolute ethanol. Pretreatment with indomethacin did not significantly affect the protection afforded by FPL-52694, but did cause a partial reversal of the protective effect of sodium cromoglycate. Changes in gastric leukotriene C4 synthesis did not correlate with the protective effects of the two agents. Both mucosal and connective tissue mast cell numbers were significantly reduced following oral ethanol administration. In the groups pretreated with FPL-52694 or sodium cromoglycate, mucosal mast cell numbers were not significantly different from those in rats not treated with ethanol. Furthermore, the connective tissue mast cell numbers were significantly lower than in ethanol-treated control rats, despite a greater than 95% reduction of ethanol-induced hemorrhagic damage. These results therefore suggest that stimulation of gastric prostaglandin synthesis is not important in the mechanism of action of FPL-52694, and neither agent appears to reduce damage through a mechanism related to effects on gastric leukotriene C4 synthesis. The present studies further suggest that the protection afforded by pretreatment with sodium cromoglycate or FPL-52694 may be unrelated to effects of these agents on the connective tissue mast cell population in the stomach.

Mastocytosis in infants and children: recognition of patterns of skin disease.

Mastocytosis is a disease characterized by an increase in the number of tissue mast cells and a concomitant increase in mast cell-derived mediators. To demonstrate the spectrum of skin disease in mastocytosis in the pediatric population, five children with mastocytosis and complaints of urticaria (4/5), bullae/vesicles (3/5), abdominal pain (3/5), flushing (2/5), headache (1/5), and bone pain (1/5) are reviewed. Confirmation of the diagnosis of cutaneous mastocytosis was obtained by histologic examination of a biopsy of lesional skin; however, mast cell numbers in lesional skin did not correlate with plasma histamine levels or the extent of cutaneous involvement. Mastocytosis is a diagnosis that must be recognized in the differential diagnosis of pediatric urticarial diseases.

Solitary mastocytoma (Urticaria Pigmentosa)

Mastocytosis implies tissue involvement with excessive numbers of tissue mast cells, the skin or any other organ system may be involved. Symptoms range from absent to severe and occasionally life threatening. In children, the solitary mastocytoma or urticaria pigmentosa is a relatively benign condition without increased risk of later systemic involvement. In adults, however, other organs and diffuse skin involvement may be present with increased morbidity and mortality. Without specific symptoms relating to a particular organ system, an elaborate and extensive staging workup is not indicated. There is, at present, no evidence of a reproducibly effective therapy for this systemic disease, and symptoms can only be controlled by various medications. In children, the solitary mastocytoma is perhaps best followed as ultimately the lesions most commonly resolve with time. If, however, vesiculation, breakdown or infection is present, or there is a cosmetic problem, the solitary lesion can be excised safely with good longterm results.

Plasma histamine concentrations in evaluation of pediatric mastocytosis

Mastocytosis is a disease characterized by an increase in the number of tissue mast cells and a concomitant increase in mast cell-derived mediators. In pediatric mastocytosis, the predominant cutaneous forms are urticaria pigmentosa and diffuse cutaneous mastocytosis. In the less commonly diagnosed systemic mastocytosis, abnormal mast cell accumulations may be found in the gastrointestinal tract, liver, spleen, and bone marrow? Adults with mastocytosis have elevated plasma and urine histamine levels 25 that correlate with the extent of bone involvement and basal gastric acid output, a'5 In contrast, little is known concerning histamine values in children with this disease. To determine whether plasma histamine concentrations are elevated in children with mastocytosis, and to assess the relationship of plasma histamine levels to the category and severity of disease, the information obtained during the routine evaluation of children with mastocytosis was correlated with plasma histamine measurements. METHODS Nine children aged 3 months to 8 years who were referred over 9 months to the National Institutes of Health with a tentative diagnosis of mastocytosis were examined to confirm the diagnosis and to assess the extent of disease. Medical evaluation consisted of a history, physical examination, laboratory studies (complete blood cell count with differential, serum chemistry, serum immunoglobulins, urinalysis), and posterior iliac crest bone marrow examination. 6 Additional diagnostic studies were performed if the patient's history or physical examination suggested systemic involvement. Informed consent was obtained for specific procedures as required by the NIH Clinical Center.

Elektronenmikroskopische experimentelle Untersuchungen zur Entladung der Gewebsmastzellen

In transplantable adenocarcinoma of salivary glands induced in Wistarrats by polyoma-virus, a large number of tissue mast cells were present in the connective tissue, and could be found in all passages of the transplantation-series. These cells were situated mostly in the perivascular tissues. The tumors were treated with bee venom, chymotrypsin and dextran by intratumoral injections, and were submitted afterwards to electron microscopic study at certain intervals. Two forms of heparin- and histamine-release could be observed: by strong stimulation (bee venom) whole granula with parts of cytoplasm were extruded from the cells (extrusion); under these conditions the mast cells could be destroyed. By slight stimulation (dextran) grain-like substances of the granula were discharged at the cell surface (excytosis); the cells themselves remained intact and were able to resynthesize new granula.

Gastrointestinal lesions in mastocytosis.

Gastrointestinal examinations in 12 patients with systemic mastocytosis have revealed peptic ulcer in 5 instances and small intestinal lesions in 5 patients. The principal bowel abnormalities are small mucosal nodules and diffuse thickening of the bowel wall. Intestinal biopsies obtained in 3 of these patients were reviewed. Correlation of the roentgen and pathologic findings indicates that the bowel wall thickening is due to infiltration of the lamina propria by a cellular infiltrate containing, as a rule, increased numbers of tissue mast cells. Marked submucosal edema in 1 patient produced an unusual small bowel pattern. Biopsy specimens failed to indicate the nature of the nodular mucosal lesion.Laboratory evidence of malabsorption was found in 2 of the 5 patients, 1 of whom had significant hypocalcemia.Awareness of the intestinal lesions in mastocytosis permits more adequate evaluation of the gastrointestinal symptoms which are common in these patients, assists in earlier recognition of malabsorption ...

Mediators of inflammation in leukocyte lysosomes. II. Mechanism of action of lysosomal cationic protein upon vascular permeability in the rat.

The vascular permeability-increasing action of rabbit PMNL lysosomes has been studied in skin and cremaster muscle of the rat. Both an extract of frozen-thawed granules and a cathepsin-free cationic protein fraction of the granules (which had previously been demonstrated to cause leukocyte adhesion and emigration in vivo) induce increased vascular permeability in skin and muscle which resembles that produced by histamine or histamine-liberators with respect to the timing of the response and the predominant type of microvessel affected. Extracts of frozen-thawed lysosomes and the inflammatory lysosomal cationic protein both cause disruption of rat mesenteric mast cells in vitro, whereas a granule-free cytoplasmic fraction of PMN leukocytes and a non-inflammatory cationic protein fraction of the granules do not do so under identical test conditions. The mastocytolytic action of lysosomal materials in vitro is not inhibited in the presence of 10 kallikrein-inhibiting units of trasylol per ml. The mast cell rupturing fraction of PMNL granules (cationic protein) possesses no detectable peroxidase activity or acid-mucopolysaccharase activity. When compared with compound 48/80 on the basis of estimated molecular weight, the lysosomal cationic protein appears to be at least as active as the latter compound with respect to in vitro mastocytolytic potency. Chronic pretreatment of rats with an agent known to reduce tissue mast cell numbers causes marked suppression of the vascular permeability change normally induced in skin and muscle by lysosomal extracts and cationic protein. Similar results are obtained if lysosomal materials are tested in rats pretreated with an antihistaminic. These observations are discussed with respect to the mode of action of PMNL lysosomes in the early and late phases of local tissue-injury reactions.