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1.
Emerg Med Clin North Am ; 40(1): 119-133, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34782083

ABSTRACT

Scombroid poisoning, systemic mastocytosis, and hereditary alpha tryptasemia all present with episodes that resemble allergic reactions. Knowledge regarding systemic mastocytosis and hereditary alpha tryptasemia is quickly evolving. Epidemiology, pathophysiology, and strategies to identify and diagnose are discussed. Evidence-based management in the emergency setting and beyond is also explored and summarized. Key differences are described between these events and allergic reactions.


Subject(s)
Angioedema/diagnosis , Hypersensitivity/diagnosis , Marine Toxins/biosynthesis , Angioedema/physiopathology , Biological Mimicry , Humans , Hypersensitivity/physiopathology , Marine Toxins/metabolism , Tryptases/analysis , Tryptases/deficiency
3.
Pigment Cell Melanoma Res ; 33(4): 579-590, 2020 07.
Article in English | MEDLINE | ID: mdl-31894627

ABSTRACT

Tryptase-positive mast cells populate melanomas, but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase-deficient (Mcpt6-/- ) versus wild-type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild-type and Mcpt6-/- mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase-positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2, and Gbp10, while the expression of 5p-miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6-/- versus wild-type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.


Subject(s)
Melanoma/enzymology , Protective Agents/metabolism , Tryptases/metabolism , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinogenesis , Cell Line, Tumor , Cell Proliferation , Chemokine CXCL9/blood , Gene Expression Regulation, Neoplastic , Interferon-gamma/blood , Mast Cells/enzymology , Mast Cells/pathology , Melanoma/blood , Melanoma/genetics , Melanoma/pathology , Mice, Inbred C57BL , Recombinant Proteins/metabolism , Skin Neoplasms/blood , Skin Neoplasms/enzymology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Stromal Cells/metabolism , Subcutaneous Tissue/pathology , Tryptases/deficiency
4.
Blood ; 128(25): 2909-2918, 2016 12 22.
Article in English | MEDLINE | ID: mdl-27789480

ABSTRACT

Recent studies have identified nonredundant roles for basophils in immune responses including allergy and protective immunity. It is well known that activated basophils release granule contents such as histamine and proteases as do mast cells. However, the functional significance of basophil-derived proteases remains poorly understood in contrast to those released from mast cells. For this study we generated a line of knockout (KO) mice deficient for mouse mast cell protease-11 (mMCP-11) that is preferentially expressed by basophils rather than mast cells. In spite of normal development of basophils, the mMCP-11-deficient mice showed amelioration of immunoglobulin E-mediated chronic allergic inflammation (IgE-CAI), with reduction of cutaneous swelling, microvascular permeability, and leukocyte infiltration in the skin lesion, when KO mice were compared with wild-type mice. Repeated administration of recombinant mMCP-11 in the skin induced infiltration of leukocytes, including basophils, in a tryptase activity-dependent manner. The transwell migration assay in vitro suggested that mMCP-11-mediated proteolytic products of serum protein promoted migration of basophils, eosinophils, and macrophages via 1 or more G protein-coupled receptors. Thus, basophil tryptase mMCP-11 is a crucial effector molecule for the induction of IgE-CAI. This is the first demonstration that the basophil-derived protease plays a significant role in vivo.


Subject(s)
Basophils/enzymology , Hypersensitivity/enzymology , Hypersensitivity/immunology , Immunoglobulin E/immunology , Inflammation/enzymology , Inflammation/immunology , Tryptases/metabolism , Animals , Capillary Permeability , Cell Movement , Chronic Disease , Hypersensitivity/complications , Hypersensitivity/pathology , Inflammation/complications , Inflammation/pathology , Mice, Inbred C57BL , Mice, Knockout , Proteolysis , Receptors, G-Protein-Coupled/metabolism , Skin/blood supply , Skin/pathology , Tryptases/deficiency
6.
Plast Reconstr Surg ; 134(3): 459-467, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24814421

ABSTRACT

BACKGROUND: Stored in the secretory granules of cutaneous mouse mast cells are mouse mast cell proteases (mMCP-4, -5, and -6). Using transgenic mouse lines that lacked these enzymes, it was shown that mMCP-4 and mMCP-5 modulate the outcome of burn-induced skin injury. Whether or not these proteases also play a role in the repair of surgically damaged skin, with or without microdeformational wound therapy, remains to be determined. METHODS: Wild-type C57BL/6 mice and transgenic C57BL/6 mouse lines lacking mMCP-4, -5, or -6 were subjected to surgical wounding of their skin. Wounds were splinted with a stabilizing patch, and the mice received either microdeformational wound therapy (n = 5) or occlusive dressing (n = 5) for 7 days. Wound healing parameters were assessed in the proliferative phase. RESULTS: Cell proliferation in the wounded wild-type mice receiving microdeformational wound therapy was 60 ± 3 percent. Cell proliferation was only 35 ± 5 percent, 25 ± 5 percent, and 45 ± 4 percent for the treated mMCP-4-, mMCP-5-, and mMCP-6-null mice, respectively (p = 0.005). Blood vessel sprouting was higher in the control mice with microdeformational wound therapy (170 ± 40 vessels/high-power field) compared with mouse mast cell protease 6-null mice with microdeformational wound therapy (70 ± 20 vessels/high-power field; p = 0.005), and higher in the control mice with occlusive dressing (110 ± 30 vessels/high-power field) compared with mMCP-4-null mice with occlusive dressing (50 ± 20 vessels/high-power field; p = 0.01). Qualitatively, the granulation tissue of all the protease-deficient groups receiving microdeformational wound therapy was disrupted. CONCLUSION: Results suggest that mouse mast cell proteases 4, 5, and 6 are mediators of the critical role mast cells play in microdeformational wound therapy in the proliferative phase of healing.


Subject(s)
Chymases/physiology , Negative-Pressure Wound Therapy , Serine Endopeptidases/physiology , Skin/injuries , Tryptases/physiology , Wound Healing/physiology , Wounds and Injuries/therapy , Animals , Biomarkers/metabolism , Cell Proliferation , Chymases/deficiency , Mast Cells/enzymology , Mice , Mice, Inbred C57BL , Mice, Knockout , Occlusive Dressings , Serine Endopeptidases/deficiency , Skin/enzymology , Skin Physiological Phenomena , Tryptases/deficiency , Wounds and Injuries/enzymology , Wounds and Injuries/physiopathology
7.
J Immunol ; 191(3): 1404-12, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23797671

ABSTRACT

Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-ß mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-ß, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-ß was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-ß was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13, which are constitutively present in articular cartilage.


Subject(s)
Aggrecans/metabolism , Cartilage, Articular/metabolism , Mast Cells/immunology , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 3/metabolism , Animals , Arthritis/metabolism , Cells, Cultured , Enzyme Precursors/metabolism , Extracellular Matrix/metabolism , Inflammation , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Tryptases/deficiency , Tryptases/genetics , Tryptases/metabolism
8.
J Allergy Clin Immunol ; 131(3): 752-62, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23380220

ABSTRACT

BACKGROUND: Cigarette smoke-induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been hampered by the lack of an animal model that mimics the human disease in a short timeframe. OBJECTIVES: We sought to create an early-onset mouse model of cigarette smoke-induced COPD that develops the hallmark features of the human condition in a short time-frame. We also sought to use this model to better understand pathogenesis and the roles of macrophages and mast cells (MCs) in patients with COPD. METHODS: Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathologic features of COPD was assessed. The roles of macrophages and MC tryptase in pathogenesis were evaluated by using depletion and in vitro studies and MC protease 6-deficient mice. RESULTS: After just 8 weeks of smoke exposure, wild-type mice had chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart and increased susceptibility to respiratory tract infections also were observed. Macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced proinflammatory responses from cultured macrophages. CONCLUSION: A short-term mouse model of cigarette smoke-induced COPD was developed in which the characteristic features of the disease were induced more rapidly than in existing models. The model can be used to better understand COPD pathogenesis, and we show a requirement for macrophages and tryptase-expressing MCs.


Subject(s)
Disease Models, Animal , Pulmonary Disease, Chronic Obstructive/immunology , Smoke/adverse effects , Tryptases/immunology , Airway Remodeling , Animals , Macrophages/immunology , Mast Cells/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiratory Function Tests , Nicotiana , Tryptases/deficiency , Tryptases/genetics
9.
Transplant Proc ; 42(7): 2759-62, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20832582

ABSTRACT

It has been shown that mast cells (MC) are absolutely required for transplant acceptance. However, only a few of the numerous mediators produced by MC have been proposed as potential mechanisms for the observed immunosuppression. The role of proteases in acquired immune tolerance as such has not yet been addressed. In this study, we have shown the requirement for MC protease 6 (MCP6), an MC-specific tryptase, to establish tolerance toward an allogeneic skin graft. The substrate for MCP6 is interleukin (IL)-6, cytokine generally considered to indicate transplant rejection. Herein we have shown an inverse correlation between MCP6 and IL-6. High expression of MCP6 is accompanied by low levels of IL-6 when the allograft is accepted, whereas low expression of MCP6 in combination with high levels of IL-6 are observed in rejecting grafts. Moreover, tolerance toward an allogeneic graft cannot be induced in MCP6(-/-) mice. Rejection observed in these mice was comparable to that of MC-deficient hosts; it is T-cell mediated. These findings suggest that MCP6 actively depletes the local environment of IL-6 to maintain tolerance.


Subject(s)
Skin Transplantation/immunology , Transplantation Tolerance/physiology , Transplantation, Homologous/methods , Tryptases/therapeutic use , Adoptive Transfer , Animals , DNA Primers , Female , Immune Tolerance , Interleukin-6/adverse effects , Isoantigens/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Spleen/transplantation , T-Lymphocytes/immunology , Transplantation Tolerance/drug effects , Tryptases/deficiency , Tryptases/genetics
10.
J Allergy Clin Immunol ; 124(5): 1099-105.e1-4, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19748655

ABSTRACT

BACKGROUND: Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic, but the nature and extent of diversity at these loci have not been fully explored. OBJECTIVE: We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations. METHODS: Tryptase allele frequencies were determined by means of direct sequencing in 270 individuals from HapMap populations of European, African, Chinese, and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations. RESULTS: We identify a new frame-shifted tryptase allele (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(FS) is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r(2)=0.83, D'=0.85) yields 2 major and 5 minor tryptase haplotypes. CONCLUSIONS: Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.


Subject(s)
Gene Dosage , Mast Cells/enzymology , Tryptases/genetics , Alleles , Amino Acid Sequence , Cell Line , Gene Frequency , Genotype , Haplotypes/genetics , Humans , Hypersensitivity/enzymology , Hypersensitivity/genetics , Linkage Disequilibrium , Molecular Sequence Data , Polymorphism, Single Nucleotide , Protein Conformation , Sequence Alignment , Tryptases/chemistry , Tryptases/deficiency
11.
J Immunol ; 180(7): 4885-91, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18354212

ABSTRACT

Although the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection.


Subject(s)
Adaptation, Biological/immunology , Immunity, Innate/immunology , Mast Cells/enzymology , Mast Cells/immunology , Trichinella spiralis/immunology , Trichinellosis/immunology , Tryptases/metabolism , Animals , Chronic Disease , Eosinophilia/genetics , Eosinophilia/immunology , Eosinophilia/metabolism , Eosinophilia/pathology , Eosinophils/immunology , Female , Immunoglobulin E/deficiency , Immunoglobulin E/genetics , Immunoglobulin E/immunology , Immunoglobulin E/metabolism , Intestines/immunology , Intestines/parasitology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Trichinellosis/metabolism , Trichinellosis/parasitology , Trichinellosis/pathology , Tryptases/deficiency , Tryptases/genetics , Tryptases/immunology
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