Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic association of some immune-mediated human uveitic diseases with histocompatibility antigens, ethnic origin, familial background, or gender have suggested the presence a hereditary component in susceptibility. Experimental autoimmune uveoretinitis (EAU) can be induced in inbred rodents by immunization with evolutionarily conserved retinal proteins, and mimics many features of human uveitis. Susceptibility to EAU is genetically controlled, and the model is being used to study mechanisms that might affect susceptibility to ocular autoimmune disease. EAU expression in mice and in rats requires the presence of both a susceptible MHC haplotype and a "permissive" genetic background. MHC control of susceptibility in H-2k mice was tentatively mapped to the I-A subregion (HLA-DR equivalent), implicating epitope recognition as a major mechanism in susceptibility. In contrast, expression of the I-Ek gene product (HLA-DQ equivalent) appeared to have an ameliorating effect on disease. Susceptible H-2 haplotypes exhibited highest disease scores on the B10 background, and disease was reduced, or even absent, on some other (nonpermissive) backgrounds. Factors which may determine "permissiveness" or "nonpermissiveness" of a particular genetic background, as studied in mice and rats, may include regulation of responses to lymphokines, hypothalamic-adrenal-pituitary axis hormones, mast cell/vascular effects, and possibly the T cell repertoire. The data are interpreted to suggest that, in individuals susceptible to uveitis by virtue of their MHC, the final expression of disease will be determined by the genetic background. These results might help to explain why only a minority of individuals with a susceptible HLA type develop uveitis, as well as the variable incidence of disease in HLA-identical populations of different ethnic backgrounds.
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PMID:Immunogenetic aspects of clinical and experimental uveitis. 129 Jul 50

A comparison was made of the capacity of bone marrow cells (BM) from genetically distinct strains of mice to develop into mast cells under defined conditions of in vitro culture. In the presence of conditioned media derived from ConA treated spleen cells from normal or Trichinella spiralis-infected mice, mast cell development occurred readily. After 21 days of culture mast cells comprised more than 90% of the total cell population. BM taken from certain strains of mice (SWR and NIH) produced large numbers of mast cells, total cell numbers increasing between 2 and 5 fold; other strains (C57BL/10 [B10] B10 congenics) produced relatively few mast cells, total cell numbers not increasing above the starting concentration or declining during culture. The genetic factors determining the strain-response phenotype (no. of mast cells in culture) were predominantly associated with the background genome. No significant differences in response were noted between the B10 congenic strains B10 [H-2b], B10.G [H-2q] or B10.BR [H-2k], which differ only at the MHC, whereas major differences were seen between B10.G and the other H-2q strains [SWR and NIH]. Response phenotype was not inherited as a simple dominant trait; F1 progeny of high x low responder strains were intermediate between the parental values. The expression of genetic influences upon mast cell response phenotype appears to be at both the level of mast cell precursor cells, as determined from limiting dilution assays of BM from high, low and F1 (high x low) strains, and at the level of mast cell proliferation, as determined by repeated sub-culture of mast cells from these strains.
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PMID:Genetic control of mast cell development in bone marrow cultures. Strain-dependent variation in cultures from inbred mice. 320 55

The number of mast cells in connective tissue from dorsal skin varied markedly among mouse strains. Inbred strains of mice were typed into three groups, high (NC and NZB mice), low (B6, B10, and BALB/c mice), and intermediate (C3H/He and DBA/2 mice), by their mast cell content in the skin. However, the strain differences in the number of mast cells was marginal at the age of weaning but became distinct with age. This could be explained mainly by the frequently observed clustering of mast cells in adult NC and NZB mice and the rarely observed clustering in younger mice as well as in adult B10 and BALB/c mice. The breeding experiment revealed that the difference in the number of mast cells between NC and B10 mice was controlled by a single autosomal dominant locus, for which we propose the designation Mcr (mast cell regulator). The role of the Mcr locus with regard to the frequency of the mast cell population in connective tissue is discussed.
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PMID:Single-locus control of the mast cell population in mouse skin. 361 Feb 52

Mast cells were studied during the induction of chronic graft-vs-host disease (GVHD) induced in mice across minor histocompatibility barriers. B10.D2 spleen cells (or control BALB/c cells) were injected into irradiated (600 rad) BALB/c recipients. Serial skin biopsies were taken over 26 days, during which time changes occurred resembling scleroderma, namely, dermal fibrosis, a mononuclear cell infiltrate, and loss of fat and appendages. Mast cells, when stained with toluidine blue, "disappeared" from GVHD, but not from control skin. Ultrastructural analysis showed that mast cells in GVHD skin were indeed present but underwent degranulation. Some mast cells showed only pale expanded sacs, indicating granule depletion. Because these cells could not be seen by toluidine blue staining but were plainly present, we have called them "phantom mast cells." Cellular activation occurred in many GVHD mast cells as shown by increased cytoplasmic activity, with numerous Golgi complexes, ribosomes, granular endoplasmic reticulum, and small vesicles. No identifiable mast cells were seen after day 19. No significant changes were seen in the mast cells of syngeneic control mice. We believe that immunologic processes in chronic GVHD cause a slow release of mast cell granule contents, which is different from anaphylactic degranulation. The depleted mast cells (invisible by toluidine blue staining) are also activated, perhaps in an attempt to replete their stores of granule contents. We discuss the relation of mast cell changes to fibrosis.
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PMID:Mast cell "disappearance" in chronic murine graft-vs-host disease (GVHD)-ultrastructural demonstration of "phantom mast cells". 374 20

A murine model of chronic graft-versus-host disease (GVHD) was induced across minor histocompatibility barriers. This was done by injecting B10.D2 (H-2d) spleen cells into irradiated BALB/c (H-2d) mice. Chronic GVHD in this model includes features common to human idiopathic scleroderma, such as dermal fibrosis, loss of dermal fat and appendages, and a mononuclear cell filtrate. Serial skin biopsies showed a progressive loss of stainable mast cells in GVHD but not in irradiated controls. Mast cell depletion was noted as well in the tongue and kidney capsule of GVHD mice. Mast cell depletion was noted as early as 11 days after GVHD induction and persisted for at least 56 days. A hypothesis is put forth linking the T-cell activation of GVHD, mast cell degranulation, and increased fibrosis. The pertinence of this hypothesis to idiopathic scleroderma is pointed out.
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PMID:Mast cell depletion in murine chronic graft-versus-host disease. 398 Oct 34

We explored the pathologic changes in the skin of mice undergoing a chronic graft-versus-host (GVH) reaction. In rodents and in man, chronic GVH includes the deposition of excess collagen in the skin-a reaction which resembles idiopathic scleroderma. GVH disease across minor histocompatibility barriers was produced by injecting B10.D2 cells into irradiated BALB/c mice. These strains are identical at the H-2 and Mls loci but differ in minor histocompatibility antigens. Control BALB/c mice received irradiation and BALB/c cells. Serial skin biopsies were taken and studied for histological changes characteristic of chronic GVHD, for mast cell density, and for the deposition of immunoreactants. GVHD was produced in B10.D2----BALB/c mice as measured by body weight loss and the production of skin changes including dermal fibrosis, loss of fat and appendages, and a mononuclear cell infiltrate. Dermal mast cells, assessed by toluidine blue staining, were normal at Day 11, but had disappeared by Days 21-63 and returned to normal by Day 104. Immunoglobulins IgG, IgA, and IgM appeared at the dermo-epidermal junction and along the basement membrane zone of hair follicles. This deposition was maximal at Day 42 and waned thereafter. Thus the appearance of immunoglobulins in the skin was maximal when mast cell staining was minimal. The changes in this GVHD model leading to a scleroderma-like picture in the skin are compatible with an immune etiology for the fibrosis. Vasodilation following liberation of mast cell mediators would facilitate the deposition of immunoglobulins. The disappearance of mast cell staining may be caused by extensive degranulation. We postulate an interaction between GVHD-activated T cells, mast cell stimulation, fibroblast activation, and fibrosis.
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PMID:Chronic graft-versus-host disease as a model for scleroderma. II. Mast cell depletion with deposition of immunoglobulins in the skin and fibrosis. 401 62

The ferredoxin (Fd) molecule is a small non-mammalian immunogenic protein containing 55 amino acid residues with only two major antigenic determinants located with the NH2-terminal heptapeptide and the COOH-terminal pentapeptide. Selective enzyme cleavages of Fd with either trypsin or carboxypeptidase A result in the inactivation of the antigenic determinants by the removal of a tripeptide at the NH2-terminal and two amino acid residues at the COOH-terminal, effectively leaving 52 and 53 amino acid fragments respectively, each containing a single antigenic determinant. Fd digested with both enzymes yielded a 50 amino acid peptide with both determinants inactivated. Purity of these digests was assessed using monoclonal antibodies in standard and antigen-blocking ELISAs. The doubly digested peptide had virtually no reactivity with anti-Fd sera, reconfirming that the central cysteine-rich region is serologically silent. It was found that the sum of the reactivities of the N- and C-determinant-bearing peptides as equal to that of the native Fd and that the ratio of the reactivities could be used to assess determinant selectivity in the response to Fd in congenic recombinant strains of mice. This method was used in mapping the determinant selectivity in the antibody response to the MHC of mice to the left of the I-B subregion. Use of the B10.HTT strain indicated that separate genes mapping to the same subregion code for the magnitude of the antibody response and the determinant selectivity of the response.
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PMID:The use of unideterminant fragments of ferredoxin in the genetic mapping of determinant specificity of the immune response. 618 Mar 12

Inbred strains of mice showed marked variation in their mast cell (MC) response to infection with Trichinella spiralis. Variation was under genetic control, the ability to respond to infection being inherited as a dominant trait. MHC-linked genes may influence the absolute level of response, but overall response kinetics appear to be controlled by genes which are not linked to the MHC. An enhanced MC response was transferred adoptively with immune mesenteric lymph node cells (IMLNC), but reciprocal adoptive transfers between H-2 compatible rapid (NIH) and slow (B10.G) responder strains showed that the degree of enhancement was determined by the response phenotype of the recipient, not that of the donor. Similarly, in bone marrow (BM) chimaeras, produced by reconstituting lethally irradiated F1 (B10.G x NIH) mice with parental BM, the MC response to T. spiralis was determined by the response phenotype of the BM donor, whether or not rapid responder IMLNC were transferred. The data are discussed in terms of a T lymphocyte regulated, bone marrow stem cell origin of mucosal MC and interpreted as showing that genetic regulation of the MC response is expressed at the level of stem cell or precursor response to T cell derived mastopoietic factors.
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PMID:Genetic factors controlling the intestinal mast cell response in mice infected with Trichinella spiralis. 712 7

The skin is a major target organ for graft-versus-host disease (GVHD), the principal complication of allogeneic bone marrow transplantation. The purpose of the present study was to test whether mast cell degranulation might be related to early target cell injury in the development of acute GVHD. We employed two irradiated murine strain combinations, one in which disease was mediated by CD4+ effector T cells (B10.D2-->DBA/2), and the other by CD8+ effector T cells (B10.BR-->CBA). As compared to controls, both models exhibited mast cell degranulation of differing extents and patterns, as well as dyskeratosis in the epidermis before the influx of effector lymphocytes. These results suggested that factors produced and released by degranulated dermal mast cells might contribute to early target cell injury. Accordingly, the possible role of tumor necrosis factor (TNF)-alpha, a cytokine recently discovered in mast cell granules, was investigated by the injection of anti-TNF-alpha antibody during the course of disease mediated by either CD4+ or CD8+ T cells. Although overall survival of recipients undergoing CD4+ T-cell-mediated GVHD was only slightly improved and the extent of mast cell degranulation was not affected by anti-TNF-alpha antibody treatment, the skin exhibited a significant diminution in the number of dyskeratotic cells/linear mm at 3-4 weeks post-transplantation. In contrast, anti-TNF-alpha antibody failed to enhance survival or reduce the number of dyskeratotic cells in the skin during CD8+ T-cell-mediated disease. Finally, to determine whether CD8+ T-cell-mediated GVHD was at all dependent upon mast cell involvement, the C3H.SW-->B6WWv strain combination was utilized, in which recipients were genetically deficient in mast cells. Onset of GVHD was significantly delayed in B6WWv mice and was clearly correlated to the appearance and increase of de novo mast cells at later time points.
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PMID:Role of mast cells in early epithelial target cell injury in experimental acute graft-versus-host disease. 790 82

Endotoxin induced uveitis in the mouse provides a useful animal model for acute anterior uveitis in humans. We have investigated the susceptibility of endotoxin-induced uveitis among various mouse strains, and have examined the relationship between genetic background and the resultant inflammatory response to endotoxin. We studied ten strains with differing major histocompatibility-2 genes, lipopolysaccharide response gene, and strains with mast cell depletion and its sham control. Anterior uveitis was induced by injecting 300 micrograms of Salmonella typhimurium endotoxin into one hind footpad. Mice were then killed 8, 12, 16, 20, 24, 48 and 72 hr after endotoxin injection, and vertical sections of the eyes through the pupil-optic nerve axis were evaluated for ocular inflammation. C3H/HeN mice developed severe uveitis. In contrast, C3H/HeJ mice (lipopolysaccharide response gene-) did not develop uveitis even though it has the same genetic background and shares the same major histocompatibility-2 haplotype with C3H/HeN mice (lipopolysaccharide response gene+). The strain that was mast-cell deficient (W/Wv) developed minimal uveitis; however, W/+ mice, with mast cells, developed more inflammation at 48 and 72 hr after endotoxin injection. C3H.SW and FVB/N mice also developed severe uveitis, and BALB/C, CBA/J, and B10.A developed mild uveitis. In conclusion, there is a wide variation in the magnitude and susceptibility to endotoxin among mouse strains. Multiple factors appear to influence this variability, including non-histocompatibility-2 genetic background, the lipopolysaccharide response gene, and the presence of mast cells.
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PMID:Endotoxin induced uveitis in the mouse: susceptibility and genetic control. 865 5


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