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1.
Eur J Gastroenterol Hepatol ; 20(5): 478-87, 2008 May.
Article in English | MEDLINE | ID: mdl-18403953

ABSTRACT

The etiology of refractory celiac sprue (RCS) is unclear. In a high proportion of cases, the clonal nature of intestinal intraepithelial lymphocytes (IEL) can be demonstrated and a pathogenetic implication of intestinal IEL has been postulated. The prognosis of this subgroup of RCS is poor, with a high risk to develop an overt lymphoma and uncontrolled malabsorption despite steroid/immunosuppressive therapy. Cases with a relatively indolent clinical course, however, exist and their early diagnosis may be difficult. To gain insight into the pathogenic implication of intestinal IEL in refractory celiac sprue, we have performed an extensive phenotypic and functional characterization of clonal intestinal IEL in a patient with an indolent form of refractory celiac sprue, using multiparametric flow cytometry. The abnormal lymphocyte infiltrate lacked surface membrane expression of CD3/T-cell receptor (TCR) complexes (TCR(-), CD4(-), CD8(-), sCD3(-)), but contained intracellular CD3(epsilon) (CyCD3(+)) and surface CD103(+) and CD7(+). In particular, these cells showed a unique spontaneous ex-vivo cytokine secretion profile with an increased percentage of CD3(-) IEL containing TNF-alpha and IL-10, in the absence of IL-2, IL-4 and IFN-gamma. Altogether our results suggest that flow cytometry immunophenotyping of intestinal IEL, in cases suspected of celiac disease and their complicated forms, could be of great help in the correct diagnosis of RCS and the understanding of the immunopathogenic mechanisms of the disease and their clinical and/or therapeutical implications.


Subject(s)
Celiac Disease/immunology , Intestinal Mucosa/immunology , T-Lymphocyte Subsets/immunology , Cell Separation/methods , Cells, Cultured , Cytokines/biosynthesis , Flow Cytometry , Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor , Humans , Immunophenotyping , Male , Middle Aged
2.
J Immunol ; 180(9): 6307-16, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18424754

ABSTRACT

Both mast cells and complement participate in innate and acquired immunity. The current study examines whether beta-tryptase, the major protease of human mast cells, can directly generate bioactive complement anaphylatoxins. Important variables included pH, monomeric vs tetrameric forms of beta-tryptase, and the beta-tryptase-activating polyanion. The B12 mAb was used to stabilize beta-tryptase in its monomeric form. C3a and C4a were best generated from C3 and C4, respectively, by monomeric beta-tryptase in the presence of low molecular weight dextran sulfate or heparin at acidic pH. High molecular weight polyanions increased degradation of these anaphylatoxins. C5a was optimally generated from C5 at acidic pH by beta-tryptase monomers in the presence of high molecular weight dextran sulfate and heparin polyanions, but also was produced by beta-tryptase tetramers under these conditions. Mass spectrometry verified that the molecular mass of each anaphylatoxin was correct. Both beta-tryptase-generated C5a and C3a (but not C4a) were potent activators of human skin mast cells. These complement anaphylatoxins also could be generated by beta-tryptase in releasates of activated skin mast cells. Of further biologic interest, beta-tryptase also generated C3a from C3 in human plasma at acidic pH. These results suggest beta-tryptase might generate complement anaphylatoxins in vivo at sites of inflammation, such as the airway of active asthma patients where the pH is acidic and where elevated levels of beta-tryptase and complement anaphylatoxins are detected.


Subject(s)
Anaphylatoxins/biosynthesis , Complement C3/metabolism , Complement C4/metabolism , Complement C5/metabolism , Mast Cells/metabolism , Tryptases/metabolism , Anaphylatoxins/chemistry , Antibodies, Monoclonal/chemistry , Asthma/enzymology , Complement C3/chemistry , Complement C4/chemistry , Complement C5/chemistry , Dextran Sulfate/chemistry , Dextran Sulfate/metabolism , Heparin/chemistry , Heparin/metabolism , Humans , Hydrogen-Ion Concentration , Immunity, Innate , Mast Cells/chemistry , Protein Structure, Quaternary , Skin/chemistry , Skin/metabolism , Tryptases/chemistry
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