ABSTRACT
The homeostatic chemokine CXCL13 is preferentially produced in B-follicles and is crucial in the lymphoid organ development by attracting B-lymphocytes that express its selective receptor CXCR5. Follicular dendritic cells (FDCs) have been identified as the main cellular source of this chemokine in lymphoid organs. Recently, genome-wide approaches have suggested follicular CD4 T-helper cells (T(H)F) as additional CXCL13 producers in the germinal centre and the neoplastic counterpart of T(H)F (CD4+ tumour T-cells in angioimmunoblastic T-cell lymphoma) retains the capability of producing this chemokine. In contrast, no data are available on CXCL13 expression on FDC sarcoma (FDC-S) cells. By using multiple approaches, we investigated the expression of CXCL13 at mRNA and protein level in reactive and neoplastic FDCs. In reactive lymph nodes and tonsils, CXCL13 protein is mainly expressed by a subset of FDCs in B-cell follicles. CXCL13 is maintained during FDC transformation, since both dysplastic FDCs from 13 cases of Castleman's disease and neoplastic FDCs from ten cases of FDC-S strongly and diffusely express this chemokine. This observation was confirmed at mRNA level by using RT-PCR and in situ hybridization. Of note, no CXCL13 reactivity was observed in a cohort of epithelial and mesenchymal neoplasms potentially mimicking FDC-S. FDC-S are commonly associated with a dense intratumoural inflammatory infiltrate and immunohistochemistry showed that these lymphocytes express the CXCL13 receptor CXCR5 and are mainly of mantle zone B-cell derivation (IgD+ and TCL1+). In conclusion, this study demonstrates that CXCL13 is produced by dysplastic and neoplastic FDCs and can be instrumental in recruiting intratumoural CXCR5+ lymphocytes. In addition to the potential biological relevance of this expression, the use of reagents directed against CXCL13 can be useful to properly identify the origin of spindle cell and epithelioid neoplasms.
Subject(s)
Biomarkers, Tumor/analysis , Chemokine CXCL13/analysis , Dendritic Cells, Follicular/immunology , Sarcoma/immunology , Adolescent , Adult , Aged , Castleman Disease/immunology , Chemokine CXCL13/genetics , Female , Humans , Immunohistochemistry , In Situ Hybridization/methods , Lymph Nodes/immunology , Male , Middle Aged , Palatine Tonsil/immunology , RNA, Messenger/analysis , Receptors, CXCR5/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , T-Lymphocytes/metabolismABSTRACT
The b-lactamases catalyze the hydrolysis of the b-lactam bond of a variety of b-lactam antibiotics destroying their antibacterial activity. During the last decades, there has been an inexorable spread of b-lactamase genes into species that previously were not known to possess them. One approach to combat the action of the b-lactamase is to inhibit the enzyme. However, inhibition of b-lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use. This review takes recent examples of synthetic b-lactam compounds developed as active-site serine b-lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.
Subject(s)
Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , beta-Lactamases/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Binding Sites , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Hydrolysis , Serine/chemistry , Stereoisomerism , beta-Lactamase Inhibitors , beta-Lactamases/classification , beta-LactamsABSTRACT
Acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (GPP) are rare pustular skin disorders with systemic involvement. IL-17A/F is a proinflammatory cytokine involved in various neutrophilic inflammatory disorders. Here we show that IL-17A/F is highly expressed by innate immune cells such as neutrophils and mast cells in both AGEP and GPP.
Subject(s)
Acute Generalized Exanthematous Pustulosis/metabolism , Immunity, Innate , Inflammation Mediators/metabolism , Interleukin-17/metabolism , Mast Cells/metabolism , Neutrophils/metabolism , Psoriasis/metabolism , Skin/metabolism , Acute Generalized Exanthematous Pustulosis/genetics , Acute Generalized Exanthematous Pustulosis/immunology , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Inflammation Mediators/immunology , Interleukin-17/genetics , Interleukin-17/immunology , Male , Mast Cells/immunology , Middle Aged , Neutrophils/immunology , Psoriasis/genetics , Psoriasis/immunology , RNA, Messenger/metabolism , Signal Transduction , Skin/immunology , Young AdultABSTRACT
The benzyl 6-fluoro-penicillanate sulfides 4a, 6a, 7a; and sulfones 6c, 7d were synthesized. The conversion to their free acids 4b, 6b, 6d, 7b, 7e and potassium salts 7c, 7f are described. These acids and salt 7c were evaluated as beta-lactamase inhibitors using beta-lactamase I from Bacillus cereus. The data indicate that substitution of the 6 alpha-hydrogen by a 6 alpha-fluorine atom on 6 beta-bromopenicillanic acid (1), leads to loss of beta-lactamase inhibitory activity. In the case of the isomers 6 beta- and 6 alpha-fluoropenicillanic acids the 6 beta-enantiomer proved to be considerably more potent. Potassium salts of 6 beta-fluoropenicillanate sulfide and sulfone were unstable in solid state and in water solution. The fragmentation of the sulfone in two parts in water solution is consistent with the hydrolytic behavior to the penicillanic acid sulfone (2) with 0.5 N NaOH.