myelin-basic-protein and Asthma

Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

Topics: Animals; Antibodies, Catalytic; Apoptosis; Asthma; Autoantibodies; Autoimmune Diseases; Biomarkers; Cytotoxicity, Immunologic; DNA; Humans; Hydrolysis; Mice; Multiple Sclerosis; Myelin Basic Protein; Prodrugs; Thyroglobulin; Thyroiditis, Autoimmune; Vasoactive Intestinal Peptide

SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergic mice. Blockade of SHP2 function by SHP2 inhibitor PHPS-1 or conditional shp2 knockdown by adenovirus-inhibited bone-marrow-derived eosinophil differentiation in vitro, with no detectable effects on the apoptosis of eosinophils. Furthermore, SHP2 induced eosinophil differentiation via regulation of the extracellular signal-regulated kinase pathway. Myeloid shp2 conditional knockout mice (LysM(cre)shp2(flox/flox)) failed to induce eosinophilia as well as airway hyper-responsiveness. The SHP2 inhibitor PHPS-1 also alleviated eosinophilic airway inflammation and airway hyper-responsiveness, accompanied by significantly reduced levels of systemic eosinophils and eosinophil lineage-committed progenitors in allergic mice. We demonstrate that inhibition of eosinophil development is SHP2-dependent and SHP2 is sufficient to promote eosinophil formation in vivo. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.

Topics: Animals; Asthma; Benzenesulfonates; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Eosinophils; Extracellular Signal-Regulated MAP Kinases; GATA1 Transcription Factor; Hydrazones; Interleukin-5; Lung; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Ovalbumin; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Recombinant Proteins; Signal Transduction

We evaluated whether bone marrow (BM) inflammatory cells have capacity to traffic into the airways following allergen exposure in a mouse model of allergen-induced airway inflammation. We also evaluated the effect of IL-5 overexpression on (i) the production of eosinophils in BM, (ii) the accumulation of eosinophils, neutrophils and lymphocytes in blood and airways and (iii) the changes in CD34+ cell numbers in BM, blood and airways. Bromodeoxyuridine (BrdU) was used to label cells produced during the exposure period. Furthermore, CD3 splenocytes were adoptively transferred to investigate the BM inflammatory response. Allergen exposure induced traffic of BM eosinophils, neutrophils and lymphocytes to the airways and increased the number of BrdU+ eosinophils, neutrophils, lymphocytes and CD34+ cells in BALf. IL-5 overexpression enhanced the eosinophilopoiesis and increased the presence of BrdU+ eosinophils and CD34+ cells in airways and enhanced the number of CD34+ cells in BM and blood after allergen exposure. Adoptive transfer of CD3 lymphocytes overexpressing IL-5 caused increased BM eosinophilia. In conclusion, allergen exposure induces traffic of not only newly produced eosinophils but also newly produced neutrophils and lymphocytes into the airways.

Topics: Adoptive Transfer; Allergens; Animals; Antigens, CD34; Asthma; Blood Cell Count; Bone Marrow Cells; Bromodeoxyuridine; Bronchoalveolar Lavage Fluid; Eosinophils; Histocytochemistry; Interleukin-5; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Myelin Basic Protein; Neutrophils; Ovalbumin

This study was performed to test the hypothesis that activated eosinophils or their secretory products can directly stimulate sensory neurons to release their neuropeptides. Neurons derived from neonatal rat dorsal root ganglia (DRG), which synthesize and store sensory neuropeptides, were placed in primary cell culture and were exposed to eosinophils or their bioactive mediators. The resultant release of substance P (SP) was measured by enzyme-linked immunosorbent assay and was expressed as a percent (mean +/- SE) of total neuronal SP content. Eosinophils were isolated from human volunteers with a history of allergic rhinitis and/or mild asthma and were activated by incubation with cytochalasin B (5 micrograms/ml) and N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 microM). Activated eosinophils [6 x 10(6)/ml, suspended in Hanks' buffered salt solution (HBSS)] applied to cultured DRG neurons for 30 min increased basal SP release 2.4-fold compared with HBSS-exposed neurons (activated eosinophils 11.10 +/- 2.48% vs. HBSS 4.59 +/- 0.99%; P = 0.002), whereas neither nonactivated eosinophils nor cytochalasin B and FMLP in HBSS influenced SP release. Additional cultured DRG neurons were exposed to soluble products made by eosinophils. Compared with SP release under control conditions (2.37 +/- 0.34%), major basic protein (MBP) increased release in a concentration-related fashion (e.g., 3 microM MBP: 6.23 +/- 0.67%, P = 0.006 vs. control), whereas neither eosinophil cationic protein (3 microM), eosinophil-derived neurotoxin (3 microM), leukotriene D4 (500 nM), platelet-activating factor (100 nM), nor H2O2 (100 microM) affected SP release. These studies demonstrate that activated eosinophils can stimulate cultured DRG neurons directly and suggest that MBP may be the responsible mediator.

Topics: Animals; Animals, Newborn; Asthma; Capsaicin; Cells, Cultured; Coculture Techniques; Cytochalasin B; Enzyme-Linked Immunosorbent Assay; Eosinophils; Ganglia, Spinal; Humans; Myelin Basic Protein; N-Formylmethionine Leucyl-Phenylalanine; Neurons; Platelet Activating Factor; Polylysine; Potassium Chloride; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic, Seasonal; Substance P; Tissue Extracts

The concentrations of the eosinophil (EOS)-derived proteins, major basic protein (MBP), EOS-derived neurotoxin (EDN), EOS peroxidase (EPO), and EOS cationic protein (ECP), and EOS counts were measured in the peripheral blood of 12 atopic subjects with asthma and 23 normal control subjects. The same measurements were performed in seven subjects with asthma with previously documented dual (early plus late) asthmatic responses after inhalation challenges with methacholine and allergen. EOSs (p less than 0.001), MBP (p less than 0.01), EDN (p less than 0.01), and ECP (p greater than 0.03) were elevated in the subjects with asthma compared with control subjects, whereas EPO (p less than 0.01) concentrations were reduced. There were no significant differences between baseline measurements of FEV1, EOSs, MBP, EDN, EPO, or ECP on the methacholine- and allergen-challenge days. When the changes in these variables after allergen challenge were compared with the corresponding changes after methacholine challenge, there were no significant differences at 0 to 60 minutes or at 3 hours, whereas EDN (p less than 0.025), EPO (p less than 0.05), and ECP (p less than 0.025) were relatively increased at 6 to 12 hours and accompanied the late falls in FEV1 (p less than 0.001). EOSs (p less than 0.025) were elevated at 24 hours when there was a small relative increase in MBP (p less than 0.05). EOSs appear to be "activated" in subjects with allergic asthma, and further activation may occur during late asthmatic responses.

Topics: Adult; Asthma; Blood Cells; Blood Proteins; Cell Count; Eosinophil Granule Proteins; Eosinophil Peroxidase; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Humans; Hypersensitivity; Male; Myelin Basic Protein; Neurotoxins; Peroxidases; Ribonucleases

Topics: Asthma; Blood Proteins; Eosinophil Granule Proteins; Eosinophilia; Eosinophils; Humans; Myelin Basic Protein; Ribonucleases

Topics: Animals; Antigens, Neoplasm; Asthma; Cell Migration Inhibition; Diagnostic Errors; Electrophoresis; Female; Guinea Pigs; Humans; Influenza, Human; Leukemia; Lymphocytes; Macrophages; Male; Multiple Sclerosis; Myasthenia Gravis; Myelin Basic Protein; Neoplasm Proteins; Neoplasms; Sarcoidosis