myelin-basic-protein and Hypersensitivity

Current drug-based therapies for autoimmune and allergic conditions are non-specific and often associated with severe side effects. Recent advances in our knowledge of how T cells see antigens points to an improved strategy. T lymphocytes recognise processed forms of antigen which can be mimicked by synthetic peptides designed and built in the laboratory. It is clear from recent work that these synthetic peptides, when given systemically in solution, induce a state of hyporesponsiveness in naive T cells thereby specifically preventing a subsequent immune response. Moreover systemic administration of soluble peptides can inhibit ongoing immune responses. Taken together this new information offers great promise for future development of antigen-based drugs for the treatment of autoimmune and allergic diseases.

Topics: Adult; Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; Dosage Forms; Drug Administration Routes; Humans; Hypersensitivity; Immune Tolerance; Immunodominant Epitopes; Immunotherapy; Myelin Basic Protein; Peptides; T-Lymphocytes

Neuropathic pain is a debilitating condition in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Specific myelin basic protein (MBP) peptides are encephalitogenic, and myelin-derived altered peptide ligands (APLs) are capable of preventing and ameliorating EAE. We investigated the effects of active immunisation with a weakly encephalitogenic epitope of MBP (MBP87-99) and its mutant APL (Cyclo-87-99[A(91),A(96)]MBP87-99) on pain hypersensitivity and neuroinflammation in Lewis rats. MBP-treated rats exhibited significant mechanical and thermal pain hypersensitivity associated with infiltration of T cells, MHC class II expression and microglia activation in the spinal cord, without developing clinical signs of paralysis. Co-immunisation with APL significantly decreased pain hypersensitivity and neuroinflammation emphasising the important role of neuroimmune crosstalk in neuropathic pain.

Topics: Animals; Disease Models, Animal; Exploratory Behavior; Freund's Adjuvant; Histocompatibility Antigens Class II; Humans; Hypersensitivity; Ligands; Lymphocyte Activation; Male; Microglia; Myelin Basic Protein; Myelitis; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Rats; Rats, Inbred Lew; Spinal Cord; T-Lymphocytes; Time Factors; Vaccination

Etiology of autism has become an area of a significant controversy. Allergy induced autism is an area of research wherein immune responses to some allergens may play a pathogenic role in autism. Allergy may induce the production of brain specific auto-antibodies in a subgroup of autistic children. We are the first to investigate the possible link between allergic manifestations and serum levels of both anti-myelin basic protein (anti-MBP) and anti-myelin associated glycoprotein (anti-MAG) brain-specific auto-antibodies, which were measured by ELISA method, in 42 autistic children in comparison to 42 healthy-matched children. Allergic manifestations (bronchial asthma, atopic dermatitis and/or allergic rhinitis) were found in 47.6% of autistic patients. Increased serum levels of anti-MBP and anti-MAG auto-antibodies were found in 57.1% and 66.7%, respectively of autistic children. In addition, 78.5% of autistic children had increased serum levels of both anti-MBP and/or anti-MAG auto-antibodies. Autistic patients with allergic manifestations had significantly higher serum levels of anti-MBP and anti-MAG auto-antibodies than those without these manifestations (P<0.001 and P=0.001, respectively). In conclusion, allergy may be a contributing factor to the increased serum levels of anti-MBP and anti-MAG auto-antibodies in some autistic children. Indeed, we need to know more about the links between allergy, immune system and brain in autism for finding new therapeutic modalities in autism.

Topics: Autistic Disorder; Autoantibodies; Biomarkers; Brain; Child; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Hypersensitivity; Male; Myelin Basic Protein; Myelin-Associated Glycoprotein

Eosinophils play a central role in the pathogenesis of allergic diseases and host protection against parasites, especially against helminths.. Eosinophil granules contain cytotoxic proteins, including cationic proteins: major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil derived neurotoxin (EDN).. Eosinophil granule proteins are implicated in the occurrence of allergic diseases and Churg-Strauss syndrome. These proteins are activation markers of eosinophils and may be useful in clinical practice.

Topics: Biomarkers; Blood Proteins; Churg-Strauss Syndrome; Cytoplasmic Granules; Eosinophils; Humans; Hypersensitivity; Myelin Basic Protein

Treatment of human autoimmune diseases may be enhanced by using adjuvants that can selectively induce immunoregulatory responses. Two versions of a novel nonionic block copolymer adjuvant suitable for human use, Optivax Oil Formulation (OF) and Optivax Aqueous Formulation (AF), were evaluated for induction of immunity to encephalitogenic and regulatory T-cell receptor (TCR) V-gene determinants. In Lewis rats immunized with myelin basic protein (BP), Optivax OF was more efficient than Optivax AF for inducing delayed type hypersensitivity (DTH), T-cell proliferation, antibodies, and even mild clinical signs of experimental autoimmune encephalomyelitis (EAE). Similarly, Optivax OF was more efficient for inducing inflammatory T-cell and antibody responses to immunoregulatory V beta 8.2 proteins and peptides than Optivax AF, which induced a noninflammatory Th2 response. In general, DTH response to the various immunogens was reflected by increased cellularity and mRNA levels for IFN-gamma in draining lymph nodes, whereas LN cell proliferation without DTH was characterized by increased IL-2 mRNA levels but low or absent IFN-gamma message. These data suggest important differential adjuvant effects of Optivax OF versus Optivax AF on the respective induction of Th1 versus Th2 responses that may be useful in the selective treatment of human immune disorders.

Topics: Adjuvants, Immunologic; Animals; Autoantibodies; Autoimmune Diseases; Female; Hypersensitivity; Lymph Nodes; Myelin Basic Protein; Polymers; Rats; Rats, Inbred Lew; T-Lymphocytes

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

Peptide CN1, a large 93 residue peptide, derived from residues 21-113 of the bovine and rabbit P2 protein of sciatic nerve myelin, induces severe allergic neuritis in Lewis rats. When complexed with phosphatidylserine and tested at 50 microgram dosage in Freund's complete adjuvant, it induces severe clinical and histologic signs (cellular infiltration and demyelination of the sciatic nerve) in most animals. It is as potent in disease induction as the P2 protein on a weight basis. In contrast, when not complexed with phosphatidylserine, Peptide CN1 induced only mild clinical signs and histologic lesions in 3 of 10 rats. CNBr peptides CN2 and CN3, derived from the carboxyl and amino terminal ends, respectively, were not active. Spleen and lymph node cells from rats sensitized to Peptide CN1 responded to both P2 and Peptide CN1 in culture in the mitogenic assay. These data show that the major neuritogenic domain for the rat resides in the CN1 region.

Topics: Animals; Cattle; Hypersensitivity; Lymph Nodes; Mitogens; Myelin Basic Protein; Myelin P2 Protein; Myelin Proteins; Neuritis; Peptide Fragments; Rabbits; Rats; Rats, Inbred Lew; Spleen

Topics: Animals; Body Weight; Disease Susceptibility; Female; Hypersensitivity; Immunity, Cellular; Immunization; Lymphocyte Activation; Male; Myelin Basic Protein; Myelin P2 Protein; Neuritis; Rats

Cleavage of bovine P2 protein by cyanogen bromide (CNBr) produced peptide fractions CN1, CN2, and CN3 which were isolated by gel filtration chromatography. CN2 was found to contain two NH2-terminals (lysine and valine) and accounted for both of the cysteine residues of P2. When reduced carboxymethylated P2 (RCM-P2) was digested with CNBr, peptides CN1 and CN3 were obtained as were (1) a peptide with NH2-terminal lysine (Lys) that contained no homoserine and only one cysteine residue and (2) a peptide with NH2-terminal valine (Val) that was co-eluted with CN3. These data and the chemical characterization of all the CNBr peptides obtained from P2 and RCM-P2 suggest that isolated P2 protein has a structure composed of the CNBr peptides in the order CN3-CN1-CN2(Val)-CN2(Lys) with an intrachain disulfide bond between the cysteine residues located in the two constituent peptides of CN2, CN2(Lys) and CN2(Val). To locate the neuritogenic region(s) within the P2 protein structure, CN1, CN2, and CN3 were tested for the ability to induced experimental allergic neuritis (EAN) in Lewis rats. The disease-inducing sites of P2 protein were found only in CN1; neither CN2 nor CN3 produced disease. EAN induced by CN1 was comparable to that induced with P2 protein as determined by disease onset, clinical symptoms, and histologic lesions.

Topics: Amino Acids; Animals; Cattle; Chemical Phenomena; Chemistry; Cyanogen Bromide; Disease Models, Animal; Female; Hypersensitivity; Myelin Basic Protein; Myelin P2 Protein; Peptide Fragments; Peripheral Nerves; Polyradiculoneuropathy; Rats; Structure-Activity Relationship

Topics: Amino Acids; Animals; Antigens; Cattle; Cerebrosides; Cholesterol; Deoxycholic Acid; Electrophoresis, Disc; Hypersensitivity; In Vitro Techniques; Microscopy, Electron; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Neuritis; Nucleotides; Peripheral Nerves; Phospholipids; Phosphoric Diester Hydrolases; Spinal Cord; Spinal Nerve Roots; Surface-Active Agents