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Titolo:
On the initial trigger of myasthenia gravis and suppression of the diseaseby antibodies against the MHC peptide region involved in the presentation of a pathogenic T-cell epitope
Autore:
Atassi, MZ; Oshima, M; Deitiker, P;
Indirizzi:
Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA Baylor Coll Med Houston TX USA 77030 Dept Biochem, Houston, TX 77030 USA Baylor Coll Med, Dept Mol Biol, Houston, TX 77030 USA Baylor Coll Med Houston TX USA 77030 Dept Mol Biol, Houston, TX 77030 USA Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA Baylor Coll Med Houston TX USA 77030 Dept Immunol, Houston, TX 77030 USA
Titolo Testata:
CRITICAL REVIEWS IN IMMUNOLOGY
fascicolo: 1-3, volume: 21, anno: 2001,
pagine: 1 - 27
SICI:
1040-8401(2001)21:1-3<1:OTITOM>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
CALIFORNICA ACETYLCHOLINE-RECEPTOR; SPERM-WHALE MYOGLOBIN; ALPHA-NEUROTOXIN BINDING; SODIUM DODECYL-SULFATE; IR GENE-CONTROL; EXTRACELLULAR PART; IMMUNE-RESPONSE; GAMMA-SUBUNIT; MONOMETHOXYPOLYETHYLENE GLYCOL; ANTIGENIC STRUCTURES;
Keywords:
antibodies; antigen mimicry; antigen presentation; autoimmune disease; immunotherapy; MHC; microbial antigens; myasthenia gravis; synthetic peptides;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
95
Recensione:
Indirizzi per estratti:
Indirizzo: Atassi, MZ Baylor Coll Med, Dept Biochem, 1 Baylor Plaza, Houston, TX 77030 USA Baylor Coll Med 1 Baylor Plaza Houston TX USA 77030 X 77030 USA
Citazione:
M.Z. Atassi et al., "On the initial trigger of myasthenia gravis and suppression of the diseaseby antibodies against the MHC peptide region involved in the presentation of a pathogenic T-cell epitope", CR R IMMUN, 21(1-3), 2001, pp. 1-27

Abstract

Myasthenia gravis (MG) is a disabling autoimmune disease caused by autoantibodies (auto-Abs) against the self-acetylcholine receptor (AChR). Althougha great deal of information is known about the molecular and cellular parameters of the disease, its initial trigger, however, is not known. To studythe possibility of the involvement of microbial antigens that mimic AChR in triggering MG, we have searched the microbial proteins in the data bank for regions that are similar in structure to the regions of human (h) AChR alpha chain recognized by auto-Abs in MG patients. Hundreds of candidate structures on a large number of bacterial and viral proteins were identified. To test the feasibility of the idea, we synthesized four microbial regions similar to each of the major autodeterminants of hAChR (alpha 12-27, alpha 111-126, alpha 122-138, alpha 182-198) and investigated their ability to bind auto-Abs in MG and normal sera controls. It was found that MG sera potentially recognized a significant number of these microbial regions. The results indicate that in some MG cases, immune responses to microbial antigens may cross-react with self-antigen (in this case hAChR) and could constituteinitial triggers of the disease. Although anti-AChR Abs directly contribute to the degradation of AChR at the neuromuscular junctions, autoreactive T cells provide help to B cells that synthesize anti-AChR auto-Abs. To cause MG, T cells must recognize the pathogenic epitopes in the context of MHC class II molecules related to MG. The ability to regulate AChR presentation (hence AChR-reactive T-cell activation) could form the basis of an effective strategy for the control of autoimmunity in MG by selectively inhibiting the function of the Ir gene loci linked to disease susceptibility. An animal model of MG (experimental autoimmune MG, EAMG) can be induced in C57BL6 (B6, H-2(b)) mice by immunization with Torpedo californica (t) AChR. A mutant mouse of B6, B6.C-H-2(bm12) (bm12), which has three amino acid changes (at residues 67, 70, and 71) in theI-A beta (b) subunit, is resistant to EAMG development. Recently, we showed that region 62-76 of I-A beta (b), which contains the above residues, is involved in the binding to a pathogenic T-cell epitope within peptide t alpha 146-162. We have prepared several monoclonal antibodies (mAbs) against peptide I-A beta (b)62-76, which are highly cross-reactive with I-A(b) molecules. These mAbs inhibited in vitro the proliferation of disease-related T cells of B6 specific to tAChR peptide t alpha 146-162. Passive transfer of these mAbs suppressed the occurrence of clinical EAMG, which was accompanied by lower T-cell and Ab responses to tAChR. The results indicated that blocking disease-related MHC by targeting a disease-associated region on MHC molecules could be an effective, straightforward, and feasible strategy for immunointervention in MG.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/09/20 alle ore 03:47:48