Inscrição na biblioteca: Guest
Portal Digital Begell Biblioteca digital da Begell eBooks Diários Referências e Anais Coleções de pesquisa
Critical Reviews™ in Immunology
Fator do impacto: 1.352 FI de cinco anos: 3.347 SJR: 0.657 SNIP: 0.55 CiteScore™: 2.19

ISSN Imprimir: 1040-8401
ISSN On-line: 2162-6472

Volumes:
Volume 39, 2019 Volume 38, 2018 Volume 37, 2017 Volume 36, 2016 Volume 35, 2015 Volume 34, 2014 Volume 33, 2013 Volume 32, 2012 Volume 31, 2011 Volume 30, 2010 Volume 29, 2009 Volume 28, 2008 Volume 27, 2007 Volume 26, 2006 Volume 25, 2005 Volume 24, 2004 Volume 23, 2003 Volume 22, 2002 Volume 21, 2001 Volume 20, 2000 Volume 19, 1999 Volume 18, 1998 Volume 17, 1997 Volume 16, 1996 Volume 15, 1995 Volume 14, 1994

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v21.i1-3.10
27 pages

On the Initial Trigger of Myasthenia Gravis and Suppression of the Disease by Antibodies Against the MHC Peptide Region Involved in the Presentation of a Pathogenic T-Cell Epitope

M. Zouhair Atassi
Baylor College of Medicine
Minako Oshima
Departments of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas
Philip Deitiker
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas

RESUMO

Myasthenia gravis (MG) is a disabling autoimmune disease caused by autoantibodies (auto-Abs) against the self-acetylcholine receptor (AChR). Although a great deal of information is known about the molecular and cellular parameters of the disease, its initial trigger, however, is not known. To study the 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 a 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 (a12–27, a111–126, a122–138, a182–198) 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 constitute initial 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 C57BL/6 (B6, H-2b) mice by immunization with Torpedo californica (t) AChR. A mutant mouse of B6, B6.C-H-2bm12 (bm12), which has three amino acid changes (at residues 67, 70, and 71) in the I-Abb subunit, is resistant to EAMG development. Recently, we showed that region 62–76 of I-Abb, which contains the above residues, is involved in the binding to a pathogenic T-cell epitope within peptide ta146–162. We have prepared several monoclonal antibodies (mAbs) against peptide I-Abb62–76, which are highly cross-reactive with I-Ab molecules. These mAbs inhibited in vitro the proliferation of disease-related T cells of B6 specific to tAChR peptide ta146–162. 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.


Articles with similar content:

Targeting the Antigen-Binding Site of HLA-Restricting Alleles in Treatment of Autoimmune Disease
Critical Reviews™ in Immunology, Vol.27, 2007, issue 3
Philip Deitiker, M. Zouhair Atassi, Minako Oshima
PART I. Peptide Immunotherapy
Natural and Autoantibodies to Human T-Cell Receptor Vβ Segments: Potential Roles in Immunomodulation

Critical Reviews™ in Immunology, Vol.27, 2007, issue 3
Ian F. Robey, Miranda K. Adelman, Samuel F. Schluter, John J. Marchalonis
Antigen Processing/Presenting and Oncogenesis
Critical Reviews™ in Oncogenesis, Vol.8, 1997, issue 4
Alexander M. Abdelnoor
Lymphocytes, Lymphokines, and Silicosis
Journal of Environmental Pathology, Toxicology and Oncology, Vol.20, 2001, issue Suppl.1
Chris E. Holmes, David R. Hemenway, Linda M. Pfeiffer, Gerald S. Davis
T-Cell Receptor-Derived Peptides in Immunoregulation and Therapy of Retrovirally Induced Immunosuppression
Critical Reviews™ in Immunology, Vol.21, 2001, issue 1-3
Ian F. Robey, Ronald R. Watson, R. Tomas Sepulveda, Allen B. Edmundson, John J. Marchalonis