RESUMO
Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200-239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.
Assuntos
Autoanticorpos/metabolismo , Doenças Fetais/metabolismo , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/metabolismo , Ribonucleoproteínas/metabolismo , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Epitopos/metabolismo , Feminino , Doenças Fetais/etiologia , Bloqueio Cardíaco/etiologia , Homeostase , Humanos , Imuno-Histoquímica , Troca Materno-Fetal/fisiologia , Dados de Sequência Molecular , Miócitos Cardíacos/metabolismo , Gravidez , Ratos , Proteínas Recombinantes/metabolismo , Ribonucleoproteínas/genética , SuéciaRESUMO
The major histocompatibility complex (MHC) regulates multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE). We created four new intra-MHC recombinant rat strains, between the MHC haplotypes RT1(n) (BN) and RT1(l) (LEW) on the LEW background, to define disease regulation and localization within the MHC. Immunization with recombinant myelin oligodendrocyte glycoprotein (a.a.1-125; MOG)/IFA induced EAE in strains expressing the MHC class II allele RT1.B(n), whereas strains expressing the RT1.B(l) were resistant. In myelin basic protein peptide (MBP(GP)63-88)/CFA-induced EAE, RT1.B(l) expressing strains were susceptible whereas strains expressing the RT1.B(n) were resistant. High levels of antigen-specific IFN-gamma secreting lymphoid cells and antigen-specific serum IgG antibodies were only recorded in rats with an MHC class II allele that permitted MOG- or MBP-EAE, respectively. Genetically, we localized the MHC regulation of the investigated EAE models to the central part of the MHC, containing the MHC class II (RT1.B/D) and the centromeric parts of the MHC class III. No influences were evident from the classical MHC class I (RT1.A), the telomeric parts of the MHC class III or the non-classical MHC class I (RT1.C/E/M) in contrast to previous reports. The MHC class II haplotype-specific regulation of EAE induced with two different CNS antigens demonstrates a strikingly specific MHC-association even within the same target organ.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Haplótipos , Complexo Principal de Histocompatibilidade/genética , Proteína Básica da Mielina/imunologia , Glicoproteína Associada a Mielina/imunologia , Animais , Animais Congênicos , Células Apresentadoras de Antígenos/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Cobaias , Imunização/métodos , Proteínas da Mielina , Glicoproteína Mielina-Oligodendrócito , Fenótipo , Ratos , Ratos Endogâmicos Lew , Especificidade da Espécie , Fatores de TempoRESUMO
With a panel of rat strains, we demonstrate a strong impact of the MHC genotype on susceptibility and disease course in experimental autoimmune neuritis induced with peripheral nerve myelin or the P2 peptide 58-81 (KNTEISFKLGQEFEETTADNRKTK). Beside the MHC genotype, non-MHC genes determined disease susceptibility and resistance. The type of disease induced with P2 58-81 was strongly correlated to the strength of the MHC class II isotype interaction with P2 58-81. These findings suggest a link between susceptibility and acute versus chronic disease courses on one hand and the strength of the MHC class II molecule/peptide affinity on the other hand.