RESUMO
The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Molécula 1 de Adesão Intercelular/genética , Neurite Autoimune Experimental/genética , Neurite Autoimune Experimental/imunologia , Transferência Adotiva , Animais , Autoimunidade/imunologia , Linfócitos B/imunologia , Epitélio , Interleucina-17 , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína P0 da Mielina/imunologia , Bainha de Mielina/imunologia , Nervos Periféricos/imunologia , Nervos Periféricos/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Timo/citologiaRESUMO
Alveolins are a recently described class of proteins common to all members of the superphylum Alveolata that are characterized by conserved charged repeat motifs (CRMs) but whose exact function remains unknown. We have analyzed the smaller of the two alveolins of Tetrahymena thermophila, TtALV2. The protein localizes to dispersed, broken patches arranged between the rows of the longitudinal microtubules. Macronuclear knockdown of Ttalv2 leads to multinuclear cells with no apparent cell polarity and randomly occurring cell protrusions, either by interrupting pellicle integrity or by disturbing cytokinesis. Correct association of TtALV2 with the alveoli or the pellicle is complex and depends on both the termini as well as the charged repeat motifs of the protein. Proteins containing similar CRMs are a dominant part of the ciliate membrane cytoskeleton, suggesting that these motifs may play a more general role in mediating membrane attachment and/or cytoskeletal association. To better understand their integration into the cytoskeleton, we localized a range of CRM-based fusion proteins, which suggested there is an inherent tendency for proteins with CRMs to be located in the peripheral cytoskeleton, some nucleating as filaments at the basal bodies. Even a synthetic protein, mimicking the charge and repeat pattern of these proteins, directed a reporter protein to a variety of peripheral cytoskeletal structures in Tetrahymena. These motifs might provide a blueprint for membrane and cytoskeleton affiliation in the complex pellicles of Alveolata.
Assuntos
Membrana Celular/genética , Citoesqueleto/genética , Metaloendopeptidases/genética , Proteínas de Protozoários/genética , Tetrahymena thermophila/genética , Motivos de Aminoácidos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Polaridade Celular , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Expressão Gênica , Metaloendopeptidases/metabolismo , Dados de Sequência Molecular , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Transporte Proteico , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Tetrahymena thermophila/metabolismo , Tetrahymena thermophila/ultraestruturaRESUMO
Cell-type specific expression of the human diphtheria toxin receptor in generally toxin resistant mice represents an innovative approach for the selective depletion of pre-defined cell populations. We demonstrate that in wildtype mice diphtheria toxin--in concentrations otherwise well tolerated--is highly toxic and lethal together with active immunization irrespective of the immunogenic peptide applied. We found increased lung cellularity as only pathological abnormality. Animal models of inflammatory diseases requiring active immunization including experimental autoimmune encephalomyelitis may thus not be applicable in diphtheria receptor transgenic mice pointing to a major limitation of this otherwise technically interesting approach.
