Epitope spreading occurs in active but not passive EAE induced by myelin basic protein

The sequential emergence of specific T lymphocyte-mediated immune reactivity directed against multiple distinct myelin epitopes (epitope spreading) has been associated with clinical relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Based on this association, an appealing and plausible model for immune-mediated progression of the advancing clinical course in MS and EAE has been proposed in which epitope spreading is the cause of clinical relapses in T cell-mediated CNS inflammatory diseases. However, the observed association between epitope spreading and disease progression is not universal, and absolute requirements for epitope spreading in progressive EAE have not been tested in the absence of multiple T cell specificities, because most prior studies have been conducted in immunocompetent mouse strains that possessed broad TCR repertoires. Consequently, the precise nature of a causal relationship between epitope spreading and disease progression remains uncertain. To determine whether relapsing or progressive EAE can occur in the absence of epitope spreading, we evaluated the course of disease in mice which possessed only a single myelin-specific TCR. These mice (transgenic/SCID +/+) exhibited a progressive and sometimes remitting/relapsing disease course in the absence of immune reactivity to multiple, spreading myelin epitopes. The results provide direct experimental evidence relevant to discussions on the mechanisms of disease progression in MS and EAE.

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 94%

Epitope Spreading Is Not Required for Relapses in Experimental Autoimmune Encephalomyelitis

Jones

Bourdette

Moes

et al. 2003

“…The dominant peptide OVA 275-264 (SIINFEKL), a subdominant peptide OVA 55-62 , KVVRFDKL (21,23), and a cryptic peptide OVA [11][12][13][14][15][16][17][18] , CFD VFKEL (20), were manufactured by the Center for Cell and Molecular Biology (University of Western Australia, Perth) at purities of 89, 90, and 95%, respectively.…”

Section: Ova and Peptidesmentioning

confidence: 99%

“…In particular, studies examining viral infections have demonstrated T cell responses to epitopes of varying affinities (14,15). Similarly, autoimmune models have demonstrated the sequential revealing of T cell responses to weaker epitopes during disease (16,17). In some tumor systems, CTL to subdominant peptides have been detected during tumor growth (18) and, when these peptides are used as immunogens, they are able to confer protection (19).…”

mentioning

confidence: 99%

In Vivo Cross-Presentation of a Soluble Protein Antigen: Kinetics, Distribution, and Generation of Effector CTL Recognizing Dominant and Subdominant Epitopes

Nelson

Bundell

Robinson

2000

Cross-presentation of exogenous Ags via the MHC class I pathway is now recognized for its role in self-tolerance, tumor immunity, and vaccine development. However, little is known about the in vivo distribution and kinetics of cross-presented protein Ags, nor the subsequent development of CTL effector responses to dominant or subdominant epitopes. We examined the location and duration of cross-presented Ag by using 5,6-carboxy-succinimidyl-fluorescein ester-labeled T cells from class I-restricted Ag-specific TCR mice. Comparisons of results from an in vitro 51Cr release CTL assay with an in vivo CTL assay provided physiologically relevant insights into the functional capacities of CTL specific for epitopes with differing affinities. These data demonstrate that efficient cross-presentation of a dominant class I-restricted Ag is dose related and remains largely localized, but not limited to the draining lymph nodes for up to 3 wk following a single injection of soluble protein. Within this period, dominant peptide-specific CTL are fully functional in vivo throughout the secondary lymphoid system. However, no in vivo responses are seen to a subdominant or cryptic epitope. Prolonging Ag cross-presentation via use of IFA promoted persisting in vivo dominant epitope-specific CTL activity and revealed dose-responsive precursor CTL to the subdominant, but not to a cryptic epitope. Analysis of functional in vivo CTL responses demonstrated that, in the presence of strong ongoing responses to the dominant peptide, lytic activity of CTL directed at weaker epitopes is undetectable.

“…It was hypothesized by the latter that that relapses are due to waxing and waning of the response against the immunodominant epitope, and that apparent epitope spreading is the result of the in vitro stimulation of neuroantigen-specific T cell found in the lymphoid organs. These differences have been ascribed to the different experimental techniques used for disease induction (34).…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Spinal Cord T Cell Repertoire During Relapsing Experimental Autoimmune Encephalomyelitis

Fritz

Wang

Zhao

2000

The CNS T cell repertoire was analyzed by RT-PCR, spectratyping, and nucleotide sequencing of the amplified products at different times following adoptive transfer of a CD4+, Th1, VB2+ encephalitogenic SJL/J proteolipid protein peptide 139–151-specific T cell clone. The third complementarity-determining region of TCR B chains in the spinal cord was used as an indicator of T cell heterogeneity. Spectratypic analysis revealed that a single peak corresponding to the third complementarity-determining region of the initiating T cell clone predominated during the acute phase. During recovery and relapse the complexity of the spectratype increased. DNA sequence analysis revealed that the donor clone predominated at the acute phase. By the first relapse the donor clone, although represented most frequently, was a minority of the total. Spectratypic analysis of the same samples for several other VB families revealed their presence during acute disease or relapses but, with the exception of VB17, their absence during the recovery stage.