Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus

Bruno, Roxana; Sabater, Lidia; Sospedra, Mireia; Ferrer-Francesch, Xavier; Escudero, Domingo; Martínez-Cáceres, Eva; Pujol-Borrell, Ricardo

doi:10.1002/1521-4141(2002010)32:10<2737::aid-immu2737>3.0.co;2-0

Cited by 80 publications

(58 citation statements)

References 56 publications

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“…However, conflicting results have been observed concerning MOG expression in human thymus. While MOG transcripts are found in purified mTEC [18] and in some but not all human thymus [20], Bruno et al [21] failed to detect MOG a and b isoforms in all human thymus tested. In C57BL/6 mice, Delarasse et al [7] have shown that MOG transcripts are expressed in thymus.…”

Section: Discussionmentioning

confidence: 95%

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

et al. 2006

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Experimental autoimmune encephalomyelitis, an experimental murine model for multiple sclerosis, is induced by stimulation of myelin-specific T lymphocytes. Myelin oligodendrocyte glycoprotein (MOG), a minor component of myelin proteins, is a potent autoantigen which contributes extensively to the anti-myelin response. In the present work, immunoscope analyses and sequencing of the oligoclonal expansions revealed anti-MOG Va and Vb public repertoires in lymphocytes infiltrating the CNS of wild-type (WT) mice. Moreover, a subset of CNS-infiltrating CD4 + T lymphocytes bearing the public Vb8.2 segment have an inflammatory phenotype strongly suggesting that it is encephalitogenic. We then observed that, in lymph node cells of MOG-deficient and WT animals, the Va and Vb public repertoires expressed by MOG-specific T cells are identical in both strains of mice and correspond to those found in the CNS of WT animals. These findings indicate that the MOG immunodominant determinant is unable to induce tolerance by deletion, and public anti-MOG T cell repertoires are selected for, regardless of the presence of MOG in the thymus and peripheral organs. The generation of MOGKO mice has enabled researchers to probe the role of this autoantigen in shaping the autoimmune response [7]. Based on anti-MOG humoral and T cell responsiveness and encephalitogenic activity of MOG-primed T cells from these mice, we have previously found no evidence to support a gross tolerogenic effect of MOG expression. Nevertheless, only a complete picture of the autoreactive T cell repertoire can fully define the contribution of MOG to self tolerance.T cell repertoire studies have previously shown that immunodominant (ID) or subdominant peptide-specific T cells may express TCR with Va-Ja and/or Vb-Db-Jb rearrangements common to all mice or humans of the same MHC haplotype [8,9]. These recurrent rearrangements are referred to as public, while private ones were also observed, consisting of Va and Vb rearrangements that differ from one individual to another [8]. In a mouse model of tolerance to maternal Igj light chains, three public Vb-Jb rearrangements specific for a Cj peptide were found. These rearrangements are highly conserved and restored sequentially throughout life as tolerance vanished with the disappearance of Cj peptide presentation in lymphoid organs [10]. Moreover, in the B10.PL model of MBP-induced EAE, encephalitogenic T lymphocytes of Th1 phenotype express preferentially the public CDR3b, DAGGGY [11,12]. These works show that public rearrangements, found in all animals of the same MHC, can be used as molecular probes to monitor the presence of T lymphocytes specific for a well-defined epitope, and thereby provide evidence for the immunological status, tolerant or not, of the hosts. On the contrary, private repertoires cannot be used in the same way since they are expressed in one or few individuals only.Here we have precisely defined the encephalitogenic public TCR in MOG-induced EAE in WT mice. CNSinfiltrating CD4 + T cells expressing t...

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Section: Discussionmentioning

confidence: 95%

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

et al. 2006

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“…Regarding immune privileged tissues, some proteins responsible for triggering the deletion of autoreactive T and B cells are not expressed in the central immune system, allowing autoreactive lymphocytes to escape from central selection. 142,143 Under normal physiological conditions, these autoreactive T and B cells are inactive because they are unable to enter immune privileged tissues; however, when immune privilege is disturbed, these autoreactive T and B cells may gain access to these tissues and cause an autoimmune response.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

et al. 2012

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Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

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“…It is also important to notice that the MBP, PLP and MOG proteins could theoretically induce different levels of self tolerance [31]. Indeed, the MOG protein is only expressed in the central nervous system whereas MBP and PLP are also expressed in the thymus [32].…”

Section: Discussionmentioning

confidence: 99%

Blood CD8⁺ T cell responses against myelin determinants in multiple sclerosis and healthy individuals

et al. 2008

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Patients with multiple sclerosis (MS) display significant peripheral blood CD8 + T cell receptor biases, suggesting clonal selection. Our objective was to identify relevant myelinderived peptides capable of eliciting responses of fresh blood CD8 + T cells in MS patients.We focused our analysis on the HLA supertypes (HLA-A3, -A2, -B7, -B27, -B44) predominant in a patient cohort. Three myelin protein (MBP, PLP and MOG) sequences were screened for HLA binding motifs and peptides were tested for their binding to HLA molecules. The cellular responses of 27 MS patients and 19 age-and sex-matched healthy controls (HC) were tested in IFN-c ELISPOT assays only detecting pre-committed CD8 + T cells. Sixty-nine new epitopes elicited positive responses, with MOG-derived peptides being the most immunogenic and peptides binding to HLA-A3 being the most frequent. However, MS patients and HC displayed the same frequency of autoreactive cells. The epitopes inducing the strongest responses were not those with the highest HLA binding, suggesting an effective thymic selection in MS patients. Our data extend the concept that the frequency of myelin-reactive T cells in MS patient blood is not increased compared to HC. The description of this set of myelin-derived peptides (MHC class I restricted, recognized by CD8 + T cells)offers new tools to explore the CD8 + cell role in MS.

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Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus

Cited by 80 publications

References 56 publications

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

Blood CD8⁺ T cell responses against myelin determinants in multiple sclerosis and healthy individuals

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Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus

Cited by 80 publications

References 56 publications

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals

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Blood CD8⁺ T cell responses against myelin determinants in multiple sclerosis and healthy individuals