Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis.

Abstract

Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cel receptor variable region genes was analyzed. A remarkable bias for use of f-chain variable region (VP) 5.2 and, to a lesser extent, Vj36.1 was seen among BP-specific clones from patients but not from controls. Multiple sclerosis (MS) is an immune-mediated disease characterized by central nervous system mononuclear cell infiltration and demyelination. Although the pathogenesis of MS is unknown, both genetic and environmental factors have been implicated in the disease process. Major elements ofthe genetic predisposition include an association of disease with particular class II major histocompatibility complex (MHC) haplotypes, in particular HLA-DR2 and -DQwl (1-5), as well as with certain polymorphisms within the T-cell receptor (TCR) a-chain and (3-chain gene complexes (6-9). These studies suggest that the disease involves CD4+ T cells bearing af3 TCR. In support of this idea, CD4+ T cells represent a major component of mononuclear cells in the brains of active patients (10), and limited sets of a-chain TCRs are present within central nervous system tissue of MS patients but not controls (11).T lymphocytes that recognize myelin basic protein (BP) have been shown to have potent demyelinating and encephalitogenic activity in animals (12-18). Accumulating evidence also suggests that BP-specific T cells may contribute to the pathogenesis ofMS. Thus, cells selected from MS patients on the basis of in vivo activation have specificity for BP (19). In addition, the frequencies of BP-reactive T cells are increased Monoclonal antibodies directed to these regions or synthetic peptides with sequences common to these TCR V regions can both protect and treat animals with clinical signs of experimental autoimmune encephalomyelitis (21,22,(25)(26)(27). For a similar approach to be applied to MS patients, it is critical to know if potentially pathogenic T cells also preferentially use a limited set of V region genes. In this manuscript, we analyze the TCR Va and Vf3 genes expressed in BP-specific T cells selected from the blood of MS patients and normal individuals. MATERIALS AND METHODSPatients. Blood samples were obtained from seven patients being followed at the Oregon Health Sciences University MS clinic. All patients had clinically and laboratory-supported definite MS with an average ambulation index of 3.2 + 1.7 (range 2-6) and an average Kurtzke disability status score of 3.8 + 2.0 (range 2-6). Four patients had relapsing/remitting disease, and three patients had chronic progressive disease. The normal individuals were from the Veterans Affairs Medical Center, selected on the basis of a positive proliferative response of peripheral blood mononuclear cells (PBMC) to human BP in culture (20). All subjects were HLA-typed by standard serological methods at the...

Restricted junctional usage of T cell receptor Vβ2 and Vβ13 genes, which are overrepresented on infiltrating T cells in the lips of patients with sjögren's syndrome

“…Uematsu et al (15) analyzed the Va and V13 repertoire in the synovial fluid of an RA patient using inverse PCR, and found that both the Va and V13 repertoires were highly heterogenous and polyclonal, but V132.1 and V133.1 were enriched. In brain biopsy specimens from patients with multiple sclerosis, ValO, V135.2, and V136.1 genes were dominantly expressed (18,19).…”

“…The TCR repertoire in human autoimmune diseases has been analyzed using PCR (15)(16)(17)(18)(19). Palliard et al (16) examined the TCR V13 repertoire in synovial fluid from RA patients and found that the frequency of Vf314-positive T cells was significantly higher in synovial fluid from affected joints than in peripheral blood lymphocytes.…”

CD1d-Independent Developmental Acquisition of Prompt IL-4 Gene Inducibility in Thymus CD161(NK1)−CD44lowCD4+CD8− T Cells Is Associated with Complementarity Determining Region 3-Diverse and Biased Vβ2/Vβ7/Vβ8/Vα3.2 T Cell Receptor Usage

“…The majority of the myelin basic proteinprimed effector CD4 ϩ T cells that mediate experimental allergic encephalomyelitis in H-2 u mice, for example, use V␤8.2 (85). In contrast, there is restricted V␤5.2/V␤6.1 usage by myelin basic protein-specific T cells of multiple sclerosis patients (81). In addition, T cell clones derived from the CNS from multiple sclerosis patients preferentially express V␤6 and produce large amounts of proinflammatory cytokines (82).…”

Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients.

“…Although the DRBl * 1501 haplotype is associated with the highest relative risk of MS, other HLA class II alleles are overrepresented among certain ethnic groups of MS patients: DR4 in Southern Italians ( 15) and Arabs (16) and DR1 3 in Japanese (17) and Mexicans ( 18). In contrast to the well-established association between HLA genes and MS, the association ofTCR genes, either in the germline ( 19,20) or in the hMBP-specific peripheral T cell repertoire (21)(22)(23)(24)(25), with MS is still unclear.…”