Myelin basic protein‐specific T‐cell responses in identical twins discordant or concordant for multiple sclerosis

Abstract

Although multiple sclerosis (MS) is thought to be an autoimmune disease, the target antigen of the immune response is unknown. Both myelin basic protein (MBP) and proteolipid protein (PLP) have been considered candidate autoantigens. Because the immune response to either foreign or self antigens is influenced by the genetic background of the host, the importance of these candidate antigens has been difficult to establish in humans because of genetic diversity. To eliminate genetic differences in MS patients and healthy controls, we have studied the MBP-specific T-cell response in 6 sets of identical twins, 3 of which were concordant and 3 discordant for MS. A total of 638 short-term T-cell lines were established and characterized for MBP-specific proliferative and cytotoxic activity, fine specificity, and human leukocyte antigen (HLA) restriction. Similar frequencies of MBP-specific T cells were observed in affected and unaffected individuals. A slightly higher percentage of cytotoxic T-cell lines was found in affected individuals. For most of the cell lines, the restriction elements were the HLA class II antigens that have been reported previously to be associated with MS; no important differences with respect to HLA restriction were found between the patients and healthy individuals. The peptide epitopes of MBP that were recognized most frequently by the T-cell lines were those previously shown to be immunodominant. Differences in specificity were seen in some discordant twins indicating that, despite genetic identity, the MBP-specific T-cell repertoire may be shaped differently. These findings indicate that differences in frequency, peptide specificity, or HLA restriction are not sufficient to implicate MBP-specific T cells in the pathogenesis of MS. However, the T-cell response to MBP may still represent one necessary component with disease occurring when this response is combined with other host characteristics such as regulation of cytokine-, adhesion molecule-, or HLA-antigen expression in the nervous system or immunoregulatory mechanisms.

Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire.

“…However, it should be noted that the difference is probably biased by the large number of TCL generated from two young healthy donors (HD1 and HD4). These observations are compatible with the view that differences in frequency between patients and controls should not be overrated in the implication of MBPspecific T cells in the pathogenesis of MS (48). More importantly, and for the first time to our knowledge, we show that the MBP region (111-129), encompassing the encephalitogenic epitopes for guinea pig strain 13 (41,58,59) and Lou/M rats (60), is largely immunodominant in human HLA-DRB1*0401-positive individuals.…”

“…Previous studies comparing reactivity to MBP in MS patients and healthy controls have reported a slightly higher frequency in MS (5,12,57), no significant differences (3,4,48), and a trend to a higher reactivity in healthy subjects (50). Methodological differences in the establishment of TCL, in calculating the precursor frequency, and immunogenetic diversity in the populations studied might account for these discrepancies.…”

“…Approaches attempting to overcome the difficulty of the heterogeneity introduced by genes shaping the immune response to MBP in humans have included studies in siblings and twins (48)(49)(50)(51). Those studies, although invaluable in addressing specific questions in genetically highly homogeneous subject groups, are not well suited to extrapolation to the general population.…”

Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls.

“…These findings suggest that the HLA-DQB1*0301 allele is associated with the ability to develop T cell proliferative responses to BPAG2 independent of BP. The presence of autoreactive T cell clones in the immune repertoire of healthy donors is not unexpected since autoreactive T cells specific for the autoantigen of multiple sclerosis (29), myasthenia gravis (30), and PV (18) were also identified in healthy carriers of the disease-associated HLA class II alleles or of HLA class II alleles homologous to the alleles prevalent in these autoimmune diseases. In light of these studies, primary responses to Dsg3, the autoantigen of PV, were also observed in this study in a single BP patient and in 10 healthy donors.…”

Meningeal Mast Cells Affect Early T Cell Central Nervous System Infiltration and Blood-Brain Barrier Integrity through TNF: A Role for Neutrophil Recruitment?

“…In both diseases, autoreactive Th1 and Th17 cells, which are activated in the peripheral lymphoid organs, must enter the immunologically privileged CNS to initiate local inflammation (2). However, myelin-specific T cells have been detected in similar frequency in peripheral tissues of patients with MS and healthy individuals (3,4) indicating that the generation of these cells in the periphery is not sufficient for disease. Rather, it is the passage of these pathologic cells through the blood-brain barrier (BBB), specialized vasculature that is relatively impermeable to cells and macromolecules, into the CNS that is one of the major determinants of disease progression (2).…”