Myelin basic protein peptide specificity and T‐cell receptor gene usage of HPRT mutant T‐cell clones in patients with multiple sclerosis

Abstract

Characterization of T cells responding to autoantigens is central to understanding autoimmune disease. We have used somatic mutation at the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene as an index of T-cell amplification in vivo. With this strategy we previously showed that myelin basic protein-reactive T cells can be isolated only from the HPRT mutant T-cell population cultured from the peripheral blood of multiple sclerosis patients and not from normal individuals. In this study, 165 HPRT mutant and 104 wild-type clones were examined for their reactivity to myelin basic protein and overlapping peptides of myelin basic protein. Five HPRT mutant clones that recognized myelin basic protein and myelin basic protein peptides along with three clones that responded to myelin basic protein peptide alone were isolated. All but one of the eight clones recognized peptides derived from the carboxy terminus of myelin basic protein (p84-168). Sequence analysis showed heterogeneous expression of T-cell receptor V alpha and V beta genes and CDR3s. These studies showed that in vivo amplified autoimmune T cells from patients with long-standing disease use diverse T-cell receptor elements in the recognition of C-terminal myelin basic protein peptides.

Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients

“…MS is also characterized by increased oxidative stress (in PBMC and brain), which can cause DNA damage and somatic mutations 54– 56 . Further, T-lymphocytes isolated from MS patients that contain somatic mutations have been shown to react to myelin peptides 57 . Specifically, T-cell clones mutant for the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene were found only in MS patients and not in HCs 57, 58 .…”

“…Further, T-lymphocytes isolated from MS patients that contain somatic mutations have been shown to react to myelin peptides 57 . Specifically, T-cell clones mutant for the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene were found only in MS patients and not in HCs 57, 58 . The MS patients studied had ‘chronic progressive MS’, clinically similar to the PPMS patients in this study 57 .…”

“…Specifically, T-cell clones mutant for the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene were found only in MS patients and not in HCs 57, 58 . The MS patients studied had ‘chronic progressive MS’, clinically similar to the PPMS patients in this study 57 . The T-cell clones recognized and proliferated to myelin basic protein peptides 57 .…”

Selection ofhprtMutant T Cells as Surrogates for Dividing Cells Reveals a Restricted T Cell Receptor BV Repertoire in Insulin-Dependent Diabetes Mellitus

“…enriched within the hprt mutant population of MS patients compared to the wild-type population (42,57). It has also recently been reported that hprt mutant cells from MS patients recognize myelin proteolipid protein peptides (58).…”

Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia

“…In diseases characterized by B-cell responses, these functions appear to be selectively reduced by cyclophosphamide therapy [28]. CD4 T cells are selectively depleted in MS patients treated with cyclophosphamide plus corticotropin [29] and evidence suggests that CD4+ cells are proliferating in MS patients based on studies of HPRT gene mutations [30,311. Taken together, these results suggest that cyclophosphamide may be inducing immune deviation by preferentially depleting T h l cells in MS, which then results in a skewed Th2 response and associated eosinophilia.…”