Expansion of a recurrent V beta 5.3+ T-cell population in newly diagnosed and untreated HLA-DR2 multiple sclerosis patients.

Abstract

We have used a PCR-based technology to study the V185 and V1317 repertoire of T-cell populations in HLA-DR2 multiple sclerosis (MS) patients. We have found that the five MS DR2 patients studied present, at the moment of diagnosis and prior to any treatment, a marked expansion of a CD4+ T-cell population bearing Ve ¶35-J.81. The characterization of T cells involved in MS is crucial to the description of the disease. Several strategies have been used to identify possible biases in the T-cell repertoire of MS patients. They include flow cytometry analysis, extensive cell cloning, and determination of the nucleotide sequences of the T-cell receptor (TcR) of T cells either present at the site of the brain lesions or proliferating on brain autoantigens. T cells reacting against myelin basic protein (MBP) are found both in the CNS and in the peripheral blood lymphocytes (PBLs). A recent review of the sequences of the TcR of MBP-reactive cells reported the absence of an association of specific VP3 and Jo3 with MS (4). However, restriction at the major histocompatibility complex was not taken into account in this review. In view of the association of MS with HLA-DR2, VP3 usage and complementarity-determining region 3 (CDR3) diversity of the TcR could be considered in their relationship with the DR type of the patients (5, 6). The techniques mentioned above tell which V,3 and which CDR3 sequence is used in the sample studied. However, they cannot tell if a T-cell clone characterized by the distinctive 1 chain of its TcR is expanded in vivo. To determine if a T-cell population is expanded in an MS patient, we have used a new PCR-based technology that generates a "snapshot" of the T-cell populations at the clonal or oligoclonal level and that tells, on the basis of VP, Jo3, and CDR3 length, which population of T cells is expanded at the moment the sample is taken (7).We have restricted our study of the T-cell repertoire in MS to genetically defined MS patients (patients and controls were all HLA-DR2). Also, to avoid the consequences of treatment on the diversity of the T-cell repertoire, we have recruited HLA-DR2 MS patients at the moment of diagnosis and prior to any treatment. In view of the large number of signals that could be generated from a unique blood sample (7) not all V1-J1 combinations could be studied. Several V,B segments other than V135 and Vf17 are used by autoreactive peripheral T cells in MS DR2 patients (8). However, the T cells infiltrating the CNS in DR2 MS patients have been found to be enriched in V,5.2/5.3+ T cells (5) and their main targets are CNS self proteins: MBP, proteolipid protein, and myelin oligodendrocyte glycoprotein (9, 10). Also, some authors have reported that T-cell clones responding to MBP use predominantly VP35.2/5.3 (6). Finally, DR2-restricted T-cell clones that proliferate with the peptide 84-102 of MBP are predominantly V,B17+ (11). We have therefore restricted the present study to the V,B5+ and V/317+ repertoires.We (12). The patients were 40 years old on the average a...

The IgE repertoire in PBMCs of atopic patients is characterized by individual rearrangements without variable region of the heavy immunoglobulin chain bias

“…D, CDR-3 profiles for the predominately used rearrangement CHe-VH3b in omalizumab-treated patients. Whereas patient 2 showed virtually no changes in IgE and IgG repertoires, patients 13 and 7 showed broader profiles of their IgG transcripts, together with unchanged (13) or reduced (7) IgE repertoires for this rearrangement. IgM (with the exception of a single peak for patient 7) remained in a Gaussian-like distribution.…”

“…12 In analogy to the T-cell receptor diversity, these rearrangements can be described as ''public'' in contrast to unique ''individual'' rearrangements. 13 Of interest, some studies showed a preferential rearrangement of the VH5 chain, 14-16 a variable chain that is used at low percentages for IgM and IgG clones. However, not all studies confirmed this preference.…”

Analysis of T-cell repertoire in hepatitis-associated aplastic anemia

“…Differences in T-cell repertoire have been observed in other immune-mediated diseases, such as multiple sclerosis, 38,39 rheumatoid arthritis, 40,41 and autoimmune hepatitis, 42 where a limited number of T cells using a restricted diversity of the V ␤ subfamilies to proliferate dominantly is revealed in different patients, 21 but the TCR repertoire pattern is different among these diseases owing to the different antigenic triggers. 39,43,44 In summary, we show that in HAA there is an infiltration of both clonal and many nonclonal T cells, giving rise to a markedly skewed T-cell repertoire, as seen in both viral and autoimmune hepatitis. This highly skewed T-cell repertoire is also evident in the blood at the time of presentation of bone marrow failure.…”

T Cells in Systemic Lupus erythematosus

“…However, none has been established in vitro so far. On the human side, there is no evidence to date of monoclonal expansions of distinctive T cell clones in SLE [16], in distinction to what has been found in some other autoimmune diseases such as multiple sclerosis [17]. The lack of results in human SLE does not, however, entirely dismiss the T cell repertoire analysis approach and rather points to the need for better defining the cohorts to be studied.…”