Altered VH6-D-JH repertoire in human insulin-dependent diabetes mellitus and autoimmune idiopathic thrombocytopenic purpura

Söderström, Ingegerd; Dijk-Härd, Iris van; Feld, Sari; Hillörn, Valter; Holmberg, Dan; Lundkvist, Inger

doi:10.1002/(sici)1521-4141(199909)29:09<2853::aid-immu2853>3.0.co;2-y

Cited by 2 publications

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“…This final event takes place in germinal centres, when B cells encounter antigen. The composition of the antibody repertoire is regulated and constrained, and there is substantial evidence that the B-cell repertoire is changed in autoimmune diseases, such as systemic lupus erythematosus [1], Sjögren's syndrome [8,9], myasthenia gravis [10], diabetes mellitus [11,12] or RA [13,14]. …”

Section: Introductionmentioning

confidence: 99%

Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody

et al. 2005

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B-cell depletive therapies have beneficial effects in patients suffering from rheumatoid arthritis. Nevertheless, the role of B cells in the pathogenesis of the disease is not clear. In particular, it is not known how the regeneration of the B-cell repertoire takes place. Two patients with active rheumatoid arthritis were treated with rituximab, and the rearranged immunoglobulin heavy-chain genes (Ig-V H ) were analysed to follow the B-cell regeneration. Patient A was treated with two courses of rituximab, and B-cell regeneration was followed over 27 months by analysing more than 680 Ig-V H sequences. Peripheral B-cell depletion lasted 7 months and 10 months, respectively, and each time was accompanied by a clinical improvement. Patient B received one treatment course. B-cell depletion lasted 5 months and was accompanied by a good clinical response. B cells regenerated well in both patients, and the repopulated Bcell repertoire was characterised by a polyclonal and diverse use of Ig-V H genes, as expected in adult individuals. During the early phase of B-cell regeneration we observed the expansion and recirculation of a highly mutated B-cell population. These cells expressed very different Ig-V H genes. They were classswitched and could be detected for a short period only. Patient A was followed long term, whereby some characteristic changes in the V H 2 family as well as in specific mini-genes like V H 3-23, V H 4-34 or V H 1-69 were observed. In addition, rituximab therapy resulted in the loss of clonal B cells for the whole period.Our data show that therapeutic transient B-cell depletion by anti-CD20 antibodies results in the regeneration of a diverse and polyclonal heavy-chain repertoire. During the early phase of B-cell regeneration, highly mutated B cells recirculate for a short time period in both the patients analysed. The longitudinal observation of a single patient up to 27 months shows subtle intraindividual changes, which may indicate repertoire modulation.

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Section: Introductionmentioning

confidence: 99%

Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody

et al. 2005

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B cells in autoimmune diseases: Insights from analyses of immunoglobulin variable (Ig V) gene usage

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Gougeon

et al. 2007

Autoimmunity Reviews

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The role of B cells in autoimmune diseases has not been fully elucidated. It is also unclear whether breaking of B cell tolerance in patients with autoimmune diseases is due to underlying defects in the molecular mechanisms involved in the arrangement of antibody genes or deficiencies in the subsequent selective influences that shape the antibody repertoire. Analysis of immunoglobulin (Ig) variable (V) gene usage is beginning to provide answers to some of these questions. Such analyses have identified some differences in the basic Ig V gene repertoire of patients with autoimmune diseases compared to healthy controls, even though none of these differences can be considered major. Defects in positive and negative selection, mutational targeting and, in some cases, receptor editing have also been detected. In addition, analysis of Ig V gene usage in target organs and tissues of patients with autoimmune diseases has clearly demonstrated that there is a highly compartmentalized clonal expansion of B cells driven by a limited number of antigens in these tissues. Great progress has been made in the structural and functional characterization of disease-associated antibodies, largely because of the development of the combinatorial library technique. Use of antibodies generated by this technique offers great promise in identifying B cell epitopes on known target antigens and in gaining greater insights into the pathogenic role of B cells in both B and T cell mediated autoimmune diseases.

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Altered VH6-D-JH repertoire in human insulin-dependent diabetes mellitus and autoimmune idiopathic thrombocytopenic purpura

Cited by 2 publications

References 49 publications

Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody

Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody

B cells in autoimmune diseases: Insights from analyses of immunoglobulin variable (Ig V) gene usage

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