VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA)

Huang, S.-C.; Jiang, R.; Hufnagle, Wendy O.; Fürst, Daniel E.; Wilske, Kenneth R.; Milner, Eric C. B.

doi:10.1046/j.1365-2249.1998.00580.x

Cited by 19 publications

(10 citation statements)

References 59 publications

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“…In particular, the gene V H 4–34 is very often used by anti-DNA antibodies [28,29] and is exclusively used by cold agglutinins [30]. In agreement with Huang and colleagues' data [13], the gene V H 3–30 was found less frequently in our RA patient than in the controls. In addition to these genes, the proportion of some other variable genes like V H 1–02, 1–18 or 4–04 also differed from the published data of normal controls and provided a distinct pattern for this patient.…”

Section: Discussionsupporting

confidence: 89%

“…Clonal expansion is a characteristic feature of the patients with RA. B-cell clones have been found in peripheral blood [13,14] and in synovial tissue [5,14]. In the present study, we were able to detect two clones within the V H 5 family before therapy.…”

Section: Discussionsupporting

confidence: 62%

“…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%

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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: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…After alkaline denaturation, plasmids were dot blotted onto replicate Magnacharge nylon membranes (Micron Separations, Westborough, MA) using a 96-well dot blotter (Bio-Rad, Hercules, CA) and cross-linked by UV irradiation. Membranes were hybridized to a set of oligonucleotide probes (M18, M16, M76, M8, E182, M19, and M41) that discriminate between several V H 3 genes (V3-23, V3-30/3-30.5, V3-30.3, and V3-33) as described previously (37)(38)(39)(40)(41)(42). Since Abs with HIV-1 gp120-binding activity can harbor gene products derived from either the V3-30 or the V3-30.5 locus (genes at these loci may have the same sequence) (31), we scored clones that bound probes diagnostic of either locus together as V3-30/3-30.5.…”

Section: Screening Of V H 3 Clones With Gene-specific Oligonucelotidesmentioning

confidence: 99%

Impact of HIV-1 Infection on VH3 Gene Repertoire of Naive Human B Cells

Scamurra

Miller

Dahl

et al. 2000

The Journal of Immunology

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B cells of the largest Ig variable heavy chain gene (VH) family, VH3, are reportedly decreased in patients with late stage HIV-1 disease. This deficit may contribute to their impaired responses to infections and vaccines. We confirmed that the VH3 family was underrepresented in serum IgM proteins, with a 45% decrease in patients with advanced HIV-1 disease. However, the proportion of VH3 within VH(1–6) IgM mRNA from peripheral B cells did not differ from that of control subjects (mean ± SD, 57.1 ± 9.7 vs 61.1 ± 8.7%). Similarly, within VH(1–6) IgD mRNA, which even more closely represents the unstimulated naive repertoire, the relative expression of VH3 mRNA was comparable in the two groups. Moreover, the frequency of individual genes within the VH3 family for IgD, particularly genes which encode putative HIV-1 gp120 binding sites, also was normal in HIV-1-infected patients. However, VH3 family expression for IgG mRNA was significantly decreased (17%) and VH4 IgG was increased (33%) relative to other VH families in advanced HIV-1-infected patients. Thus, the changes in VH family expression were more readily apparent in previously activated IgG “memory” B cell populations and, likely, in cells actively producing IgM rather than in resting naive cells. The presence of a relatively normal naive VH3 IgM and IgD mRNA repertoire in resting cells supports the prospect that with proper stimulation, particularly in conjunction with effective antiviral therapy, vigorous humoral immune responses to infections and vaccines may be elicited in this high-risk population.

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“…Some of the VH genes used in these HmAbs AMA are also used in autoantibodies with other specificities in systemic lupus erythematosus and rheumatoid arthritis. [25][26][27] Although it has been reported that V H 3 and V H 4 with highly mutated CDR are used in AMA, [9][10][11] and V H 3-21, V H 3-23 are used also in both the patient-and the XenoMouse-derived AMA HmAbs, the CDRs of these AMAs are distinct. Analysis of the Ig gene repertoire used by the human-type monoclonal antibodies generated in this study showed a restricted repertoire in their CDRs.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Sasaki¹

2001

Hepatology

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Antimitochondrial antibodies (AMA) are detected in Ͼ95% of sera from patients with primary biliary cirrhosis (PBC) and recognize the highly conserved mitochondrial 2-oxo-acid dehydrogenase complex (OADC enzyme complex), including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), the E2 subunit of the 2-oxoglutarate dehydrogenase complex (OGDC-E2), and E3BP (E3-binding protein or protein X). [1][2][3][4] We hypothesized that utilization of specific members of the human immunoglobulin (Ig) repertoire plays a critical role in specific epitope recognition of PDC-E2 and initiates a cascade of mucosal autoimmune responses against mitochondrial autoantigens, as a result of specific structural features of the autoantigens or of specific oddities of the etiologic process. To address this issue, we have taken advantage of a unique transgenic animal, XenoMouse (Abgenix Inc., Fremont, CA), that contains the human heavy (H) and light chain loci cloned on yeast artificial chromosomes. 5,6 The yeast artificial chromosomes in XenoMouse include approximately 66 V H (ϳ80%) and 32 V (ϳ75%) gene regions, rendering these mice capable of producing high-affinity, fully functional IgM and IgG2 antibodies, which closely resemble those seen in humans, to multiple antigens. 7,8 Moreover, the Ig gene usage toward immunizing antigens has been shown to be quite diverse. 7 Therefore, the production of human antibodies in XenoMouse provides a valuable tool to investigate the nature and specificity of the human antibody response to autoantigens. Here, we report the successful generation and characterization of human mAbs (HmAbs) to the major mitochondrial autoantigens in PBC, together with a comparison of Ig gene usage with that found in patients with PBC. 9-11 Our data have implications for identifying the causative agent of PBC.Abbreviations: AMA, antimitochondrial antibody; PBC, primary biliary cirrhosis; OADC, the E2 component of the 2-oxo-acid dehydrogenase complex; PDC-E2, the E2 component of pyruvate dehydrogenase; BCOADC-E2, the E2 component of the branched-chain 2-oxo-acid dehydrogenase complex; OGDC-E2, the E2 component of the 2-oxoglutarate dehydrogenase complex; E3BP, E3-binding protein; Ig, immunoglobulin; HmAbs, human monoclonal antibody; r, recombinant; KLH, keyhole limpet hemocyanin; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; RT, room temperature; HRP, horseradish peroxidase; SDS, sodium dodecyl sulfate; ILD, inner lipoyl domain; PSC, primary sclerosing cholangitis; DIG, digoxigenin.From the

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VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA)

Cited by 19 publications

References 59 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

Impact of HIV-1 Infection on VH3 Gene Repertoire of Naive Human B Cells

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

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