Somatic hypermutation and antigen-driven selection of B cells are altered in autoimmune diseases

Zuckerman, Neta S.; Hazanov, Helena; Barák, Michal; Edelman, Hanna; Hess, Shira; Shcolnik, Hadas; Dunn-Walters, Deborah K.; Mehr, Ramit

doi:10.1016/j.jaut.2010.07.004

Cited by 49 publications

(43 citation statements)

References 70 publications

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“…Indeed, this is hypothesized to be the case in some autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and myasthenia gravis. 40,41 In this study, myoferlin was identified as an antigen that was uniquely recognized by one patient's tumor. Whereas myoferlin is not highly expressed in FL tumor cells, 42 immunohistochemical staining of malignant lymphoma biopsies for myoferlin show scattered cell staining.…”

Section: Discussionmentioning

confidence: 96%

Self-antigen recognition by follicular lymphoma B-cell receptors

Sachen¹,

Strohman

Singletary³

et al. 2012

Blood

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IntroductionFollicular lymphoma (FL) is a slowly progressive and largely incurable human B-cell malignancy. Transformation to a more aggressive lymphoma, such as diffuse large B-cell lymphoma, is common and strongly associated with an increase in morbidity and mortality. A chromosomal translocation t(14:18) is the hallmark of this disease, and it is found in 85%-90% of cases. It results in the juxtaposition of the BCL2 proto-oncogene with the immunoglobulin (Ig) heavy chain gene, IGH, leading to deregulated overexpression of Bcl-2 protein, a major inhibitor of apoptosis. However, the t(14:18) translocation is insufficient to cause malignancy as it is detectable in rare B cells from healthy persons. 1-3 Thus, FL pathogenesis requires additional signals beyond that imparted by the deregulation of BCL2. The observation that FL cells isolated from patients fail to survive in vitro and undergo spontaneous apoptosis supports the hypothesis that extrinsic microenvironmental factors are required for maintenance and expansion of FL. 4 Phenotypically, FL tumor cells resemble antigen-experienced germinal center B cells. Their Ig genes, which are rearranged to produce a functional B-cell receptor (BCR), have numerous point mutations compared with their germline counterparts, and this process of somatic hypermutation (SHM) is ongoing as the malignant clone expands and diversifies. Thus, individual tumor cells can each have slightly different Ig variable region sequences. 5 Random mutations should eventually result in stop codons and loss of BCR protein expression. However, FL tumors maintain a surface BCR, indicating a selective force favoring retention of a functional BCR. Furthermore, therapy with anti-idiotype antibodies directed against the BCR did not select for the outgrowth of BCR-negative variants. Rather, this therapy selected for the outgrowth of cells that had amino acid substitutions in the targeted V region sequence, making them unrecognizable by the anti-idiotype antibody. 6 Other in vitro studies with malignant B-cell lines have shown that experimental knockdowns of the BCR and members of its signaling pathway result in growth arrest, implicating their importance in tumor cell survival. 7 The BCR can transmit a tonic survival signal, but this is greatly augmented on its binding to a cognate antigen. 8 There is indirect evidence to suggest that antigen recognition plays a role in the pathogenesis of FL. SHM can introduce silent or replacement mutations, the latter leading to an amino acid substitution. In a normal immune response, B cells with mutations resulting in higher binding affinity for the inciting antigen preferentially survive. This selective pressure leads to enrichment of replacement mutations in the complementarity determining regions (CDRs) of the BCR, and an under representation of replacement mutations in the framework regions (FWRs). 9 This same distribution of replacement and silent mutations has been reported for the BCRs of FL cells, 5 and the intraclonal diversity resulting from ongoing SHM...

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Section: Discussionmentioning

confidence: 96%

Self-antigen recognition by follicular lymphoma B-cell receptors

Sachen¹,

Strohman

Singletary³

et al. 2012

Blood

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“…Yet, to this day, the structural basis and repertoire use of mature IgG autoantibodies in human autoimmune diseases remains poorly understood despite isolated studies of limited numbers of Abs in some cases using phage-display technology that precludes identification of the original H and L chain pairs (65,66). These limitations have been largely resolved by the generation of mAbs from single cells (3,4) and more recently by the emergent use of large scale next-generation sequencing (67,68). However, although single-cell studies have identified multiple tolerance checkpoints, their open-ended analysis of relatively small numbers of unselected B cells have limited their ability to detect SLE-associated autoreactivity beyond the global ANA reactivity present in a significant fraction of all human B cells (3,4).…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Richardson

Chida

Adlowitz

et al. 2013

The Journal of Immunology

116

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9G4+ IgG Abs expand in systemic lupus erythematosus (SLE) in a disease-specific fashion and react with different lupus Ags including B cell Ags and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. In this study, a large panel of recombinant 9G4+ mAbs from single naive and memory cells was generated and tested against B cells, apoptotic cells, and other Ags. Mutagenesis eliminated the framework-1 hydrophobic patch (HP) responsible for the 9G4 idiotype. The expression of the HP in unselected VH4-34 cells was assessed by deep sequencing. We found that 9G4 Abs recognize several Ags following two distinct structural patterns. B cell binding is dependent on the HP, whereas anti-nuclear Abs, apoptotic cells, and dsDNA binding are HP independent and correlate with positively charged H chain third CDR. The majority of mutated VH4-34 memory cells retain the HP, thereby suggesting selection by Ags that require this germline structure. Our findings show that the germline-encoded HP is compulsory for the anti–B cell reactivity largely associated with 9G4 Abs in SLE but is not required for reactivity against apoptotic cells, dsDNA, chromatin, anti-nuclear Abs, or cardiolipin. Given that the lupus memory compartment contains a majority of HP+ VH4-34 cells but decreased B cell reactivity, additional HP-dependent Ags must participate in the selection of this compartment. This study represents the first analysis, to our knowledge, of VH-restricted autoreactive B cells specifically expanded in SLE and provides the foundation to understand the antigenic forces at play in this disease.

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“…This measure was also performed for each sample separately, yielding the same results; however, when comparing conditions, we chose to show the pooled analysis for simplicity. Additional mutational analyses were carried out as described in previous studies (27, 28, 30), however, no significant differences between the conditions were found.…”

Section: Methodsmentioning

confidence: 99%

Immunoglobulin Gene Repertoire Diversification and Selection in the Stomach â€“ From Gastritis to Gastric Lymphomas

et al. 2014

Self Cite

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Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.

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Somatic hypermutation and antigen-driven selection of B cells are altered in autoimmune diseases

Cited by 49 publications

References 70 publications

Self-antigen recognition by follicular lymphoma B-cell receptors

Self-antigen recognition by follicular lymphoma B-cell receptors

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Immunoglobulin Gene Repertoire Diversification and Selection in the Stomach â€“ From Gastritis to Gastric Lymphomas

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