Response: common variable immunodeficiency patients with increased CD21−/lo B cells suffer from altered receptor editing and defective central B-cell tolerance

Romberg, Neil; Ng, Yen-Shing; Cunningham‐Rundles, Charlotte; Meffre, Eric

doi:10.1182/blood-2011-09-373969

Cited by 13 publications

(10 citation statements)

References 10 publications

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“…Polyreactive B cells were even more prevalent in patients with two TACI mutations comprising 28.5%-39.9% of their new emigrant/transitional B cells and were also frequent in CVID patients without TACI mutations as previously reported ( Figure 1, A and B, and ref. 29). This increase in autoreactive clones in patients with two TACI mutations compared with subjects with a single TACI mutation was further evidenced by the significantly increased frequency of both HEp-2-reactive and nuclear-reactive new emigrant/transitional B cells in these subjects (Figure 1, B-D).…”

Section: Central B Cell Tolerance Is Defective In All Subjects With Tmentioning

confidence: 68%

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Romberg¹,

Chamberlain²,

Saadoun³

et al. 2013

J. Clin. Invest.

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152

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Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6-expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.

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Section: Central B Cell Tolerance Is Defective In All Subjects With Tmentioning

confidence: 68%

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Romberg¹,

Chamberlain²,

Saadoun³

et al. 2013

J. Clin. Invest.

Self Cite

152

198

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“…Decreased secondary recombination potentially corresponding to a failure to induce receptor editing may also lead to abnormal central B cell tolerance. Indeed, a subset of common variable immunodeficiency disease (CVID) patients with expanded autoreactive CD21 −/lo B cell populations (CVID group Ia 53 ) suffer from a defective central B cell tolerance checkpoint associated with an Igκ repertoire characterized by a dearth of secondary recombination events 54,55 . Interestingly, new emigrant B cells from untreated active RA patients who also suffer from defective central B cell tolerance 10,56,57 express distinct patterns of Igκ light chain antibody repertoires, some of which altered by defective regulation of secondary recombination, a feature also reported in SLE patient's B cells 58–60 .…”

Section: Central B Cell Tolerance Defects Correlate With Altered Recementioning

confidence: 95%

The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases

Meffre

2011

Annals of the New York Academy of Sciences

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134

145

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Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II–deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions.

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“…Moreover the CD21 −/low B cell subset was enriched for autoreactivity. The CD21 −/low B cells have been described as anergic naïve B cells as well as resembling exhausted tissue‐like memory B cells . These two conclusions differ markedly as to the origin of the CD21 −/low B cells; defective central tolerance would lead to anergic naïve B cells, whereas exhausted memory‐like B cells would be a consequence of activation‐driven peripheral exhaustion.…”

Section: Cd21−/low B Cells In Health and Diseasementioning

confidence: 99%

CD21^−/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease

et al. 2015

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a These authors contributed equally. AbstractB cells represent one of the cellular components of the immune system that protects the individual from invading pathogens. In response to the invader, these cells differentiate into plasma cells and produce large amounts of antibodies that bind to and eliminate the pathogen. A hallmark of autoimmune diseases is the production of autoantibodies i.e. antibodies that recognize self. Those that are considered pathogenic can damage tissues and organs, either by direct binding or when deposited as immune complexes. For decades, B cells have been considered to play a major role in autoimmune diseases by antibody production. However, as pathogenic autoantibodies appear to derive mainly from T cell dependent responses, T cells have been the focus for many years. The successful treatment of patients with autoimmune diseases with either B cell depletion therapy (rituximab) or inhibition of B cell survival (belimumab), suggested that not only the autoantibodies but also other B cell features are important. This has caused a surge of interest in B cells and their biology resulting in the identification of various subsets e.g. regulatory B cells, several memory B cell subsets etc. Also, in other conditions such as chronic viral infections and primary immunodeficiency, several B cell subsets with unique characteristics have been identified. In this review, we will discuss one of these subsets, a subset that is expanded in conditions characterized by chronic immune stimulation. This B cell subset lacks, or expresses low, surface levels of the complement receptor 2 (CD21) and has therefore been termed CD21 À/low B cells.

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Response: common variable immunodeficiency patients with increased CD21−/lo B cells suffer from altered receptor editing and defective central B-cell tolerance

Cited by 13 publications

References 10 publications

CVID-associated TACI mutations affect autoreactive B cell selection and activation

CVID-associated TACI mutations affect autoreactive B cell selection and activation

The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases

CD21^−/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease

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Response: common variable immunodeficiency patients with increased CD21−/lo B cells suffer from altered receptor editing and defective central B-cell tolerance

Cited by 13 publications

References 10 publications

CVID-associated TACI mutations affect autoreactive B cell selection and activation

CVID-associated TACI mutations affect autoreactive B cell selection and activation

The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases

CD21−/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease

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CD21^−/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease