DNA-reactive B cells in lupus

Suurmond, Jolien; Calise, Justine; Malkiel, Susan; Diamond, Betty

doi:10.1016/j.coi.2016.07.002

Cited by 26 publications

(28 citation statements)

References 63 publications

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“…SLE patients exhibit increased frequencies of self-reactive B cells, both in recently emigrating and mature naïve B cell subsets, demonstrating a breach in early B cell tolerance pathways [83]. In addition, DNA-reactive B cells are more likely to mature, participate in germinal center reactions, and undergo plasma cell differentiation in lupus patients [84]. …”

Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

“…B cell intrinsic risk alleles including BANK1, BLK, CSK, FCGR2B , and PTPN22 have been linked to increased susceptibility to SLE [84]. Each of these genes, except for PTPN22 , leads to hyper-responsiveness to B cell receptor (BCR) engagement and enhanced B cell activation [84].…”

Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

“…Each of these genes, except for PTPN22 , leads to hyper-responsiveness to B cell receptor (BCR) engagement and enhanced B cell activation [84]. The PTPN22 risk allele results in altered PTPN22 signaling, with decreased phosphorylation of proteins in the BCR pathway, and it has been shown to diminish tolerance in human immature B cells [84].…”

Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

See 2 more Smart Citations

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

Moulton

Suárez‐Fueyo

Meidan

et al. 2017

Trends in Molecular Medicine

338

213

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end-organs. Emerging evidence on the role of these factors has increased our knowledge of this complex disease, guiding therapeutic strategies and identifying putative biomarkers. Recent findings include the characterization of genetic/epigenetic factors linked to SLE, as well as cellular effectors. Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities. The intricate web of involved factors and pathways dictates the adoption of tailored therapeutic approaches to conquer this disease.

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Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

Section: T Lymphocyte Abnormalities and Sle Pathogenesismentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

Moulton

Suárez‐Fueyo

Meidan

et al. 2017

Trends in Molecular Medicine

338

213

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“…Production of these autoantibodies requires a break of B-cell tolerance because B cells reactive to nuclear antigens have been shown to be tolerized 1, 9 . Genes expressed in B cells are enriched in SLE-associated genes whereas those expressed in CD4 + T cells are enriched in genes associated with rheumatoid arthritis 10 , suggesting that defects in B cells play a central role in the development of SLE.…”

Section: Introductionmentioning

confidence: 99%

B-cell tolerance and autoimmunity

Tsubata

2017

F1000Res

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Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.

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“…Both healthy individuals and SLE patients have at least two types of serum anti-DNA antibodies, unrelated directly with autoimmunity. First, there are low ainity antibodies, directed mainly against single-stranded DNA, which can be atributed to natural autoantibodies repertoire [18]. Another type consists of antibodies that are highly speciic to microbial single-stranded DNA [19].…”

Section: Introductionmentioning

confidence: 99%

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

Trofimenko¹

2017

Lupus

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The distinctive feature of systemic lupus erythematosus (SLE) is an immune reaction directed to diverse spectrum of autoantigens, which tends to change along with the disease spreading. The most common targets of the autoantibodies are protein and nucleoprotein components of cell nuclei: dsDNA, histones, nucleosomes, Sm antigen, and Ro and La antigens. Considering that the exact causes of this tolerance loss are unknown, a certain number of hypotheses are now discussed. One of the most promising is "waste disposal" concept, which makes a link between broken elimination of cellular debris, mononuclear phagocyte system dysfunction, and initiation of autoimmunity by the antigen presenting cells in SLE. This chapter concerns the ways nuclear antigens release from cells, necrosis, and apoptosis, as well as the key molecular mechanisms of transport and elimination of these antigens, its disturbances in SLE, and connection with innate immunity by mononuclear cells. Special atention is paid to nucleosomes and DNA degradation process, its principal factors (DNase I, C1q, SAP), blood DNA transportation by immune complexes, and immune stimulating action of DNA in SLE. Current pros and cons for the waste disposal concept and existing research trends in this ield are discussed.

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DNA-reactive B cells in lupus

Cited by 26 publications

References 63 publications

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

B-cell tolerance and autoimmunity

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

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