Opsonization of late apoptotic cells by systemic lupus erythematosus autoantibodies inhibits their uptake via an Fcγ receptor–dependent mechanism

Reefman, Esther; Horst, G.; Nijk, Marije T.; Limburg, Pieter C.; Kallenberg, Cees G. M.; Bijl, Marc

doi:10.1002/art.22947

Cited by 46 publications

(51 citation statements)

References 31 publications

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“…Yet, 9G4 Abs may also react with ssDNA, dsDNA (11,(24)(25)(26), as well as apoptotic cells as shown own by our studies of SLE sera (27)(28)(29) and by chronic lymphocytic leukemia studies (30). The latter reactivity is of great interest because apoptotic cells accumulate in SLE GC (31) and may induce antiapoptotic cell Abs (APCA) with pathogenic functions (32)(33)(34)(35)(36)(37)(38)(39)(40).…”

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confidence: 73%

“…Understanding the participation of apoptotic cells, a rich source of self-Ags including chromatin, in the diversification and selection of autoreactive memory B cells is particularly important in SLE, in which these cells accumulate in the GC (31,(34)(35)(36)(37) and may activate pathogenic autoreactive B cells (31). The ensuing APCA may play a powerful effector pathogenic role not only through conventional type III hypersensitivity reactions but also through their ability to induce type I IFN production by dendritic cells (40).…”

Section: Discussionmentioning

confidence: 99%

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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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confidence: 73%

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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“…Consequently, the proportion of circulating cell-derived MPs with surface-bound IgG was significantly increased in the SLE group (median [5th-95th percentile] 3.5% [0. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].3%] in the SLE patient group versus 0.4% [0.02-4.3%] in the healthy control group; P Ͻ 0.0001).…”

Section: Resultsmentioning

confidence: 99%

“…Exploration of the immunostimulatory properties of MPs alone and of IC-carrying MPs compared to soluble ICs containing nucleic acids would thus be of interest. Second, bound immunoglobulins may initiate the classical pathway of complement and contribute to the systemic complement activation observed in SLE (14,16,18,19,35,36). Third, MPs provide adhesion and costimulatory molecules that result in IC deposition when MPs bind to various cells, e.g., to endothelial cells in kidney glomeruli.…”

Section: Discussionmentioning

confidence: 99%

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Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Nielsen

Østergaard

Stener

et al. 2012

Arthritis & Rheumatism

154

146

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Objective. To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters.Methods. Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) were included. The numbers of annexin V-binding MPs displaying IgG, IgM, or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP IgG load was determined by flow cytometric analysis of all samples from SLE patients and healthy controls.Results. SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P ‫؍‬ 0.0004), with a much higher average IgG load per MP (P < 0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P ‫؍‬ 0.006 and P ‫؍‬ 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P < 0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption. Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations (1). One of the serologic hallmarks of SLE is the presence of circulating, high-affinity autoantibodies against nuclear constituents (2). These autoantibodies may form circulating proinflammatory immune complexes (ICs) that directly trigger plasmacytoid dendritic cells (PDCs) and the complement system, e.g., in the kidneys (3). Also, IC and autoantibody activation of SLE neutrophils prone to NETosis, i.e., specialized neutrophil cell death, contributes to the sustained PDC activation that is typical of SLE (4,5). The etiology of antinuclear autoimmunity in SLE remains unclear, but persistent, poorly cleared circulating cellular remnants, including microparticles (MPs) and neutrophil extracellular traps, are likely sources of immunogenic autoantigens (6-9). Conclusion. Our findings indicate that circulating cell-derived MPs in SLE patients

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9G4+ Autoantibodies Are an Important Source of Apoptotic Cell Reactivity Associated With High Levels of Disease Activity in Systemic Lupus Erythematosus

Jenks

Palmer

Marin

et al. 2013

Arthritis & Rheumatism

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Objective To determine the prevalence anti-apoptotic cell antibodies with the 9G4+ idiotype (9G4+) and the relationship between this reactivity and other known 9G4+ specificities and disease activity. Methods Sera from 60 SLE patients and 40 healthy control donors were incubated with apoptotic Jurkat cells and assayed for binding of 9G4+ antibodies by flow cytometry. These samples were also tested for 9G4+ reactivity against naïve B cells and total IgG and IgM anti-apoptotic cell antibody (AACA) reactivity. Results 9G4+ antibodies bound late apoptotic cells in a majority of SLE patients (60%) but only 2 healthy control sera. Among samples with global IgM or IgG AACA, samples with 9G4+ AACA predominated. Patients with high levels of 9G4+ AACA were more likely to have active disease and this remained true even in patients with IgG AACA, or anti-dsDNA. Patients with lupus nephritis were also more likely to have 9G4+ AACA. While 9G4+ reactivity to apoptotic cells often coincided with anti-B cell reactivity, some samples had distinct anti-apoptotic cell or anti-B cell reactivity. Conclusion 9G4+ antibodies represent a major species of anti-apoptotic cell antibodies in SLE serum and this autoreactivity is associated with disease activity. The anti-apoptotic cell reactivity of 9G4+ antibodies can be separated from the germline VH4-34 encoded anti-B cell autoreactivity. Our results indicate that apoptotic cells are an important antigenic source in SLE that positively select B cells with intrinsic autoreactivity against other self-antigens. This selection of 9G4+ B cells by apoptotic cells may represent an important step in disease progression.

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Opsonization of late apoptotic cells by systemic lupus erythematosus autoantibodies inhibits their uptake via an Fcγ receptor–dependent mechanism

Cited by 46 publications

References 31 publications

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

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

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

9G4+ Autoantibodies Are an Important Source of Apoptotic Cell Reactivity Associated With High Levels of Disease Activity in Systemic Lupus Erythematosus

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