Apoptosis in the pathogenesis of systemic lupus erythematosus

Muñoz, Luis; Bavel, C.C.A.W. van; Franz, Sandra; Berden, Jo H. M.; Herrmann, Martin; Vlag, Johan van der

doi:10.1177/0961203308089990

Cited by 187 publications

(144 citation statements)

References 31 publications

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…The inability to properly remove AB has been associated with the development of autoimmune responses to nuclear antigens, such as dsDNA (12)(13)(14)(15). However, because TIM-4 deficiency only affected clearance of AB by cells in the peritoneal cavity and not in the spleen, it was not clear whether TIM-4 deficiency would result in the development of autoantibodies associated with defective AB clearance.…”

Section: Tim-4-deficient Peritoneal Macrophages and B-1 Cells Cannot mentioning

confidence: 93%

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

Rodriguez-Manzanet

Sanjuán

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

167

178

View full text Add to dashboard Cite

TIM-4, a member of the TIM family expressed on antigen-presenting cells, binds to phosphatidylserine exposed on the surface of apoptotic bodies. However, the significance of this interaction in vivo remains unknown because other receptors have been implicated in the clearance of apoptotic bodies and could compensate for the TIM-4 deficiency in vivo. In this study, we describe the generation of TIM-4-deficient mice and address whether TIM-4 serves a unique function in vivo. We show that TIM-4 −/− peritoneal macrophages and B-1 cells do not efficiently engulf apoptotic bodies in vitro, or clear apoptotic bodies in vivo. TIM-4-deficient mice have hyperactive T and B cells, elevated levels of serum Ig, and develop antibodies to double-stranded DNA. Taken together, we show that TIM-4 is critical for the clearance of apoptotic bodies in vivo, and that lack of TIM-4 results in aberrant persistence of apoptotic bodies leading to dysregulated lymphocyte activation and signs of systemic autoimmunity.phosphatidylserine receptor | phagocytosis | autoantibody | apoptosis T he T cell, Ig, mucin domain (TIM) family includes four expressed Tim genes (Tim-1 through Tim-4) and four predicted genes (Tim-5 through Tim-8) on mouse chromosome 11B1.1, whereas a syntenic region on human chromosome 5q33.2 contains three TIM genes (TIM-1, TIM-3, and TIM-4) (1-3). The syntenic genetic intervals containing the TIM loci in both mice and man have been linked to susceptibility to autoimmune and allergic disorders (2-4).TIM-4, the only TIM protein not expressed on T cells, is found on antigen-presenting cells (APC), including dendritic cells and macrophages (5, 6). First described as a ligand for TIM-1 (7), which is expressed on activated T cells, we showed that TIM-4 costimulates T cell activation by promoting cell survival (5). We now know that TIM-4 exerts a bimodal effect on T cell immunity by inhibiting naïve T cells during the initiation phase of an immune response, and later enhancing T cell responses during the elicitation phase of T cell immunity (6). It is unclear, though, whether activating or inhibitory functions of TIM-4 predominate in vivo. With the generation of TIM-4-deficient mice, we are able to directly address the in vivo role of TIM-4.Two independent groups found that TIM-4 binds to phosphatidylserine (PtdSer) and that blocking TIM-4 with anti-TIM-4 mAb inhibits the engulfment of apoptotic bodies (AB) by TIM-4-expressing macrophages (8,9). Although these studies clearly showed that TIM-4 binds to AB through PtdSer, the physiologic role of TIM-4 in vivo has not been addressed owing to lack of TIM-4-deficient mice. It remains unknown whether TIM-4 is necessary for clearing AB in vivo or whether other receptors that bind AB, such as BAI1 (10) and stabilin-2 (11), compensate for TIM-4 deficiency.Clearance of AB is a critical mechanism for maintaining normal tissue homeostasis in multicellular organisms. AB that are not rapidly cleared progress to secondary necrosis, during which autoand neoantigens are exposed in an inflammato...

show abstract

Section: Tim-4-deficient Peritoneal Macrophages and B-1 Cells Cannot mentioning

confidence: 93%

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

Rodriguez-Manzanet

Sanjuán

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

167

178

View full text Add to dashboard Cite

show abstract

“…SLE is a prototype type III hypersensitivity reaction in which immune complex depositions of chromatin and antichromatin autoantibodies cause a wide spectrum of clinical symptoms such as fever, rashes, photosensitivity, joint and muscle pain, pericarditis and nephritis. It is widely thought that abnormalities in apoptosis play an important role in SLE autoimmunization (reviewed in [1]). Apoptosis is a highly organized and immunologically silent cell death pathway that plays an important role in tissue homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus

Pieterse

Hofstra

Berden

et al. 2014

Clinical and Experimental Immunology

Self Cite

View full text Add to dashboard Cite

Original ArticleAcetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus OTHER ARTICLES PUBLISHED IN THIS SERIESDying autologous cells as instructors of the immune system. Clinical and Experimental Immunology 2015, 179: 1-4. Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for systemic lupus erythematosus: critical remarks. Clinical and Experimental Immunology 2015, 179: 5-10. The effect of cell death in the initiation of lupus nephritis. Clinical and Experimental Immunology 2015, 179: 11-16 SummaryIn addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLEderived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE.

show abstract

“…Because ANCAs in SLE are, in most cases, not directed to PR3 (35-37), a role for mPR3 expression on neutrophil activation by ANCAs cannot be substantiated. Otherwise, neutrophils do play a role in the pathogenesis of SLE, by interacting with immune complexes or by inducing or exacerbating autoimmune responses when these cells accumulate in an apoptotic state (38). Indeed, accelerated apoptosis of neutrophils and decreased uptake of apoptotic neutrophils has been observed in SLE (39,40).…”

mentioning

confidence: 99%

Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

Hu¹,

Westra²,

Huitema³

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Wegener's granulomatosis (WG) is strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against proteinase 3 (PR3). Recent studies have shown that membranebound PR3 (mPR3) is differentially expressed and colocalizes with CD177/NB1 on circulating neutrophils. We undertook this study to assess the differential expression of CD177 on neutrophils from patients with ANCA-associated systemic vasculitis (ASV) in comparison with patients with systemic lupus erythematosus (SLE), patients with rheumatoid arthritis (RA), and healthy individuals, and to investigate whether colocalization of mPR3 and CD177 affects anti-PR3-mediated neutrophil activation.Methods. Expression of CD177 and mPR3 was analyzed by flow cytometry on isolated neutrophils from patients with ASV (n ‫؍‬ 53), those with SLE (n ‫؍‬ 30), those with RA (n ‫؍‬ 26), and healthy controls (n ‫؍‬ 31). Neutrophil activation mediated by anti-PR3 antibodies was assessed by measuring the oxidative burst with a dihydrorhodamine assay.Results. Percentages of CD177-expressing neutrophils were significantly higher in patients with ASV and those with SLE than in healthy controls. In 3 healthy donors, CD177 expression was not detected. After priming with tumor necrosis factor ␣, neutrophils remained negative for CD177 while mPR3 expression was induced. Neutrophils from CD177-negative donors or CD177؊ neutrophils sorted from donors with bimodal expression were susceptible to anti-PR3-mediated oxidative burst. Variation in the extent of anti-PR3-mediated neutrophil activation among different donors occurred independent of the percentage of CD177-expressing neutrophils.Conclusion. Membrane expression of CD177 on circulating neutrophils is increased in patients with ASV and in those with SLE, but not in RA patients. However, primed neutrophils from CD177-negative individuals also express mPR3 and are susceptible to anti-PR3-mediated oxidative burst, suggesting that recruitment of CD177-independent mPR3 is involved in anti-PR3-induced neutrophil activation.

show abstract

Apoptosis in the pathogenesis of systemic lupus erythematosus

Cited by 187 publications

References 31 publications

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus

Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

Contact Info

Product

Resources

About