Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Potter, Paul K.; Cortés-Hernández, Josefina; Quartier, Pierre; Botto, Marina; Walport, Mark J.

doi:10.4049/jimmunol.170.6.3223

Cited by 158 publications

(130 citation statements)

References 57 publications

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“…6). Interestingly, a defect in macrophage clearance of apoptotic cells has been noted in human lupus and in autoimmune MRL/Mp mice (13,44,45), suggesting that the initiation of an anti-Sm response in MRL/Mp mice and lupus patients does not require a B cell intrinsic defect. However, a role for a B cell intrinsic defect in murine or human lupus cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…The loss of tolerance and an intrinsic B cell defect are not necessarily required. Defects in apoptotic cell clearance, as has been detected in MRL mice (45), may be sufficient to at least initiate an anti-Sm response from functional MZ and B-1 cells. However, intrinsic defects may play a role in activation, e.g., by increasing sensitivity to Ag.…”

Section: Discussionmentioning

confidence: 99%

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Impaired Clearance of Apoptotic Cells Induces the Activation of Autoreactive Anti-Sm Marginal Zone and B-1 B Cells

Qian

Wang

Clarke

2004

The Journal of Immunology

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Since apoptotic cell Ags are thought to be a source of self-Ag in systemic lupus erythematosus, we have examined the role of apoptotic cells in the regulation and activation of B cells specific for Sm, a ribonucleoprotein targeted in human and murine lupus. Using Ig-transgenic mice that have a high frequency of anti-Sm B cells, we find that apoptotic cell injection induces a transient splenic B cell response, while simultaneously causing extensive splenic and peritoneal anti-Sm B cell death. In contrast, mice deficient in the clearance of apoptotic cells develop a chronic anti-Sm response beginning at 1–2 mo of age. These mice have expanded marginal zone and B-1 B cell populations and anti-Sm B cells of both types are activated to form Ab-secreting cells. This activation appears to be Ag-specific, suggesting that activation is due to increased availability of apoptotic cell Ags. Since marginal zone and B-1 cells are positively selected, these data suggest a loss of ignorance rather than a loss of tolerance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired Clearance of Apoptotic Cells Induces the Activation of Autoreactive Anti-Sm Marginal Zone and B-1 B Cells

Qian

Wang

Clarke

2004

The Journal of Immunology

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“…Thus, no Ag presentation to T cells occurs with down-regulation of inflammation. An impaired ability of macrophages from lupus-prone mice to engulf apoptotic cells has been shown using both in vivo and in vitro cell clearance assays (30). In SLE, apoptotic cells are not properly cleared by macrophages, and there is accumulation of secondary necrotic cells (31).…”

Section: Discussionmentioning

confidence: 99%

Expansion of Bone Marrow IFN-α-Producing Dendritic Cells in New Zealand Black (NZB) Mice: High Level Expression of TLR9 and Secretion of IFN-α in NZB Bone Marrow

Lian

Kikuchi

Yang

et al. 2004

The Journal of Immunology

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Patients with systemic lupus erythematosus have elevated IFN-α production. Furthermore, sera IFN-α levels correlate with disease activity. We have focused our attention on whether this phenotype is also seen in the New Zealand Black (NZB) mice and simultaneously addressed the underlying mechanisms. Specifically, we analyzed: 1) levels of sera IFN-α after type A CpG ODN 2216 injection in autoimmunity-prone NZB and control mice, and 2) levels of IFN-α synthesized by IFN-α-producing dendritic cells (IPDCs) using highly enriched populations of CD11c+B220+ IPDCs derived from NZB and control mice; IPDCs are divided into two subpopulations (CD4+CD11c+B220+ and CD4−CD11c+B220+). Our data demonstrate that NZB mice produced higher levels of sera IFN-α after type A CpG ODN 2216 injection when compared with control mice (p < 0.01). In addition, the cell numbers, frequency, and TLR9 mRNA levels of CD4+ and CD4− IPDC were markedly increased in the bone marrow (BM) of NZB mice. Upon in vitro stimulation with TLR9 ligand-CpG ODN 2216, higher levels of IFN-α were synthesized by IPDCs from the BM of NZB. The major contributor of IFN-α was the CD4−CD11c+B220+ IPDC subpopulation. Furthermore, NZB BM IPDCs manifest impaired expression of homing chemokine CCR7 and CD62L, and IL-12 production. These data on the functional characteristics of the IPDC lineages explain in part the mechanism of hyper-IFN-α production and help clarify the mechanism for the expansion of NZB BM IPDCs.

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Section: An Elevated Intravascular Concentration Of Nuclear Antigens mentioning

confidence: 99%

“…The intravascular DNA may be from apoptotic bodies, which have been proposed to be a source of nuclear autoantigens [7]. It has been demonstrated that complement C1q [4,38] and C4 [5] deficient mice have impaired elimination of administered apoptotic bodies and accumulate these within tissues, although not all murine models with apoptotic cell clearing defects are prone to SLE [39], probably as a result of an abnormal B cell homeostasis.The splenic MZ is a barrier for blood-borne pathogens, T-independent antigens and IgM-IC [22,40,41], and it supports the humoral immune response in C4 null mice [22]. Here, we tested if additional endogenous DNA could be targeted to the spleen by i.v.…”

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confidence: 99%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

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Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Cited by 158 publications

References 57 publications

Impaired Clearance of Apoptotic Cells Induces the Activation of Autoreactive Anti-Sm Marginal Zone and B-1 B Cells

Impaired Clearance of Apoptotic Cells Induces the Activation of Autoreactive Anti-Sm Marginal Zone and B-1 B Cells

Expansion of Bone Marrow IFN-α-Producing Dendritic Cells in New Zealand Black (NZB) Mice: High Level Expression of TLR9 and Secretion of IFN-α in NZB Bone Marrow

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

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