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Inflammatory etiopathogenesis of systemic lupus erythematosus: an update.

Podolska MJ, Biermann MH, Maueröder C, Hahn J, Herrmann M - J Inflamm Res (2015)

Bottom Line: Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance).Indeed, the germline variants of autoantibodies often do not show autoreactivity.Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology and Rheumatology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

ABSTRACT
The immune system struggles every day between responding to foreign antigens and tolerating self-antigens to delicately maintain tissue homeostasis. If self-tolerance is broken, the development of autoimmunity can be the consequence, as it is in the case of the chronic inflammatory autoimmune disease systemic lupus erythematosus (SLE). SLE is considered to be a multifactorial disease comprising various processes and cell types that act abnormally and in a harmful way. Oxidative stress, infections, or, in general, tissue injury are accompanied by massive cellular demise. Several processes such as apoptosis, necrosis, or NETosis (formation of Neutrophil Extracellular Traps [NETs]) may occur alone or in combination. If clearance of dead cells is insufficient, cellular debris may accumulate and trigger inflammation and leakage of cytoplasmic and nuclear autoantigens like ribonucleoproteins, DNA, or histones. Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance). The improper exposure of nuclear autoantigens in this delicate location is consequently prone to break self-tolerance to nuclear autoantigens. Indeed, the germline variants of autoantibodies often do not show autoreactivity. The subsequent production of autoantibodies plays a critical role in the development of the complex immunological disorder fostering SLE. Immune complexes composed of cell-derived autoantigens and autoantibodies are formed and get deposited in various tissues, such as the kidney, leading to severe organ damage. Alternatively, they may also be formed in situ by binding to planted antigens of circulating autoantibodies. Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

No MeSH data available.


Related in: MedlinePlus

The role of neutrophils in the etiopathogenesis of SLE.Notes: Activated neutrophils release NETs covered with α-NE, α-LF, α-MPO, or α-LL-37. Chromatin and associated compounds are hallmark antigens of the autoimmune response of patients with SLE. Decreased activity of DNase I combined with a general (anti-inflammatory) clearance deficiency leads to the accumulation of NETs covered with proinflammatory and cytotoxic intracellular constituents. Opsonization of NETs with autoantbodies comes with immune complex formation followed by inflammatory clearance by blood-borne phagocytes. This process causes inflammation and tissue damage, thus stimulating pDC to secrete IFN-α and IL-6, ultimately resulting in the so-called “IFNα signature” typical of SLE. The pro-inflammatory cytokines secreted by pDCs induce long-lived plasma cell formation and massive autoantibody production.Abbreviations: α-NE, antibodies against neutrophil elastase; α-MPO, antibodies against myeloperoxidase; α-LF, antibodies against lactoferrin; NET, neutrophil extracellular trap; IFN-α, interferon-alpha; IL-6, interleukin-6; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; MΦ: macrophage.
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f1-jir-8-161: The role of neutrophils in the etiopathogenesis of SLE.Notes: Activated neutrophils release NETs covered with α-NE, α-LF, α-MPO, or α-LL-37. Chromatin and associated compounds are hallmark antigens of the autoimmune response of patients with SLE. Decreased activity of DNase I combined with a general (anti-inflammatory) clearance deficiency leads to the accumulation of NETs covered with proinflammatory and cytotoxic intracellular constituents. Opsonization of NETs with autoantbodies comes with immune complex formation followed by inflammatory clearance by blood-borne phagocytes. This process causes inflammation and tissue damage, thus stimulating pDC to secrete IFN-α and IL-6, ultimately resulting in the so-called “IFNα signature” typical of SLE. The pro-inflammatory cytokines secreted by pDCs induce long-lived plasma cell formation and massive autoantibody production.Abbreviations: α-NE, antibodies against neutrophil elastase; α-MPO, antibodies against myeloperoxidase; α-LF, antibodies against lactoferrin; NET, neutrophil extracellular trap; IFN-α, interferon-alpha; IL-6, interleukin-6; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; MΦ: macrophage.

Mentions: As mentioned earlier, several patients suffering from SLE are seropositive for antibodies that recognize cytoplasmic autoantigens from neutrophils. These autoantibodies recognize components of NETs like neutrophil elastase, myeloperoxidase, LL-37, or lactoferrin.65 In addition, these autoantibodies promote IFN-α production by pDC and thus contribute to the IFN-α signature. Autoantibodies specific for surface-expressed LL-37 induce the release of NETs by neutrophils. Enhanced LL-37 surface expression in turn fuels inflammation and autoantibody production via IFN-α.66,67 Furthermore, NETosis is accompanied by the release of noxious intracellular constituents such as heat shock proteins, modified histones, or HMGB1. These intracellular proteins are able to activate DC and may thus challenge immune tolerance.68 Since NETs are composed of DNA, they are prone to degradation by DNase I. In the case of patients with SLE, this nuclease may act insufficiently as a result of inhibitors, anti-DNase I antibodies, or genetic variations.69 This may cause persistence of NETs serving as a source for potential autoantigens, thereby challenging self-tolerance (Figure 1). Importantly, a neutrophil subpopulation enriched in the blood of patients suffering from SLE is more prone to execute NETosis.66,67 It has recently been shown that neutrophils isolated from patients with SLE reveal a robust pattern of demethylation of the IFN-regulated genes, suggesting a pathogenic role for neutrophils in lupus.70


Inflammatory etiopathogenesis of systemic lupus erythematosus: an update.

Podolska MJ, Biermann MH, Maueröder C, Hahn J, Herrmann M - J Inflamm Res (2015)

The role of neutrophils in the etiopathogenesis of SLE.Notes: Activated neutrophils release NETs covered with α-NE, α-LF, α-MPO, or α-LL-37. Chromatin and associated compounds are hallmark antigens of the autoimmune response of patients with SLE. Decreased activity of DNase I combined with a general (anti-inflammatory) clearance deficiency leads to the accumulation of NETs covered with proinflammatory and cytotoxic intracellular constituents. Opsonization of NETs with autoantbodies comes with immune complex formation followed by inflammatory clearance by blood-borne phagocytes. This process causes inflammation and tissue damage, thus stimulating pDC to secrete IFN-α and IL-6, ultimately resulting in the so-called “IFNα signature” typical of SLE. The pro-inflammatory cytokines secreted by pDCs induce long-lived plasma cell formation and massive autoantibody production.Abbreviations: α-NE, antibodies against neutrophil elastase; α-MPO, antibodies against myeloperoxidase; α-LF, antibodies against lactoferrin; NET, neutrophil extracellular trap; IFN-α, interferon-alpha; IL-6, interleukin-6; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; MΦ: macrophage.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548750&req=5

f1-jir-8-161: The role of neutrophils in the etiopathogenesis of SLE.Notes: Activated neutrophils release NETs covered with α-NE, α-LF, α-MPO, or α-LL-37. Chromatin and associated compounds are hallmark antigens of the autoimmune response of patients with SLE. Decreased activity of DNase I combined with a general (anti-inflammatory) clearance deficiency leads to the accumulation of NETs covered with proinflammatory and cytotoxic intracellular constituents. Opsonization of NETs with autoantbodies comes with immune complex formation followed by inflammatory clearance by blood-borne phagocytes. This process causes inflammation and tissue damage, thus stimulating pDC to secrete IFN-α and IL-6, ultimately resulting in the so-called “IFNα signature” typical of SLE. The pro-inflammatory cytokines secreted by pDCs induce long-lived plasma cell formation and massive autoantibody production.Abbreviations: α-NE, antibodies against neutrophil elastase; α-MPO, antibodies against myeloperoxidase; α-LF, antibodies against lactoferrin; NET, neutrophil extracellular trap; IFN-α, interferon-alpha; IL-6, interleukin-6; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; MΦ: macrophage.
Mentions: As mentioned earlier, several patients suffering from SLE are seropositive for antibodies that recognize cytoplasmic autoantigens from neutrophils. These autoantibodies recognize components of NETs like neutrophil elastase, myeloperoxidase, LL-37, or lactoferrin.65 In addition, these autoantibodies promote IFN-α production by pDC and thus contribute to the IFN-α signature. Autoantibodies specific for surface-expressed LL-37 induce the release of NETs by neutrophils. Enhanced LL-37 surface expression in turn fuels inflammation and autoantibody production via IFN-α.66,67 Furthermore, NETosis is accompanied by the release of noxious intracellular constituents such as heat shock proteins, modified histones, or HMGB1. These intracellular proteins are able to activate DC and may thus challenge immune tolerance.68 Since NETs are composed of DNA, they are prone to degradation by DNase I. In the case of patients with SLE, this nuclease may act insufficiently as a result of inhibitors, anti-DNase I antibodies, or genetic variations.69 This may cause persistence of NETs serving as a source for potential autoantigens, thereby challenging self-tolerance (Figure 1). Importantly, a neutrophil subpopulation enriched in the blood of patients suffering from SLE is more prone to execute NETosis.66,67 It has recently been shown that neutrophils isolated from patients with SLE reveal a robust pattern of demethylation of the IFN-regulated genes, suggesting a pathogenic role for neutrophils in lupus.70

Bottom Line: Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance).Indeed, the germline variants of autoantibodies often do not show autoreactivity.Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology and Rheumatology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

ABSTRACT
The immune system struggles every day between responding to foreign antigens and tolerating self-antigens to delicately maintain tissue homeostasis. If self-tolerance is broken, the development of autoimmunity can be the consequence, as it is in the case of the chronic inflammatory autoimmune disease systemic lupus erythematosus (SLE). SLE is considered to be a multifactorial disease comprising various processes and cell types that act abnormally and in a harmful way. Oxidative stress, infections, or, in general, tissue injury are accompanied by massive cellular demise. Several processes such as apoptosis, necrosis, or NETosis (formation of Neutrophil Extracellular Traps [NETs]) may occur alone or in combination. If clearance of dead cells is insufficient, cellular debris may accumulate and trigger inflammation and leakage of cytoplasmic and nuclear autoantigens like ribonucleoproteins, DNA, or histones. Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance). The improper exposure of nuclear autoantigens in this delicate location is consequently prone to break self-tolerance to nuclear autoantigens. Indeed, the germline variants of autoantibodies often do not show autoreactivity. The subsequent production of autoantibodies plays a critical role in the development of the complex immunological disorder fostering SLE. Immune complexes composed of cell-derived autoantigens and autoantibodies are formed and get deposited in various tissues, such as the kidney, leading to severe organ damage. Alternatively, they may also be formed in situ by binding to planted antigens of circulating autoantibodies. Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

No MeSH data available.


Related in: MedlinePlus