NETosis May Provide Novel Target in SLE

SNOWMASS, COLO. – Neutrophil extracellular traps are a recently identified component of innate immunity shaping up as a potential driving force in systemic lupus erythematosus and small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies.

Many key questions about neutrophil extracellular traps (NETs) remain to be answered in the next few years. The most clinically relevant include these: Can suppression of abnormal NET formation improve systemic lupus erythematosus (SLE) or small-vessel vasculitis? And can NET activity – that is, the NETosis level – serve as a biomarker for disease activity in patients with these disabling autoimmune disorders?

NETosis is the process by which activated neutrophils undergo a unique, nonapoptotic form of cell death. Intracellular chromatin unwinds, the nuclear membrane disintegrates, and the plasma membrane opens. This allows extrusion of large, net-like strands comprised of chromatin fibers, antimicrobial proteins, elastase, myeloperoxidase, and defensins. These cast nets are capable of rapidly trapping a broad range of microbes. But microbes aren’t the only entities that can trigger NETosis; interferon alpha and tumor necrosis factor can activate netting neutrophils as well, Dr. Mary Beth Humphrey explained at the symposium.

It had long been recognized that neutrophils figure in the pathogenesis of SLE, but their precise role has remained unknown until quite recently. Then last year, separate groups of investigators reported that netting neutrophils activate the immune system in both adult and pediatric SLE.

"Our results support a model that positions this unique type of neutrophil death linked with plasmacytoid dendritic cell activation and type I interferon production at the core of SLE pathogenesis," said Dr. Gina S. Carcia-Romo and associates at the Baylor Institute for Immunology Research, Dallas (Sci. Transl. Med. 2011;3:73ra20).

Separately, investigators at Houston’s M.D. Anderson Cancer Center showed that a large percentage of SLE patients have high titer antibodies against NET proteins, including the antimicrobial protein LL37 and human neutrophil peptides. This results in formation of highly stable immunogenic complexes composed of these proteins plus self-DNA. In vitro, these immune complexes activate dendritic cells, causing release of large quantities of interferon alpha, which is part of the lupus signature in both adult and pediatric SLE. In contrast, neither healthy controls nor patients with scleroderma make antibodies against NETs (Sci. Transl.Med. 2011;3:73ra19).

The current thinking is that NETosis, under the wrong circumstances, results in the creation of stable self-DNA/antibody complexes that are recognized by B cells and shown to toll-like receptor 9, leading to formation of autoantibodies. The emerging picture is one of a vicious cycle of chronic autoimmunity. But there aren’t yet enough data to say which comes first in lupus: abnormal NETosis leading to excessive presentation of chromatin and nuclear antigens, or autoantigens triggering overexuberant NETosis.

"The innate immune scientist in me would like to believe that it’s the abnormal netting that starts the process in the right genetic background," confessed Dr. Humphrey of the University of Oklahoma at Oklahoma City.

Putting lupus aside, Dr. Humphrey noted that an international team of investigators from the University of California, San Francisco, and multiple German universities have reported that NETosis appears to trigger vasculitis and promotes the autoimmune response in patients with small-vessel vasculitis. They showed that ANCAs trigger NETosis, and the nets that are subsequently cast contain the autoantigens proteinase-3 and myeloperoxidase, which figure prominently in Wegener’s granulomatosis and microscopic polyangiitis, respectively.

Also, they demonstrated that NETs are deposited in the inflamed kidneys of individuals with small-vessel vasculitis. And they also offered the tantalizing observation that another autoinflammatory condition – psoriasis – can be driven by activated plasmacytoid dendritic cells in the presence of LL37, which, as it turns out, is highly expressed in the skin of psoriasis patients (Nat. Med. 2009;15:623-5).

How might NET formation be suppressed to the benefit of patients with SLE or vasculitis? NETosis is a process driven by reactive oxygen species. Potential strategies include administering reactive oxygen scavengers and blocking nicotinamide adenine dinucleotide phosphate oxidase, according to Dr. Humphrey.

She reported having no financial conflicts.

SNOWMASS, COLO. – Neutrophil extracellular traps are a recently identified component of innate immunity shaping up as a potential driving force in systemic lupus erythematosus and small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies.

Many key questions about neutrophil extracellular traps (NETs) remain to be answered in the next few years. The most clinically relevant include these: Can suppression of abnormal NET formation improve systemic lupus erythematosus (SLE) or small-vessel vasculitis? And can NET activity – that is, the NETosis level – serve as a biomarker for disease activity in patients with these disabling autoimmune disorders?

NETosis is the process by which activated neutrophils undergo a unique, nonapoptotic form of cell death. Intracellular chromatin unwinds, the nuclear membrane disintegrates, and the plasma membrane opens. This allows extrusion of large, net-like strands comprised of chromatin fibers, antimicrobial proteins, elastase, myeloperoxidase, and defensins. These cast nets are capable of rapidly trapping a broad range of microbes. But microbes aren’t the only entities that can trigger NETosis; interferon alpha and tumor necrosis factor can activate netting neutrophils as well, Dr. Mary Beth Humphrey explained at the symposium.

It had long been recognized that neutrophils figure in the pathogenesis of SLE, but their precise role has remained unknown until quite recently. Then last year, separate groups of investigators reported that netting neutrophils activate the immune system in both adult and pediatric SLE.

"Our results support a model that positions this unique type of neutrophil death linked with plasmacytoid dendritic cell activation and type I interferon production at the core of SLE pathogenesis," said Dr. Gina S. Carcia-Romo and associates at the Baylor Institute for Immunology Research, Dallas (Sci. Transl. Med. 2011;3:73ra20).

Separately, investigators at Houston’s M.D. Anderson Cancer Center showed that a large percentage of SLE patients have high titer antibodies against NET proteins, including the antimicrobial protein LL37 and human neutrophil peptides. This results in formation of highly stable immunogenic complexes composed of these proteins plus self-DNA. In vitro, these immune complexes activate dendritic cells, causing release of large quantities of interferon alpha, which is part of the lupus signature in both adult and pediatric SLE. In contrast, neither healthy controls nor patients with scleroderma make antibodies against NETs (Sci. Transl.Med. 2011;3:73ra19).

The current thinking is that NETosis, under the wrong circumstances, results in the creation of stable self-DNA/antibody complexes that are recognized by B cells and shown to toll-like receptor 9, leading to formation of autoantibodies. The emerging picture is one of a vicious cycle of chronic autoimmunity. But there aren’t yet enough data to say which comes first in lupus: abnormal NETosis leading to excessive presentation of chromatin and nuclear antigens, or autoantigens triggering overexuberant NETosis.

"The innate immune scientist in me would like to believe that it’s the abnormal netting that starts the process in the right genetic background," confessed Dr. Humphrey of the University of Oklahoma at Oklahoma City.

Putting lupus aside, Dr. Humphrey noted that an international team of investigators from the University of California, San Francisco, and multiple German universities have reported that NETosis appears to trigger vasculitis and promotes the autoimmune response in patients with small-vessel vasculitis. They showed that ANCAs trigger NETosis, and the nets that are subsequently cast contain the autoantigens proteinase-3 and myeloperoxidase, which figure prominently in Wegener’s granulomatosis and microscopic polyangiitis, respectively.

Also, they demonstrated that NETs are deposited in the inflamed kidneys of individuals with small-vessel vasculitis. And they also offered the tantalizing observation that another autoinflammatory condition – psoriasis – can be driven by activated plasmacytoid dendritic cells in the presence of LL37, which, as it turns out, is highly expressed in the skin of psoriasis patients (Nat. Med. 2009;15:623-5).

How might NET formation be suppressed to the benefit of patients with SLE or vasculitis? NETosis is a process driven by reactive oxygen species. Potential strategies include administering reactive oxygen scavengers and blocking nicotinamide adenine dinucleotide phosphate oxidase, according to Dr. Humphrey.

She reported having no financial conflicts.

SNOWMASS, COLO. – Neutrophil extracellular traps are a recently identified component of innate immunity shaping up as a potential driving force in systemic lupus erythematosus and small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies.

Many key questions about neutrophil extracellular traps (NETs) remain to be answered in the next few years. The most clinically relevant include these: Can suppression of abnormal NET formation improve systemic lupus erythematosus (SLE) or small-vessel vasculitis? And can NET activity – that is, the NETosis level – serve as a biomarker for disease activity in patients with these disabling autoimmune disorders?

NETosis is the process by which activated neutrophils undergo a unique, nonapoptotic form of cell death. Intracellular chromatin unwinds, the nuclear membrane disintegrates, and the plasma membrane opens. This allows extrusion of large, net-like strands comprised of chromatin fibers, antimicrobial proteins, elastase, myeloperoxidase, and defensins. These cast nets are capable of rapidly trapping a broad range of microbes. But microbes aren’t the only entities that can trigger NETosis; interferon alpha and tumor necrosis factor can activate netting neutrophils as well, Dr. Mary Beth Humphrey explained at the symposium.

It had long been recognized that neutrophils figure in the pathogenesis of SLE, but their precise role has remained unknown until quite recently. Then last year, separate groups of investigators reported that netting neutrophils activate the immune system in both adult and pediatric SLE.

"Our results support a model that positions this unique type of neutrophil death linked with plasmacytoid dendritic cell activation and type I interferon production at the core of SLE pathogenesis," said Dr. Gina S. Carcia-Romo and associates at the Baylor Institute for Immunology Research, Dallas (Sci. Transl. Med. 2011;3:73ra20).

Separately, investigators at Houston’s M.D. Anderson Cancer Center showed that a large percentage of SLE patients have high titer antibodies against NET proteins, including the antimicrobial protein LL37 and human neutrophil peptides. This results in formation of highly stable immunogenic complexes composed of these proteins plus self-DNA. In vitro, these immune complexes activate dendritic cells, causing release of large quantities of interferon alpha, which is part of the lupus signature in both adult and pediatric SLE. In contrast, neither healthy controls nor patients with scleroderma make antibodies against NETs (Sci. Transl.Med. 2011;3:73ra19).

The current thinking is that NETosis, under the wrong circumstances, results in the creation of stable self-DNA/antibody complexes that are recognized by B cells and shown to toll-like receptor 9, leading to formation of autoantibodies. The emerging picture is one of a vicious cycle of chronic autoimmunity. But there aren’t yet enough data to say which comes first in lupus: abnormal NETosis leading to excessive presentation of chromatin and nuclear antigens, or autoantigens triggering overexuberant NETosis.

"The innate immune scientist in me would like to believe that it’s the abnormal netting that starts the process in the right genetic background," confessed Dr. Humphrey of the University of Oklahoma at Oklahoma City.

Putting lupus aside, Dr. Humphrey noted that an international team of investigators from the University of California, San Francisco, and multiple German universities have reported that NETosis appears to trigger vasculitis and promotes the autoimmune response in patients with small-vessel vasculitis. They showed that ANCAs trigger NETosis, and the nets that are subsequently cast contain the autoantigens proteinase-3 and myeloperoxidase, which figure prominently in Wegener’s granulomatosis and microscopic polyangiitis, respectively.

Also, they demonstrated that NETs are deposited in the inflamed kidneys of individuals with small-vessel vasculitis. And they also offered the tantalizing observation that another autoinflammatory condition – psoriasis – can be driven by activated plasmacytoid dendritic cells in the presence of LL37, which, as it turns out, is highly expressed in the skin of psoriasis patients (Nat. Med. 2009;15:623-5).

How might NET formation be suppressed to the benefit of patients with SLE or vasculitis? NETosis is a process driven by reactive oxygen species. Potential strategies include administering reactive oxygen scavengers and blocking nicotinamide adenine dinucleotide phosphate oxidase, according to Dr. Humphrey.

She reported having no financial conflicts.