Targeted IgA Fc receptor I (FcαRI) therapy in the early intervention and treatment of pristane-induced lupus nephritis in mice

Liu, C.; Kanamaru, Yutaka; Watanabe, Takashi; Tada, Norio; Horikoshi, Satoshi; Suzuki, Yusuke; Liu, Z.; Tomino, Yasuhiko

doi:10.1111/cei.12647

Cited by 22 publications

(20 citation statements)

References 30 publications

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“…Pristane has previously been shown to induce nephritis in C57BL/6J mice characterized by glomerular proliferation, mesangial expansion, and proteinuria 17 18 . These changes are associated with elevated levels of anti-dsDNA antibodies.…”

Section: Resultsmentioning

confidence: 99%

Psgl-1 Deficiency is Protective against Stroke in a Murine Model of Lupus

Wang

Knight

Hodgin

et al. 2016

Sci Rep

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Systemic lupus erythematosus (SLE) is associated with an elevated risk of vascular complications, including premature stroke. Therapies targeting leukocyte recruitment may be beneficial in reducing vascular complications associated with SLE. Lupus was induced in female wild-type (WT) and P-selectin glycoprotein ligand-1 deficient (Psgl-1−/−) mice with pristane. Stroke was induced following photochemical injury to the middle cerebral artery (MCA). Stroke size was increased in pristane-treated WT mice compared to non-pristane-treated WT controls. However, stroke size was not increased in pristane-treated Psgl-1−/− mice compared to controls, despite evidence of increased nephritis in Psgl-1−/− mice. Pristane-treated WT mice showed elevated anti-dsDNA, anti-snRNP, CXCL1, and MCP-1 levels compared to untreated mice; however levels of anti-snRNP, MCP-1, and CXCL1 were reduced in pristane-treated Psgl-1−/− mice compared to pristane-treated WT mice. Infiltration of neutrophils and macrophages at the cerebral infarction site were reduced in pristane-treated Psgl-1−/− mice compared to pristane-treated WT mice. In conclusion, the increase in stroke size associated with lupus is prevented by Psgl-1 deficiency while nephritis is exacerbated. Therapies targeting Psgl-1 may be useful in the management of SLE patients at high risk of acute vascular complications although elucidation of downstream pathways will be necessary to identify targets that do not promote nephritis.

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Section: Resultsmentioning

confidence: 99%

Psgl-1 Deficiency is Protective against Stroke in a Murine Model of Lupus

Wang

Knight

Hodgin

et al. 2016

Sci Rep

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“…Thus, it seems that a threshold of high IgA autoantibodies is required for neutrophil activation, which could explain the findings that IgA RF and IgA ACPA correlated with worse disease course in RA patients (10)(11)(12)15). It was reported that monovalent targeting of FcaRI can induce inhibitory ITAM (ITAMi) signaling (48,49). As such, it might be possible that the anti-FcaRI mAb MIP8a did not block binding and activation through FcaRI but induced ITAMi signaling, which would decrease activation via binding of IgG RF to FcgR.…”

Section: Discussionmentioning

confidence: 99%

IgA Complexes in Plasma and Synovial Fluid of Patients with Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI

Aleyd

Tuk

et al. 2016

The Journal of Immunology

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Autoantibodies, including rheumatoid factor (RF), are an important characteristic of rheumatoid arthritis (RA). Interestingly, several studies reported a correlation between the presence of IgA autoantibodies and worse disease course. We demonstrated previously that triggering the IgA Fc receptor (FcαRI) on neutrophils results in neutrophil recruitment and the release of neutrophil extracellular traps (NETs). Because this can lead to tissue damage, we investigated whether IgA immune complexes in plasma and synovial fluid of RA patients activate neutrophils. RF isotypes were measured with ELISA, and immune complexes were precipitated using polyethylene glycol 6000. Isolated neutrophils were incubated with immune complexes, and activation and release of NETs were determined in the presence or absence of FcαRI-blocking Abs. Plasma and SF of RA patients contained IgM, IgG, and IgA RFs. Patient plasma IgA RF and IgM RF showed a strong correlation. No uptake of IgM and minimal endocytosis of IgG immune complexes by neutrophils was observed, in contrast to avid uptake of IgA complexes. Incubation of neutrophils with immune complexes resulted in the production of reactive oxygen species, as well as the release of NETs, lactoferrin, and chemotactic stimuli. Importantly, activation of neutrophils was reduced when FcαRI was blocked. Neutrophils were activated by IgA immune complexes, which suggests that neutrophils play a role in inducing joint damage in RA patients who have IgA autoantibody complexes, thereby increasing the severity of disease. Blocking FcαRI inhibited neutrophil activation and, as such, may represent an additional attractive novel therapeutic strategy for the treatment of RA.

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“…Using a FcαRI transgenic mice model with glomerulonephritis and obstructive nephropathy caused by accumulation of IgG immune complexes, the Fab A77 targeting FcαRI was shown to be able to suppress inflammation [208]. It was also established that renal inflammation induced by different agents can be alleviated by the use of Fab fragments that target FcαRI (MIP8a) or monomeric IgA [209,210]. Therefore, targeting FcαRI either through IgA binding or the use of specific antibodies, can be used as a strategy to initiate anti-inflammatory responses in inflammatory diseases that involve myeloid cells.…”

Section: Fcαri Blocking Agentsmentioning

confidence: 99%

IgA: Structure, Function, and Developability

2019

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Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA to effective immune defence is signalled by the fact that more IgA is produced than all the other immunoglobulin classes combined. Indeed, IgA is not just the most prevalent antibody class at mucosal sites, but is also present at significant concentrations in serum. The unique structural features of the IgA heavy chain allow IgA to polymerise, resulting in mainly dimeric forms, along with some higher polymers, in secretions. Both serum IgA, which is principally monomeric, and secretory forms of IgA are capable of neutralising and removing pathogens through a range of mechanisms, including triggering the IgA Fc receptor known as FcαRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structure–function relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena.

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Targeted IgA Fc receptor I (FcαRI) therapy in the early intervention and treatment of pristane-induced lupus nephritis in mice

Cited by 22 publications

References 30 publications

Psgl-1 Deficiency is Protective against Stroke in a Murine Model of Lupus

Psgl-1 Deficiency is Protective against Stroke in a Murine Model of Lupus

IgA Complexes in Plasma and Synovial Fluid of Patients with Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI

IgA: Structure, Function, and Developability

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