High‐Mobility Group Box 1 Inhibition Alleviates Lupus‐Like Disease in <scp>BXSB</scp> Mice

Zhang, C.; Li, C.; Jia, Shanshan; Yao, Ping-Bao; Yang, Qingrui; Zhang, Y.

doi:10.1111/sji.12165

Cited by 30 publications

(25 citation statements)

References 26 publications

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“…The results presented here appear to contradict a recent study by Zhang et al (36) showing that treatment with anti-HMGB1 antibodies reduced lupus-like disease, including proteinuria and glomerulonephritis, in lupus-prone BXSB mice (36). Lupus in BXSB mice is characterized by lymph node and spleen enlargement, hypergammaglobulinemia, anti-nuclear antibodies and immune complex glomerulonephritis, which usually becomes evident at around 5 months of age.…”

Section: Discussioncontrasting

confidence: 56%

“…Therefore, because of high levels of HMGB1 locally, the dose of mAb 2G7 used here may have been insufficient to neutralize HMGB1 completely. Although we cannot exclude this possibility, previous studies in BXSB lupus mice and a sepsis model have clearly shown a positive effect of anti-HMGB1 antibody treatment, despite the development of splenomegaly (21,36).…”

mentioning

confidence: 85%

“…In the disease models described by Li et al and Zhang et al, which do show a positive effect of blocking HMGB1, it is unclear whether anti-HMGB1 antibodies are also present (33,36). At present, the role of endogenously formed anti-HMGB1 antibodies in disease pathogenesis is unclear and warrants further investigation.…”

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confidence: 87%

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Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

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Section: Discussioncontrasting

confidence: 56%

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confidence: 85%

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Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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“…Administration of monoclonal anti-HMGB1 antibodies have shown opposing effects in animal models of lupus [83,84]. In animal models of arthritis anti-HMGB1 treatment have attenuated the disease [85,86].…”

Section: Antibodies Against High Mobility Group Box Protein-1 (Hmgb1)mentioning

confidence: 99%

“…Studies in animal models of arthritis have shown that treatment with anti-HMGB1 antibodies can attenuate disease by blocking pro-inflammatory actions of HMGB1 [85,86]. Opposing effects of anti-HMGB1 have been demonstrated in two different murine lupus models [83,84]. HMGB1 has different…”

Section: Antibodies Against High Mobility Group Box Protein-1 (Hmgb1)mentioning

confidence: 99%

Biomarkers of disease activity and organ damage in systemic lupus erythematosus

Wirestam¹

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Jag tror att när vi går igenom tiden att allt det bästa inte hänt än Håkan Hellström ABSTRACTSystemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients.High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation.Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated.As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels.Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity.Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up.In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.

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