Inhibition of Experimental Autoimmune Encephalomyelitis in Human C-Reactive Protein Transgenic Mice Is FcRIIB Dependent

Hu, Xianzhen; Wright, Tyler; Jones, Nicholas; Ramos, Theresa N.; Skibinski, Gregory A.; McCrory, Mark A.; Barnum, Scott R.; Szalai, Alexander J.

doi:10.4061/2011/484936

Cited by 12 publications

(25 citation statements)

References 25 publications

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“…Notably, transgenic expression of CRP has also been shown to be protective in mouse models of other autoimmune diseases wherein Th1 cells play a detrimental role (12–14), including spontaneous lupus (5) and collagen-induced arthritis (CIA) (8). In addition, the prolonged effect of a single dose of administered CRP observed in this study and previous ones (6, 48) strongly suggests that CRP is able to prominently and permanently remodel the adaptive immune response. A direct action of CRP on naïve T cells may be the explanation that ties these observations together, since CRP treatment 2 or 9 days following disease induction is still very effective (see Figures 5 and 6 and refs.…”

Section: Discussionsupporting

confidence: 80%

“…In CRPtg mice with EAE, wherein disease is less severe compared to wild type mice (not shown and ref. 6, 7), significantly fewer CD3 + CD4 + IFN-γ + T cells (p<0.05) were recovered from the spinal cord (Figure 6E). Collectively, these data suggest that the observed capacity of CRP to suppress Th1 responses in vitro is recapitulated in vivo , and that CRP’s ability to alleviate EAE likely involves inhibition of the pathological Th1 response.…”

Section: Resultsmentioning

confidence: 97%

“…To extend our findings to an in vivo setting wherein T cells are known to be integral and wherein CRP has been shown to play a beneficial role, we immunized C57BL/6 mice with MOG peptide to induce EAE, followed 2 days later by a single s.c. injection of CRP (6, 7). Splenocytes were collected 7 days later to assess Th1/Th2 balance.…”

Section: Resultsmentioning

confidence: 99%

“…A direct action of CRP on naïve T cells may be the explanation that ties these observations together, since CRP treatment 2 or 9 days following disease induction is still very effective (see Figures 5 and 6 and refs. 6 and 44). Notably, in preliminary experiments we also observed a moderate influence of CRP on the response of already differentiated Th1 and Th2 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis

Zhang

Liu

Wright

et al. 2015

The Journal of Immunology

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Human C-reactive protein (CRP) is a serum soluble pattern recognition receptor (PRR) that serves as a marker of inflammation and directly contributes to innate immunity. Herein we show that human CRP also directly contributes to adaptive immunity, i.e. native CRP binds specifically to human Jurkat T cells and to mouse naïve CD4+ T cells and modulates their T helper (Th) 1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naïve CD4+ T cells. In vivo for human CRP transgenic (CRPtg) compared to wild type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover in both CRPtg mice and in wild type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble PRR to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis

Zhang

Liu

Wright

et al. 2015

The Journal of Immunology

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“…Conversely, the closely related pentraxin C-reactive protein (CRP) is proinflammatory and promotes fibrosis (5,16). However, under some conditions, CRP decreases inflammation, indicating that much remains to be understood about this molecule (5,17). Despite the strong effects of pentraxins on the innate immune system and fibrosis (5,6), little is known about their mechanism of action.…”

mentioning

confidence: 99%

DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice

Cox

Pilling

2015

Proc. Natl. Acad. Sci. U.S.A.

109

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Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.F ibrosing diseases such scleroderma, pulmonary fibrosis, and renal fibrosis are caused by aberrant scar tissue formation in internal organs and are associated with 45% of deaths in the United States (1). At a fibrotic lesion, monocytes leave the blood, enter the tissue, and differentiate into cells such as macrophages and fibrocytes (2). Fibrocytes and macrophages then secrete extracellular matrix (ECM) proteins, ECM modifying enzymes, and/or cytokines such as IL-4 to promote scar tissue formation and fibrosis (3, 4).Pentraxins are a family of highly conserved secreted proteins that have a profound effect on the development of fibrosis and the regulation of the innate immune system (5-7). The pentraxin serum amyloid P (SAP) reduces neutrophil activation and recruitment (8, 9), inhibits the differentiation of monocytes into fibroblast-like cells called fibrocytes (8, 10), and promotes IL-10-secreting macrophages (11-13). In animal models and two human trials (6, 14, 15), injections of SAP decrease fibrosis, indicating that SAP has a dominant effect on a disease that is mediated in part by the innate immune system. Conversely, the closely related pentraxin C-reactive protein (CRP) is proinflammatory and promotes fibrosis (5, 16). However, under some conditions, CRP decreases inflammation, indicating that much remains to be understood about this molecule (5, 17). Despite the strong effects of pentraxins on the innate immune system and fibrosis (5, 6), little is known about their mechanism of action. For instance, pentraxins such as SAP and CRP appear to bind the same Fcγ receptors (FcγR) with similar affinities (7,8,18), but they generally have opposite effects. What causes this functional difference is not known.Dendritic ce...

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Collagen‐induced arthritis is exacerbated in C‐reactive protein–deficient mice

Jones

Pegues

McCrory

et al. 2011

Arthritis & Rheumatism

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Objective Blood C-Reactive Protein (CRP) is routinely measured to gauge inflammation and in rheumatoid arthritis (RA), heightened CRP is predictive of a poor outcome and lowered CRP indicative of a positive response to therapy. CRP interacts with the innate and adaptive immune systems in ways that suggest it may be causal in RA and, although this is not proven, it is widely assumed CRP makes a detrimental contribution to the disease process. Paradoxically, animal studies indicate CRP might be beneficial in RA. Methods We compared the impact of CRP deficiency versus transgenic over-expression on the inflammatory and immune responses using CRP deficient mice (Crp−/−) versus human CRP transgenic mice (CRPTg), respectively, and we compared the susceptibility of wild type, Crp−/−, and CRPtg to collagen-induced arthritis (CIA), a disease that resembles RA in humans. Results CRP deficiency significantly altered the inflammatory cytokine response evoked by challenge with endotoxin or anti-CD3 antibody, and heightened some immune responses. Compared to CIA in wild type mice, CIA in Crp−/− progressed more rapidly and was more severe whereas CIA in CRPTg was dramatically attenuated. Despite these disparate clinical outcomes, anti-collagen autoantibody responses during CIA did not differ among the genotypes. Conclusion CRP exerts an early and beneficial effect in mice with CIA. The mechanism of this effect remains unknown but does not involve improvement of the autoantibody profile. In humans the presumed detrimental role of heightened blood CRP during active RA might be balanced by a beneficial effect of baseline CRP manifest during the pre-clinical stages of disease.

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Inhibition of Experimental Autoimmune Encephalomyelitis in Human C-Reactive Protein Transgenic Mice Is FcRIIB Dependent

Cited by 12 publications

References 25 publications

C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis

C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis

DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice

Collagen‐induced arthritis is exacerbated in C‐reactive protein–deficient mice

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