C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity.
Du Clos Terry W,Mold Carolyn
Immunologic research
C-reactive protein (CRP) is an acute-phase serum protein and a member of the pentraxin protein family. Its host defense functions predate the adaptive immune system by millions of years. Our current understanding of CRP interactions with complement and with Fcgamma receptors (FcgammaR) have led to an increased appreciation of the regulatory role of CRP in inflammation and autoimmunity. This review outlines the role of CRP in infection, inflammation, and autoimmune disease. We provide a description of recent studies, which suggest that CRP acts through FcgammaR to reduce inflammation and protect from certain autoimmune diseases. A general description of the proposed function of CRP is provided as a framework for future investigation.
10.1385/IR:30:3:261
Anti-TNFalpha therapy in rheumatoid arthritis and autoimmunity.
Caramaschi Paola,Biasi Domenico,Colombatti Marco,Pieropan Sara,Martinelli Nicola,Carletto Antonio,Volpe Alessandro,Pacor Luisa Maria,Bambara Lisa Maria
Rheumatology international
The aim of the study was to evaluate a panel of autoantibodies in patients affected by rheumatoid arthritis (RA) treated with anti-TNFalpha blockers, and to consider a different autoantibody induction effect by infliximab and etanercept; and in addition to evaluate in these cases a relationship between antinuclear antibody (ANA) titre and both C-reactive protein (CRP) and Blys levels. Fifty-four patients (8 men, 46 women, mean age 51.4 years, mean duration of disease 13.6 years) affected by refractory RA were treated with anti-TNFalpha blockers for 12 consecutive months; 43 patients were given infliximab and 11 etanercept. At baseline and every 4 months a panel of autoantibodies consisting of rheumatoid factor, antinuclear, anti-double-stranded DNA, anti-ENA, anti-mitochondrial, anti-thyroid and anti-neutrophil cytoplasmic antibodies (ANCA) was tested. At the same time CRP level was measured. Blys level was determined at baseline and after 1 year in five cases that developed a strong positivity for ANA during infliximab therapy. In 41 cases (95.3%) treated with infliximab, ANA were detected on at least one occasion, and in almost half of these cases the titre was very high, equal to or higher than 1:1.280. On the other hand, patients treated with etanercept presented ANA positivity in a lower percentage of cases and at a low titre. No correlation was found between ANA titre and CRP level; Blys level did not present a constant trend in patients who developed a very high positivity for ANA. Anti-double-stranded DNA, anti-thyroid or ANCA were found only in a few patients, in the absence of a clinical picture indicative of systemic lupus erythematosus, autoimmune thyroiditis or ANCA-associated vasculitis. A different incidence of ANA positivity was found in infliximab- and etanercept-treated RA patients; this finding might be due to the partially different method of inhibition of TNFalpha between the two drugs. Both CRP and Blys do not seem to participate in this phenomenon. Other autoantibodies were detected in a few patients, but no case of onset of new autoimmune disorders was observed.
10.1007/s00296-004-0542-1
C-reactive protein (CRP) and autoimmune disease: facts and conjectures.
Szalai Alexander J
Clinical & developmental immunology
C-reactive protein (CRP) is a blood component comprised of five identical subunits with a combined molecular mass of 110 kDa; in the presence of Ca++ it binds phosphocholine (PC) with high affinity. Ligand-bound CRP activates complement and the protein reportedly binds various Fc receptors. Coincident with a now decade-long resurgence in clinical interest in associations of CRP with disease, our laboratory has been investigating the biology of CRP in vivo using human CRP transgenic mice (CRPtg). At that time we confirmed that CRP affects a host defense function mediated at least in part through the elimination of pathogens. Less appreciated and not as well understood as CRP's ability to bind antigen and aid in the elimination of microbes, is its known ability to bind autoantigens and presumed capacity to promote clearance of apoptotic cells. These latter properties of CRP have long been suspected to contribute to homeostasis and to autoimmune disease. In this article we review and update the evidence generated in CRPtg by our group and in vitro by others' that indicates CRP is more than just an antimicrobial molecule and convenient marker of inflammation-rather, it protects against autoimmunity. A mechanistic hypothesis is presented to account for this cause-and-effect relationship.
10.1080/17402520400001751
Serum amyloid A and C-reactive protein concentrations are differently associated with markers of autoimmunity in patients with primary Sjögren's syndrome.
Pertovaara Marja,Jylhävä Juulia,Uusitalo Hannu,Pukander Juhani,Helin Heikki,Hurme Mikko
The Journal of rheumatology
OBJECTIVE:Primary Sjögren's syndrome (pSS) is an autoimmune disease in which the concentration of the acute-phase protein serum C-reactive protein (CRP) is low. We investigated whether levels of another acute-phase protein, serum amyloid A (SAA), are increased in patients with pSS and whether the immunological markers in patients with pSS are associated with variation in SAA levels. METHODS:Serum SAA concentrations were measured by ELISA in 74 patients with pSS and in 56 control subjects with sicca symptoms. RESULTS:Median SAA levels did not differ significantly between patients with pSS and subjects with sicca symptoms. In patients with pSS SAA concentrations correlated significantly with age, leukocyte count, CRP, interleukin 6, and C4. Unlike CRP, there was a significant inverse correlation between SAA and serum IgG levels and anti-SSA antibody titers, as well as a trend towards an inverse correlation between SAA and antinuclear antibody and rheumatoid factor titers. CONCLUSION:Our data imply that high SAA production could constitute a protective element in pSS: high SAA levels inhibit in particular various signs of B cell hyperreactivity, i.e., IgG and autoantibody production.
10.3899/jrheum.090300
C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity.
The Journal of experimental medicine
C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca(2+)-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor beta. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.
10.1084/jem.192.9.1353
C-reactive protein, immunoglobulin G and complement co-localize in renal immune deposits of proliferative lupus nephritis.
Sjöwall Christopher,Olin Anders I,Skogh Thomas,Wetterö Jonas,Mörgelin Matthias,Nived Ola,Sturfelt Gunnar,Bengtsson Anders A
Autoimmunity
The pattern recognition molecules C-reactive protein (CRP) and C1q are of big interest in relation to the pathogenesis of systemic lupus erythematosus (SLE). Circulating autoantibodies against CRP and C1q are frequently found in SLE patients with active disease, particularly in lupus nephritis (LN), and rising levels reportedly relate to disease activity and outcome. If CRP-, or dsDNA- and/or C1q-containing immune complexes (ICs) are pathogenic in LN, glomerular IgG-deposits would be expected to co-localize with these antigens. In search for proof of this concept, renal biospsies from patients with active LN (n = 5) were examined with high-resolution immunogold electron microscopy. Renal biopsies from patients with Henoch-Schönlein purpura, pauci-immune nephritis and renal cancer served as controls. IgG antibodies against CRP, C1q and nucleosomes were analyzed in pre-post flare sera. We could demonstrate that CRP, C1q, C3c and dsDNA were co-localized with IgG in electron dense deposits in the glomerular basement membrane/subendothelial space in all of the 5 LN patients. Deposits of IgG, CRP, complement and dsDNA were 10-fold higher in LN compared to controls. All SLE patients had circulating anti-nucleosome antibodies; 4/5 had serum antibodies against CRP, dsDNA, and C1q at biopsy/flare. Despite a limited number of cases, the results support the notion of a pathogenic role not only for anti-dsDNA antibodies, but also for anti-CRP and anti-C1q in LN. The glomerular ICs may have been generated by deposition of circulating ICs or by in situ IC formation.
10.3109/08916934.2013.764992
C-Reactive Protein Impairs Dendritic Cell Development, Maturation, and Function: Implications for Peripheral Tolerance.
Frontiers in immunology
C-reactive protein (CRP) is the prototypical acute phase reactant, increasing in blood concentration rapidly and several-fold in response to inflammation. Recent evidence indicates that CRP has an important physiological role even at low, baseline levels, or in the absence of overt inflammation. For example, we have shown that human CRP inhibits the progression of experimental autoimmune encephalomyelitis (EAE) in CRP transgenic mice by shifting CD4 T cells away from the T1 and toward the T2 subset. Notably, this action required the inhibitory Fcγ receptor IIB (FcγRIIB), but did not require high levels of human CRP. Herein, we sought to determine if CRP's influence in EAE might be explained by CRP acting on dendritic cells (DC; antigen presenting cells known to express FcγRIIB). We found that CRP (50 µg/ml) reduced the yield of CD11c bone marrow-derived DCs (BMDCs) and CRP (≥5 μg/ml) prevented their full expression of major histocompatibility complex class II and the co-stimulatory molecules CD86 and CD40. CRP also decreased the ability of BMDCs to stimulate antigen-driven proliferation of T cells . Importantly, if the BMDCs were genetically deficient in mouse FcγRIIB then (i) the ability of CRP to alter BMDC surface phenotype and impair T cell proliferation was ablated and (ii) CD11c-driven expression of a human transgene rescued the CRP effect. Lastly, the protective influence of CRP in EAE was fully restored in mice with CD11c-driven human FcγRIIB expression. These findings add to the growing evidence that CRP has important biological effects even in the absence of an acute phase response, i.e., CRP acts as a tonic suppressor of the adaptive immune system. The ability of CRP to suppress development, maturation, and function of DCs implicates CRP in the maintenance of peripheral T cell tolerance.
10.3389/fimmu.2018.00372
CRP and the disposal of dying cells: consequences for systemic lupus erythematosus and rheumatoid arthritis.
Vogt Birgit,Führnrohr Barbara,Müller Rüdiger,Sheriff Ahmed
Autoimmunity
C reactive protein (CRP) levels directly correlate with the disease activity of many inflammatory diseases, e.g. sepsis, infection, and various autoimmunopathies such as rheumatoid arthritis (RA). In contrast, insufficient CRP levels are implicated in the development of systemic lupus erythematosus (SLE). This article reports on the level-depended effects of CRP in various diseases. In detail we show that increased and decreased levels of CRP, as demonstrated in patients with RA and SLE, respectively can contribute to disease progression.
10.1080/08916930701358925
Therapeutic Lowering of C-Reactive Protein.
Jimenez Rachel V,Szalai Alexander J
Frontiers in immunology
In the blood of healthy individuals C-reactive protein (CRP) is typically quite scarce, whereas its blood concentration can rise robustly and rapidly in response to tissue damage and inflammation associated with trauma and infectious and non-infectious diseases. Consequently, CRP plasma or serum levels are routinely monitored in inpatients to gauge the severity of their initial illness and injury and their subsequent response to therapy and return to health. Its clinical utility as a faithful barometer of inflammation notwithstanding, it is often wrongly concluded that the biological actions of CRP (whatever they may be) are manifested only when blood CRP is elevated. In fact over the last decades, studies done in humans and animals (e.g. human CRP transgenic and CRP knockout mice) have shown that CRP is an important mediator of biological activities even in the absence of significant blood elevation, i.e. even at baseline levels. In this review we briefly recap the history of CRP, including a description of its discovery, early clinical use, and biosynthesis at baseline and during the acute phase response. Next we overview evidence that we and others have generated using animal models of arthritis, neointimal hyperplasia, and acute kidney injury that baseline CRP exerts important biological effects. In closing we discuss the possibility that therapeutic lowering of baseline CRP might be a useful way to treat certain diseases, including cancer.
10.3389/fimmu.2020.619564
The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus.
Enocsson Helena,Karlsson Jesper,Li Hai-Yun,Wu Yi,Kushner Irving,Wetterö Jonas,Sjöwall Christopher
Journal of clinical medicine
C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.
10.3390/jcm10245837
Anti-CRP antibodies in systemic lupus erythematosus.
Meyer Olivier
Joint bone spine
C-reactive protein (CRP) is an acute-phase protein whose concentration rises sharply during the inflammatory response (1000-fold). CRP belongs to the pentraxin family of proteins, of which a key property is the ability to opsonize apoptotic cells, which can then undergo phagocytosis without triggering an inflammatory response, in marked contrast to the phagocytosis of necrotic cells. The low CRP concentrations in patients with systemic lupus erythematosus (SLE) may contribute to defective clearance of apoptotic particles, thereby promoting the development of autoimmunity to apoptotic vesicle components. In normal populations, serum CRP concentrations remain below 5-10mg/L. Within this normal range, five quintiles of CRP concentrations can be distinguished using an ultrasensitive CRP assay. Individuals who are consistently within the highest quintile are at higher risk for cardiovascular death and recurrent myocardial infarction than are individuals in the lowest quintile. Thus, the ultrasensitive CRP concentration (US-CRP) is a cardiovascular risk factor, together with the classic risk factors identified by the Framingham studies. CRP plays a role in atheroma plaque development via its ability to attract macrophages, which convert to foam cells. Any chronic inflammatory disease associated with increased CRP production can accelerate the development of atheroma. Paradoxically, the inflammatory process in patients with SLE is associated with a fairly small elevation of serum CRP concentrations. Nevertheless, this elevation is sufficient to increase the cardiovascular risk. Anti-CRP autoantibodies, which are found in 35 to 40% of SLE patients, increase the cardiovascular risk by interacting with the monomeric (degraded) form of CRP. CRP/anti-CRP immune complexes developed in the arterial wall may promote growth of the atheroma plaque.
10.1016/j.jbspin.2010.04.010
[Association between systemic inflammation and autoimmunity parameters and plasma lipid in patients with rheumatoid arthritis].
Xue Chao,Liu Wen-ling,Sun Yi-hong,Ding Rong-jing,Hu Da-yi
Zhonghua xin xue guan bing za zhi
OBJECTIVE:The purpose of this study was to observe the association between inflammation status/autoimmune antibodies and plasma lipid in patients with rheumatoid arthritis (RA). METHODS:A total of 402 RA patients were admitted into our hospital during January 2008 to March 2009 and 225 RA patients who met the inclusion criteria were selected to perform a full lipid profile examination including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), anti-keratin antibody (AKA), anti-perinuclear factor autoantibody (APF) and complement (C) were also evaluated. Atherogenic index of plasma (AIP) was calculate by the formula Log (TG/HDL-C). RESULTS:(1) There were 12.9%, 10.2% and 14.2% patients with elevated TC, LDL-C and TC respectively, patients with reduced HDL-C accounted for 43.6%. (2) C(3) was higher in elevated TC group than normal TC group (P < 0.05). ESR and CRP were significantly higher in decreased HDL-C group than in normal HDL-C group (P < 0.05). CRP, C(3) and C(4) were significantly higher in elevated LDL-C group than in normal LDL-C group (P < 0.05). (3) Multiple stepwise regression analysis showed that C(3) was positively correlated with TC (R(2) = 0.067, P < 0.05). Both ESR and CRP were negative correlated with HDL-C (R(2) = 0.202, P < 0.05). CRP and anti-CCP were positively correlated with LDL-C (R(2) = 0.129, P < 0.05). ESR and C(4) were positively correlated with AIP (R(2) = 0.046, P < 0.05). CONCLUSION:This study showed that rheumatoid arthritis is associated with an abnormal lipid profile, especially in patients with increased inflammation markers and autoimmune antibodies. Moreover, ESR and C(4) were predictors of increased AIP in this cohort.
Tissue metabolite of type I collagen, C1M, and CRP predicts structural progression of rheumatoid arthritis.
Bay-Jensen Anne C,Platt Adam,Jenkins Martin A,Weinblatt Michael E,Byrjalsen Inger,Musa Kishwar,Genovese Mark C,Karsdal Morten A
BMC rheumatology
BACKGROUND:Biomarkers of rheumatoid arthritis (RA) disease activity typically measure inflammation or autoimmunity (e.g. CRP, RF). C1M and C3M, metabolites of type I and III collagen, are markers reflecting tissue metabolism. These markers have been documented to provide additional prognostic and predictive value compared to commonly used biomarkers. We investigated the relationship of high serum levels of C1M or C3M to radiographic progression, and benchmarked them to CRP and RF. METHODS:Placebo treated patients of the OSK1, 2 and 3 studies (Phase III clinical trials testing efficacy of fostamatinib) with baseline serum biomarkers C1M, C3M, CRP and RF were included (n = 474). Van der Heijde mTSS was calculated at baseline and 24-week (n = 261). Progression was defined as moderate or rapid by ΔmTSS ≥0.5 or ≥ 5 units/year. Patients were divided into subgroups; low (L), high (H) or very high (V) C1M, C3M and CRP, or RF negative, positive and high positive. Difference in clinical parameters were analyzed by Mann-Whitney or χtests, and modelling for prediction of progression by logistic regression including covariates (age, gender, BMI, and clinical assessment scores). RESULTS:Levels of C1M, C3M, CRP and RF were significantly ( < 0.05) associated with measures of disease activity and mTSS at baseline. For prognostic measures, there were 2.5 and 4-fold as many rapid progressors in the C1M and CRP (p < 0.05), and in the C1M and CRP groups ( < 0.001) compared C1M and CRP, respectively. C1M and CRP performed similarly in the predictive analysis, where high levels predicted moderate and rapid progression with odds ratio of 2.1 to 3.8 and 3.7 to 13.1 after adjustment for covariates. C3M and RF did not provide prognostic value alone. DISCUSSION:Serum C1M and CRP showed prognostic value and may be tools for enrichment of clinical trials with structural progressor. The two markers reflect two different aspect of disease pathogenesis (tissue turnover vs. inflammation), thus may provide individual and supplementary information.
10.1186/s41927-019-0052-0
C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205.
Enocsson Helena,Gullstrand Birgitta,Eloranta Maija-Leena,Wetterö Jonas,Leonard Dag,Rönnblom Lars,Bengtsson Anders A,Sjöwall Christopher
Frontiers in immunology
Objectives:Patients with systemic lupus erythematosus (SLE) often display modest elevations of C-reactive protein (CRP) despite raised disease activity and increased interleukin (IL-) 6. We asked to what extent IL-6 levels, the CRP polymorphism rs1205, and the type I interferon (IFN) gene signature affects the basal CRP levels in patients with SLE during a quiescent phase of the disease. Methods:CRP and IL-6 were analyzed in plasma from 57 patients meeting established classification criteria for SLE. The CRP polymorphism rs1205 was assessed and gene expression analyzed including four type I IFN-regulated genes (IGS). Results:CRP was increased in patients with detectable IL-6 levels (p=0.001) and decreased among IGS-positive subjects (p=0.033). A multiple linear regression model revealed IL-6 to have a positive association with CRP levels, whereas both IGS-positivity and CRP genotype (rs1205) AA/GA were negatively associated with CRP-levels. Conclusion:Our data offer an explanation to the modest CRP levels seen in viral infections and IFN-α driven autoimmunity and corroborate prior observations showing an IFN-α dependent downregulation of CRP. The latter observation, together with the fact that the CRP-lowering polymorphism rs1205 is overrepresented in human SLE, could explain low basal CRP and inadequate CRP-responses among patients with active SLE.
10.3389/fimmu.2020.622326
Innate immune-responses and their role in driving autoimmunity.
Toubi Elias,Vadasz Zahava
Autoimmunity reviews
Autoimmunity and autoimmune diseases were always considered to be driven mainly by adaptive immune responses, namely by auto-reactive B and T cell over-activity. The continuous stimulation of dendritic cells by autoantigens increases B cell activity, driving auto-reactive B cells to increase the production of autoantibodies and of pro-inflammatory cytokines. On the other hand, a subset of dendritic cells is established being of tolerogenic properties thus becoming important in maintaining self-tolerance. However, early innate immune responses are continuously appreciated to be highly important in the development of immune-mediated inflammation in general and autoimmunity in particular. The innate immune system is a complex network of structured cells/proteins such as antigen presenting cells (macrophages and dendritic cells), the complement cascade, and many receptors/cytokines/proteins. Of these, one may mention the high expression of toll-like receptors 7 and 9 in antigen presenting cells, and B cells of systemic lupus erythematosus patients contributing to the expansion of auto-reactive B cells. C-reactive protein (CRP) and C1q are crucially important for efficient uptake of apoptotic cells. However, CRP is appreciated to have a role in maintaining anti-inflammatory responses and in altering autoimmunity. Natural killer cells (NK) are responsible for cytotoxicity responses but some of them (mainly CD56high), are important in maintaining peripheral self-tolerance, thus considered to be immune-regulatory cells. In this review we will cover most of the new data on innate immune system and discuss its importance in the development of autoimmunity. New treatments were developed following our better understanding of these pathways, the targeting of which, opened new therapeutic avenues in treating autoimmune diseases.
10.1016/j.autrev.2018.10.005