Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein.

Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity.

Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

BACKGROUND: CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor). Given the proinflammatory function of dissociated CRP and the important role of inflammation in the pathogenesis of AS, we investigated whether shear stress can modify CRP conformation and induce inflammatory effects relevant to AS. METHODS: To determine the effects of pathological shear rates on the function of human CRP, pCRP was subjected to pathophysiologically relevant shear rates and analyzed using biophysical and biochemical methods. To investigate the effect of shear on CRP conformation in vivo, we used a mouse model of arterial stenosis. Levels of mCRP and pCRP were measured in patients with severe AS pre- and post-transcatheter aortic valve implantation, and the presence of CRP was investigated on excised valves from patients undergoing aortic valve replacement surgery for severe AS. Microfluidic models of AS were then used to recapitulate the shear rates of patients with AS and to investigate this shear-dependent dissociation of pCRP and its inflammatory function. RESULTS: Exposed to high shear rates, pCRP dissociates into its proinflammatory monomers (mCRP) and aggregates into large particles. Our in vitro findings were further confirmed in a mouse carotid artery stenosis model, where the administration of human pCRP led to the deposition of mCRP poststenosis. Patients undergoing transcatheter aortic valve implantation demonstrated significantly higher mCRP bound to circulating microvesicles pre-transcatheter aortic valve implantation compared with post-transcatheter aortic valve implantation. Excised human stenotic aortic valves display mCRP deposition. pCRP dissociated in a microfluidic model of AS and induces endothelial cell activation as measured by increased ICAM-1 and P-selectin expression. mCRP also induces platelet activation and TGF-ß (transforming growth factor beta) expression on platelets. CONCLUSIONS: We identify a novel mechanism of shear-induced pCRP dissociation, which results in the activation of cells central to the development of AS. This novel mechanosensing mechanism of pCRP dissociation to mCRP is likely also relevant to other pathologies involving increased shear rates, such as in atherosclerotic and injured arteries.

Recognition of Highly Branched N-Glycans of the Porcine Whipworm by the Immune System.

Glycans are key to host-pathogen interactions, whereby recognition by the host and immunomodulation by the pathogen can be mediated by carbohydrate binding proteins, such as lectins of the innate immune system, and their glycoconjugate ligands. Previous studies have shown that excretory-secretory products of the porcine nematode parasite Trichuris suis exert immunomodulatory effects in a glycan-dependent manner. To better understand the mechanisms of these interactions, we prepared N-glycans from T. suis and both analyzed their structures and used them to generate a natural glycan microarray. With this array, we explored the interactions of glycans with C-type lectins, C-reactive protein, and sera from T. suis-infected pigs. Glycans containing LacdiNAc and phosphorylcholine-modified glycans were associated with the highest binding by most of these proteins. In-depth analysis revealed not only fucosylated LacdiNAc motifs with and without phosphorylcholine moieties but phosphorylcholine-modified mannose and N-acetylhexosamine-substituted fucose residues, in the context of maximally tetraantennary N-glycan scaffolds. Furthermore, O-glycans also contained fucosylated motifs. In summary, the glycans of T. suis are recognized by both the innate and adaptive immune systems and also exhibit species-specific features distinguishing its glycome from those of other nematodes.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

BACKGROUND: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. METHODS: The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. RESULTS: Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. CONCLUSIONS: Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project.

BACKGROUND AND AIMS: Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. METHODS: Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). RESULTS: Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). CONCLUSIONS: While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

Sex-specific Prediction of Cardiogenic Shock After Acute Coronary Syndromes: The SEX-SHOCK Score.

BACKGROUND: and aims: Cardiogenic shock (CS) remains the primary cause of in-hospital death after acute coronary syndromes (ACS), with its plateauing mortality rates approaching 50%. To test novel interventions, personalized risk prediction is essential. The ORBI (Observatoire Régional Breton sur l'Infarctus) score represents the first-of-its-kind risk score to predict in-hospital CS in ACS patients undergoing percutaneous coronary intervention (PCI). However, its sex-specific performance remains unknown, and refined risk prediction strategies are warranted. METHODS: This multinational study included a total of 53 537 ACS patients without CS on admission undergoing PCI. Following sex-specific evaluation of ORBI, regression and machine-learning models were used for variable selection and risk prediction. By combining best-performing models with highest-ranked predictors, SEX-SHOCK was developed, and internally and externally validated. RESULTS: The ORBI score showed lower discriminative performance for the prediction of CS in females than males in Swiss (AUC [95% CI]: 0.78 [0.76-0.81] vs. 0.81 [0.79-0.83]; p=0.048) and French ACS patients (0.77 [0.74-0.81] vs. 0.84 [0.81-0.86]; p=0.002). The newly developed SEX-SHOCK score, now incorporating ST-segment elevation, creatinine, C-reactive protein, and left ventricular ejection fraction, outperformed ORBI in both sexes (females: 0.81 [0.78-0.83]; males: 0.83 [0.82-0.85]; p<0.001), which prevailed following internal and external validation in RICO (females: 0.82 [0.79-0.85]; males: 0.88 [0.86-0.89]; p<0.001) and SPUM-ACS (females: 0.83 [0.77-0.90], p=0.004; males: 0.83 [0.80-0.87], p=0.001). CONCLUSIONS: The ORBI score showed modest sex-specific performance. The novel SEX-SHOCK score provides superior performance in females and males across the entire spectrum of ACS, thus providing a basis for future interventional trials and contemporary ACS management.

Interleukin-6 positively correlates with cardiovascular disease predictor algorithms and biomarker in rheumatoid arthritis patients.

Chronic inflammation is believed as the main culprit of the link between cardiovascular disease (CVD) and rheumatoid arthritis (RA). Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a key role in RA pathophysiology and also correlates with joint destruction and disease activity. This study evaluates the association between IL-6 plasma level and cardiac biomarker NT-proBNP, HS-CRP, CVD predictor algorithms, Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE), as well as with CXCL9 and its receptor, CXCR3 in RA patients compared to the controls. Sixty RA patients (30 early and 30 late) and 30 healthy persons were included in this study. IL-6 and NT-proBNP plasma levels were measured by the ELISA. Also, HS-CRP plasma levels were quantified using the immunoturbidimetric assay. The CVD risk was assessed by the FRS and SCORE. IL-6 plasma levels were significantly higher in the early and late RA patients compared to the controls (p < 0.001). There was a positive correlation between IL-6 with DAS-28 (p = 0.007, r = 0.346), BPS (p = 0.002, r = 0.396), BPD (p = 0.046, r = 0.259), SCORE (p < 0.001, r = 0.472), and FRS (p < 0.001, r = 0.553), and a negative association with HDL (p = 0.037, r = -0.270), in the patients. Also, IL-6 plasma level positively correlated with HS-CRP (p = 0.021, r = 0.297) and NT-proBNP (p = 0.045, r = 0.260) in the patients. Furthermore, a positive association was found between IL-6 plasma levels and CXCL9 (p = 0.002, r = 0.386), and CXCR3 (p = 0.018, r = 0.304) in the patients. Given the interesting association between IL-6 with various variables of CVD, IL-6 may be considered a biomarker for assessing the risk for future cardiovascular events in RA patients.

Interleukin-6, C-Reactive Protein, and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data.

BACKGROUND: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction. METHODS: Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship. RESULTS: There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P<0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit logeIL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; Pinteraction=0.03). After adjustment for risk factors/medication, the association remained for postacute IL-6 when analyzed per logeunit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP. CONCLUSIONS: Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies.

Evaluation of C-Reactive Protein and Computer-Aided Analysis of Chest X-rays as Tuberculosis Triage Tests at Health Facilities in Lesotho and South Africa.

BACKGROUND: To improve tuberculosis case-finding, rapid, non-sputum triage tests need to be developed according to the World Health Organization target product profile (TPP) (>90% sensitivity, >70% specificity). We prospectively evaluated and compared artificial intelligence-based, computer-aided detection software, CAD4TBv7, and C-reactive protein assay (CRP) as triage tests at health facilities in Lesotho and South Africa. METHODS: Adults (≥18 years) presenting with ≥1 of the 4 cardinal tuberculosis symptoms were consecutively recruited between February 2021 and April 2022. After informed consent, each participant underwent a digital chest X-ray for CAD4TBv7 and a CRP test. Participants provided 1 sputum sample for Xpert MTB/RIF Ultra and Xpert MTB/RIF and 1 for liquid culture. Additionally, an expert radiologist read the chest X-rays via teleradiology. For primary analysis, a composite microbiological reference standard (ie, positive culture or Xpert Ultra) was used. RESULTS: We enrolled 1392 participants, 48% were people with HIV and 24% had previously tuberculosis. The receiver operating characteristic curve for CAD4TBv7 and CRP showed an area under the curve of .87 (95% CI: .84-.91) and .80 (95% CI: .76-.84), respectively. At thresholds corresponding to 90% sensitivity, specificity was 68.2% (95% CI: 65.4-71.0%) and 38.2% (95% CI: 35.3-41.1%) for CAD4TBv7 and CRP, respectively. CAD4TBv7 detected tuberculosis as well as an expert radiologist. CAD4TBv7 almost met the TPP criteria for tuberculosis triage. CONCLUSIONS: CAD4TBv7 is accurate as a triage test for patients with tuberculosis symptoms from areas with a high tuberculosis and HIV burden. The role of CRP in tuberculosis triage requires further research. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier: NCT04666311.

Comparison of the stability of glycoprotein acetyls and high sensitivity C-reactive protein as markers of chronic inflammation.

It has been suggested that glycoprotein acetyls (GlycA) better reflects chronic inflammation than high sensitivity C-reactive protein (hsCRP), but paediatric/life-course data are sparse. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we compared short- (over weeks) and long-term (over years) correlations of GlycA and hsCRP, cross-sectional correlations between GlycA and hsCRP, and associations of pro-inflammatory risk factors with GlycA and hsCRP across the life-course. GlycA showed high short-term (weeks) stability at 15 years (r = 0.75; 95% CI = 0.56, 0.94), 18 years (r = 0.74; 0.64, 0.85), 24 years (r = 0.74; 0.51, 0.98) and 48 years (r = 0.82 0.76, 0.86) and this was comparable to the short-term stability of hsCRP at 24 years. GlycA stability was moderate over the long-term, for example between 15 and 18 years r = 0.52; 0.47, 0.56 and between 15 and 24 years r = 0.37; 0.31, 0.44. These were larger than equivalent correlations of hsCRP. GlycA and concurrently measured hsCRP were moderately correlated at all ages, for example at 15 years (r = 0.44; 0.40, 0.48) and at 18 years (r = 0.55; 0.51, 0.59). We found similar associations of known proinflammatory factors and inflammatory diseases with GlycA and hsCRP. For example, BMI was positively associated with GlycA (mean difference in GlycA per standard deviation change in BMI = 0.08; 95% CI = 0.07, 0.10) and hsCRP (0.10; 0.08, 0.11). This study showed that GlycA has greater long-term stability than hsCRP, however associations of proinflammatory factors with GlycA and hsCRP were broadly similar.

Inflammation at diagnosis and cognitive impairment two years later in breast cancer patients from the Canto-Cog study.

BACKGROUND: Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. METHODS: Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. RESULTS: Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06-7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05-5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43-36.6, p = 0.010). CONCLUSIONS: In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.

Epigenetic and Molecular Alterations in Obesity: Linking CRP and DNA Methylation to Systemic Inflammation.

Obesity is marked by excessive fat accumulation in the adipose tissue, which disrupts metabolic processes and causes chronic systemic inflammation. Commonly, body mass index (BMI) is used to assess obesity-related risks, predicting potential metabolic disorders. However, for a better clustering of obese patients, we must consider molecular and epigenetic changes which may be responsible for inflammation and metabolic changes. Our study involved two groups of patients, obese and healthy donors, on which routine analysis were performed, focused on BMI, leukocytes count, and C-reactive protein (CRP) and completed with global DNA methylation and gene expression analysis for genes involved in inflammation and adipogenesis. Our results indicate that obese patients exhibited elevated leukocytes levels, along with increased BMI and CRP. The obese group revealed a global hypomethylation and upregulation of proinflammatory genes, with adipogenesis genes following the same trend of being overexpressed. The study confirms that obesity is linked to systematic inflammation and metabolic dysfunction through epigenetic and molecular alterations. The CRP was correlated with the hypomethylation status in obese patients, and this fact may contribute to a better understanding of the roles of specific genes in adipogenesis and inflammation, leading to a better personalized therapy.

Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP.

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer's disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk.

The anti-mCRP199-206 antibodies aggravate tubulointerstitial lesions in lupus nephritis.

Tubulointerstitial lesions could also be prominent in lupus nephritis, and the pathogenesis of tubulointerstitial lesions may be different from glomerular lesions. Previous studies have showed that plasma antibodies against modified /monomeric C-reactive protein (mCRP) are associated with renal tubulointerstitial lesions in patients with lupus nephritis, and amino acid (aa) 199-206 was one of the major epitopes of mCRP. However, the role of anti-mCRP199-206 antibodies in the pathogenesis of tubulointerstitial lesions in lupus nephritis is unknown. A total of 95 patients with renal biopsy-proven lupus nephritis were enrolled in this study. Plasma levels of anti-mCRP199-206 antibodies were screened by enzyme-linked immunosorbent assay (ELISA). A lupus prone mouse model was immunized using peptides mCRP199-206 to explore the potential role of anti-mCRP199-206 antibodies in tubulointerstitial lesions. The mechanism of anti-mCRP199-206 antibodies damage to renal tubular epithelial cells was investigated in vitro. Plasma antibodies against mCRP199-206 were associated with renal tubulointerstitial lesions and prognosis in patients with lupus nephritis. Immunization with peptides mCRP199-206 in lupus prone mice could aggravate tubulointerstitial lesions and drive tubulointerstitial inflammation and fibrosis. Anti-mCRP 199-206 antibodies could activate the TGF-ß1/Smad3 signal pathway and induce tubular damage by binding with CRP. Circulating antibodies against mCRP199-206 could be a biomarker to reveal tubulointerstitial lesion, and participate in the pathogenesis of tubulointerstitial lesions, which might provide a potential therapeutic target for lupus nephritis.

A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis.

C-reactive protein (CRP) is an inflammatory biomarker with associated clinical utility in a wide number of inflammatory disorders, including rheumatoid arthritis (RA). The interaction of CRP with pro-inflammatory cytokines has been explored before, however its role in complement regulation is more subtle, where CRP is capable of both up and downregulating the complement cascade. CRP is produced in a pentameric form and can dissociate to a monomeric form in circulation which has significant implications for its ability to interact with receptors and binding partners. This dichotomy of CRP structure could have relevance in patients with RA who have significant dysfunction in their complement cascade and also widely varying CRP levels including at the time of flare. This review aims to bring together current knowledge of CRP in its various forms, its effects on complement function and how this could influence pathology in the context of RA.

Association of body shape phenotypes and body fat distribution indexes with inflammatory biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank.

BACKGROUND: The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis. RESULTS: Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men. CONCLUSIONS: Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

PURPOSE: We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). METHODS: Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. RESULTS: Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations. CONCLUSION: There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Sex-differences in Mediterranean diet: a key piece to explain sex-related cardiovascular risk in obesity? A cross-sectional study.

BACKGROUND: Mediterranean Diet (MD) has many health benefits, particularly in reducing cardiovascular risk (CVR). However, it is still little known if there are any sex differences in following this nutritional pattern and, thus, the potential sex-related repercussions on CVR in obesity. The study aimed to characterize sex-related adherence to MD and its association with CVR factors in subjects with obesity. METHODS: A total of 968 females (33.81 ± 11.06 years; BMI 34.14 ± 7.43 kg/m2) and 680 males (aged 34.77 ± 11.31years; BMI 33.77 ± 8.13 kg/m2) were included in a cross-sectional observational study. Lifestyle habits, anthropometric parameters, high sensitivity C-reactive protein (hs-CRP), and adherence to MD were evaluated. RESULTS: Females had significantly higher adherence to MD and lower hs-CRP levels than males (p < 0.001). Additionally, females consumed significantly more vegetables, fruits, legumes, fish/seafood, nuts, and sofrito sauce and less quantity of olive oil, butter, cream, margarine, red/processed meats, soda drinks (p = 0.001), red wine, and commercial sweets and confectionery than their counterparts. A PREDIMED score of ≤ 6 was associated with a significantly increased CVR in both sexes. CONCLUSIONS: Females had higher adherence to MD, lower CVR, and different food preferences than males. Although the same PREDIMED threshold has been identified as a spy of CVR, the sex-related preference of individual foods included in the MD could explain the different impact of this nutritional pattern on CVR in both sexes.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.