Complement receptor 2 (CR2/CD21)

Human complement receptor type 2 (CR2/CD21) is a surface-associated glycoprotein which binds to a variety of endogenous ligands, including the complement component C3 fragments iC3b, C3dg and C3d, the low-affinity IgE receptor CD23, and the type I cytokine, interferon-alpha. This receptor serves as an important interface between the complement system and adaptive immunity. It is expressed on B-lymphocytes, follicular dendritic cells, some epithelial cells, peripheral blood T cells. CR2 also play an important role in enhancing humoral immunity to T-dependent and T-independent foreign antigens and in regulating T-cell immunity to self and non-self-antigens. It is an important receptor that amplifies B lymphocyte activation by bridging the innate and adaptive immune systems. CR2 ligands include complement C3d and Epstein-Barr virus glycoprotein 350/220. Regions of EBV have structural similarity to C3dg, which allows it to bind CR2, and thereby gain access to cell’s interior. It also acts as receptor for other components or activators of innate immunity such as IFN-α, an anti-viral cytokine and DNA-DNA containing complexes such as chromatin. The binding of CR2 to IFN-α is speculated to cause B cell activation but their roles are still not clear. Variations or deletions of the CR2 gene in humans, or the Cr2 gene in mice associate with a variety of autoimmune and inflammatory conditions

Expression and modulation of complement receptor 2 (CR2/CD21) in the pathophysiology of rheumatoid arthritis

Background: The involvement of B cells, complement activation and subsequent immune complex deposition has been implicated in the pathogenesis of rheumatoid arthritis (RA). Although the reduced expression of complement receptor 2 (CR2, CD21) on the B cells of RA patients is known for long, we aimed at determining the modulation and expression of CR2 on PBMC of healthy individuals and RA patients.Methods: Sixty controls and 57 RA patients were enrolled. PBMC-CR2 transcript levels were correlated with the levels of C3, C3d and circulating immune complexes (CIC) in controls and patients and with DAS28 in patients only. CIC levels were determined by PEG precipitation, C3 levels by nephlometry and C3d levels were determined by enzyme linked immunosorbent assay (ELISA). Sixteen patients were recruited for 6 months follow up studies of transcript levels of PBMC correlated with DAS28 score. Appropriate statistical methods were used for the analyses of data.Results: PBMC- CR2 transcript levels were declined in patients as compared to controls. PBMC-CR2 levels correlated negatively with DAS28 score. DAS28 correlated positively with levels of CIC, C3 and C3d. Levels of PBMC -CR2 increased in patients with decline in DAS28 scores in 6 months follow-up patients.Conclusions: Low level of CR2 expression in patients may, thus, contribute significantly to the pathological manifestation of RA. Cause-effect relationships of the up regulation of CR2 on improvement of health condition with the pathophysiology of RA and their importance as putative disease markers is being confirmed.

Complement and membrane-bound complement regulatory proteins as biomarkers and therapeutic targets for autoimmune inflammatory disorders, RA and SLE

701-713Complement system is a major effecter system of the innate immunity that bridges with adaptive immunity. The system consists of about 40 humoral and cell surface proteins that include zymogens, receptors and regulators. The zymogens get activated in a cascade fashion by antigen-antibody complex, antigen alone or by polymannans, respectively, by the classical, alternative and mannose binding lectin (MBL) pathways. The ongoing research on complement regulators and complement receptors suggest key role of these proteins in the initiation, regulation and effecter mechanisms of the innate and adaptive immunity. Although, the complement system provides the first line of defence against the invading pathogens, its aberrant uncontrolled activation causes extensive self tissue injury. A large number of humoral and cell surface complement regulatory protein keep the system well-regulated in healthy individuals. Complement profiling had brought important information on the pathophysiology of several infectious and chronic inflammatory disorders. In view of the diversity of the clinical disorders involving abnormal complement activity or regulation, which include both acute and chronic diseases that affect a wide range of organs, diverse yet specifically tailored therapeutic approaches may be needed to shift complement back into balance. This brief review discusses on the complement system, its functions and its importance as biomarkers and therapeutic targets for autoimmune diseases with focus on SLE and RA. </span

An association between apo-A4 gene polymorphism (Thr347Ser and Gln360His) and coronary artery disease in northern India

Background: Coronary artery disease (CAD) is emerging as a major health problem in India. It is predicted that by 2020, India will be at the verge of CAD epidemic. A low level of high-density lipoproteins (HDL) is prevalent in Asian Indians and is the major lipid risk factor for CAD. HDL contains Apo A, E, C and antioxidant enzymes. The genetic variants of these proteins appear to influence the occurrence and frequency of CAD. In this context APO A4 have drawn much attention. The polymorphisms at Thr347Ser and Gln360His of the apo A4 gene are under investigation in different parts of the world in relation to dyslipidemias, diabetes and CAD. Since data are conflicting and no conclusive data is available from India. Objective: We aimed at studying the relationship between apoA4 gene polymorphisms (Thr347Ser and Gln360His) and coronary artery disease in northern Indian participants. Method: We recruited 200 control (Group-I) and 200 patients (Group-II) and used PCR-RFLP to study the gene polymorphisms. Enzymatic Kits were used to estimate the lipids and lipoproteins. Result: We observed not any significant association for ApoA4 Thr347Ser polymorphism as well as lipid profile [total cholesterol (TC), triglyceride (TG), HDL, low-density lipoproteins (LDL) and HDL/LDL] levels among AA, AT and TT Individuals in controls and patients. However, after adjusting for age and sex, among control AA genotype had significantly lower levels of oxidised LDL (OXLDL) as compared to AT genotype and in patients, levels of OXLDL in AT genotype was lower than with AA genotype and for ApoA4 Gln360His polymorphism, after adjusting for age and sex, and no significant difference was observed in TC, TG, HDL, LDL and HDL/LDL, OXLDL and LDL / OXLDL levels among 1–1, and 1–2. Individuals in controls and patients. Conclusion: To accomplish, this preliminary study brought the information on the ApoA4 polymorphism in the Asian Indians residing in Delhi and adjacent areas. The minor alleles of the Ser347 and His360 showed significant association with lipid risk factors like high levels of OXLDL, TC, and low HDL levels. However neither of these polymorphisms showed an association with CAD

Portal pressure and blood nitric oxide levels as predictors of outcome in biliary atresia

Aim: To evaluate the incidence of portal hypertension (PHT) in biliary atresia (BA) patients and to monitor its progress after Kasai portoenterostomy (KP) by measuring nitric oxide (NO) levels in peripheral blood. Materials and Methods: A prospective cross-sectional study conducted over a period of 2 years. Intraoperative portal pressure (PP) and blood NO levels at presentation, 1-month, 3-month, and 6-month follow-up, were correlated with clinical and biochemical parameters in BA patients. The mean NO level in age-matched control group was 4.64 ± 2.32 μmol/L. Results: Thirty-four BA patients underwent KP over a period of 2 years. The mean age of presentation was 2.7 months (range 1-4 months). The mean intraoperative PP was 21.3 ± 5.4 mmHg. The mean PP in patients aged 90 days was 18.53 ± 4.45 mmHg, 20.33 ± 3.07 mmHg, and 26.5 ± 5.01 mmHg, respectively. The mean PP in the patients who underwent successful KP was 16.75 ± 3.54 mmHg while for those who continued to have jaundice it was 23.94 ± 4.63 mmHg (P < 0.001). NO levels closely followed the PP as shown by the regression equation NO = 4.79 + 0.64 PP mmHg, R2 = 0.69. The mean NO level at presentation was 18.48 ± 4.17 μmol/L and at 1-month, 3-month, and 6-month follow-up was 11.94 ± 5.62 μmol/L, 10.79 ± 6.02 μmol/L, and 9.93 ± 6.53 μmol/L, respectively (P < 0.001). The difference in NO levels was also statistically significant between the patients who cleared jaundice and those with persisting jaundice. Conclusion: All BA patients had PHT at presentation. PHT worsens with age and has an adverse effect on outcome of KP. NO levels in blood closely follow PP and higher levels are associated with poor outcome

Pre-operative hepatic artery resistive index is a non-invasive predictive indicator of prognosis in biliary atresia

Aims: The aim of this study is to evaluate hepatic artery resistive index (HARI) as a noninvasive prognostic predictor by correlating it with peripheral blood nitric oxide (NO) levels, portal pressure (PP) and histopathological changes in the liver in patients of biliary atresia (BA). Materials and Methods: Twenty-five patients were included in the study prospectively from November 2012 to June 2014. All patients underwent Doppler sonography to calculate the HARI preoperatively. Peripheral blood NO was also measured preoperatively. Biochemical liver function tests (LFTs) were measured preoperatively and at 1, 3, and 6 months postoperatively. The PP was measured intraoperatively, and a liver biopsy was taken in all patients. Disappearance of jaundice defined successful surgical treatment. Postoperatively, a hepatobiliary IminoDiacetic Acid scan (HIDA) was done to demonstrate a patent bilio-enteric pathway. Results: The mean preoperative HARI was 0.78 ± 0.105, and the median was 0.80 (range 0.60–1.0). The median HARI was used to correlate the other parameters; 13 (52%) patients had HARI ≥0.8. The mean PP was 24.96 ± 6.54 mmHg. The HARI had a strong correlation with PP (P = 0.0001) and (NO) (P = 0.0001); with every 0.1 increase in HARI, there was 5.2 mmHg increase in PP and 3.8 μmol/L increase in NO. The histological parameters which reached significance in relation to HARI were hepatocellular damage, bile duct inflammation, portal inflammation, and portal fibrosis. The postoperative improvement in LFT was significantly better in patients with HARI 0.8, elevated PP, and NO levels. Conclusions: Preoperative HARI was found to have a direct correlation with PP and peripheral blood NO as a measure of portal hypertension. A preoperative HARI ≥0.8 should be considered as a risk factor for poor outcomes in BA