Effect of Filarial Infection on Serum Inflammatory and Atherogenic Biomarkers in Coronary Artery Disease (CURES-121)

Helminth infections can potentially confer protection against metabolic disorders, possibly through immunomodulation. In this study, the baseline prevalence of lymphatic filariasis (LF) among subjects without (N = 236) and with (N = 217) coronary artery disease (CAD) was examined as part of the Chennai Urban Rural Epidemiological Study (CURES). The prevalence of LF was not significantly different between CAD(−) and CAD(+) subjects. The LF antigen load and antibody levels indicated comparable levels of infection and exposure between the groups. Within the CAD group, LF(+) and LF(−) subjects had no significant difference in the intimal medial thickness and high-sensitivity C-reactive protein values. However, LF infection was associated with augmented levels of tumor necrosis factor-α and interleukin-6 among CAD(+) subjects. The LF infection had no effect on serum adipocytokine profile. In conclusion, unlike type-2 diabetes, there is no association between the prevalence of LF and CAD and also no evidence of protective immunomodulation of LF infection on CAD in the Asian Indian population

Decreased Prevalence of Lymphatic Filariasis among Diabetic Subjects Associated with a Diminished Pro-Inflammatory Cytokine Response (CURES 83)

Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates of sero-positivity of LF among diabetic subjects was carried out (n = 1416) as part of the CURES study. There was a significant decrease in the prevalence of LF among diabetic subjects (both newly diagnosed [5.7%] and those under treatment [4.3%]) compared to pre-diabetic subjects [9.1%] (p = 0.0095) and non-diabetic subjects [10.4%] (p = 0.0463). A significant decrease in filarial antigen load (p = 0.04) was also seen among diabetic subjects. Serum cytokine levels of the pro-inflammatory cytokines—IL-6 and GM-CSF—were significantly lower in diabetic subjects who were LF positive, compared to those who were LF negative. There were, however, no significant differences in the levels of anti-inflammatory cytokines—IL-10, IL-13 and TGF-β—between the two groups. Although a direct causal link has yet to be shown, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished pro-inflammatory cytokine response in Asian Indians with diabetes and concomitant LF

Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury

Background: Macrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro-and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice)

Increased levels of both Th1 and Th2 cytokines in subjects with metabolic syndrome (CURES-103)

Objective: Metabolic syndrome (MS) is a cluster of metabolic abnormalities associated with obesity, insulin resistance (IR), dyslipidemia, and hypertension in which inflammation plays an important role. Few studies have addressed the role played by T cell-derived cytokines in MS. The aim of the study was to look at the T-helper (Th) 1 (interleukin [IL]-12, IL-2, and interferon-γ [IFN-γ]) and Th2 (IL-4, IL-5, and IL-13) cytokines in MS in the high-risk Asian Indian population. Research Design and Methods: Study subjects were recruited from the Chennai Urban Rural Epidemiology Study. MS was defined using National Cholesterol Education Program-Adult Treatment Panel III criteria modified for waist according to World Health Organization Asia Pacific guidelines. Serum cytokine profile was determined by multiplex cytokine assay in subjects with (n = 21) and without (n=33) MS. Results: Both Th1 and Th2 cytokines showed up-regulation in MS. IL-12 (5.40 pg/mL in MS vs. 3.24 pg/mL in non-MS; P < 0.01), IFN-γ (6.8pg/mL in MS vs. 4.7 pg/mL in non-MS; P < 0.05), IL-4 (0.61 pg/mL in MS vs. 0.34 pg/mL in non-MS; P < 0.001), IL-5 (4.39 pg/mL in MS vs. 2.36 pg/mL in non-MS; P < 0.001), and IL-13 (3.42 pg in MS vs. 2.72 pg/mL in non-MS; P < 0.01) were significantly increased in subjects with MS compared with those without. Both Th1 and Th2 cytokines showed a significant association with fasting plasma glucose level even after adjusting for age and gender. The Th1 and Th2 cytokines also showed a negative association with adiponectin and a positive association with the homeostasis model of assessment of IR and high-sensitivity C-reactive protein. Conclusions: Apart from pro-inflammatory cytokines, Th cytokines might play an important role in inflammation, IR, and MS

Decreased serum interleukin-17 and increased transforming growth factor - βlevels in subjects with metabolic syndrome (Chennai Urban Rural Epidemiology Study-95)

The term metabolic syndrome (MS) refers to a conglomeration of many metabolic disorders. Recent studies suggest that inflammation plays a vital role in MS. There are however no data available on the recently characterized novel T-cell-derived cytokine interleukin (IL)-17 in MS; studies on the anti-inflammatory cytokine transforming growth factor (TGF)-β are also limited. The aim of the study was to look at IL-17 and TGF-β levels in subjects with and without MS. The study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai (formerly Madras) in southern India. Group 1 consisted of subjects without MS (non-MS) (n = 98) and group 2 consisted of subjects with MS (n = 156). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria modified for waist, according to the World Health Organization Asia Pacific guidelines. Serum IL-17 and TGF-β levels were estimated by enzyme-linked immunosorbent assay. Interleukin-17 levels were decreased (P < .001) and TGF-β levels (P < .001) were increased in subjects with MS compared to those without. With an increase in the number of metabolic risk factors, the IL-17 levels showed a decline, whereas the TGF-β levels showed an increase (P < .001). With respect to individual components of MS, TGF-β and IL-17 showed a significant association with blood pressure and blood glucose even after adjusting for age and sex. We report that IL-17 levels are decreased, whereas TGF-β levels are increased, among Asian Indians with MS

Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice

Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB mice, which have spontaneous multiorgan autoimmune disease. RelB thymi were organized, with medullary structures containing AIRE mTECs, DCs, and CD4 thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation

Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

Several animal studies have shown a protective effect of helminth infections against type-1 diabetes mellitus (T1DM). However, epidemiologic studies demonstrating this protective relationship with T1DM are largely lacking, although an inverse correlation between the prevalence of lymphatic filariasis (LF) and prevalence of allergies and autoimmunity has been shown. A cross-sectional study was undertaken in southern India to assess the baseline prevalence of seropositivity of LF among persons with T1DM (n = 200) and normal glucose tolerant (NGT) persons (n = 562). The prevalence of LF was 0% among persons with T1DM and 2.6% among NGT persons ( P = 0.026). The percentage of persons who were positive for filarial antigen-specific IgG4 (but not antigen-specific IgG) was also significantly lower in persons with T1DM (2%) compared with NGT persons (28%) ( P < 0.001). Thus, there appears to be a striking inverse relationship between the prevalence of LF and T1DM in southern India

Decreased prevalence of lymphatic filariasis among diabetic subjects associated with a diminished pro-inflammatory cytokine response (CURES 83). PLoS Negl Trop Dis 4: e707. doi: 10.1371/journal.pntd.0000707

Abstract Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates of sero-positivity of LF among diabetic subjects was carried out (n = 1416) as part of the CURES study. There was a significant decrease in the prevalence of LF among diabetic subjects (both newly diagnosed [5.7%] and those under treatment [4.3%]) compared to pre-diabetic subjects [9.1%] (p = 0.0095) and non-diabetic subjects [10.4%] (p = 0.0463). A significant decrease in filarial antigen load (p = 0.04) was also seen among diabetic subjects. Serum cytokine levels of the pro-inflammatory cytokines-IL-6 and GM-CSF-were significantly lower in diabetic subjects who were LF positive, compared to those who were LF negative. There were, however, no significant differences in the levels of anti-inflammatory cytokines-IL-10, IL-13 and TGF-b-between the two groups. Although a direct causal link has yet to be shown, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished pro-inflammatory cytokine response in Asian Indians with diabetes and concomitant LF