A possible schematic role of inflammatory cells networks on T2D and CVD.

<p>(A) The situation in animal models of T2D and CVD without the presence of helminths and in humans living in affluent areas not endemic for helminths. (B) The situation in animal models in the presence of helminths and in humans living in areas endemic for helminths. Although it is known that genes and lifestyle factors are involved in the development of insulin resistance and cardiovascular disease, it is becoming increasingly accepted that the immune system and inflammation play an important role as well. Obese people with metabolic syndrome have a higher degree of inflammation, characterized by increased TNF, a cytokine associated with insulin resistance. When the balance of T cell subsets is disturbed, increased frequencies of pro-inflammatory T cells such as T helper (Th) 1 and Th17 can drive classically activated macrophages (CAMs) which release TNF and, when in metabolic organs such as the adipose tissue, can interfere with insulin signaling. There is also evidence that, under inflammatory conditions, mast cells (MCs) contribute to the pathogenesis of metabolic disorders. High-affinity IgE, present on MCs, can lead to degranulation and initiate inflammation when cross-linked (A). However, the immune system is also endowed with cells such as Th2 and Treg that can exert anti-inflammatory activity and counterbalance the effects of TNF. The balance between pro- and anti-inflammatory activities in the immune system would determine insulin sensitivity. The situation seems to be different in rural areas of LMICs where helminth infections are highly prevalent. Helminths need nutrients from their host for their growth and reproduction, and this might use the energy of their host and therefore forestall obesity and insulin resistance. However, helminths can also lead to the expansion of alternatively activated Th2 and Treg. Th2 cytokines result in increased eosinophilia (EO) and, when in adipose tissue, can lead to the alternative activation of macrophages in this metabolically active organ; the AAMs in turn release anti-inflammatory cytokines such as IL-10. The signaling pathways are currently being dissected, but so far there is evidence that this cascade of events involves the activation of PPAR, STAT6, and/or Akt. Moreover, it has been noted that when the immune system is exposed to chronic helminth infections, EO and MCs no longer behave as pro-inflammatory immune cells, and IgE under these conditions appears to be of low affinity showing poor functional activity in terms of inducing MC degranulation. Thus, in the presence of helminth infections, the immune system is in an anti-inflammatory mode that is considered to be disadvantageous to the development of T2D and CVD (B). The solid lines represent associations based on data available, while dotted lines represent theoretical associations that are yet to be tested.</p

Altered filaria-specific cytokine production in different study groups.

<p>PBMC from uninfected endemic normals (EN), microfilaremic (MF) and chronic pathology (CP) subjects were stimulated with BmA. After 4 days of culture supernatants were harvested and assessed for IFN-γ (A), IL-13 (B), IL-17 (C) and IL-10 (D) production. Plotted values are age- and sex-adjusted means and standard errors; *p≤.05 **p≤.01 ***p≤.001, p-values between 0.05 and 0.10 are indicated.</p

Removal of Tregs enhances filaria-specific Th1 and Th2 responses.

<p>Cytokine secretion was assessed in mock- (M) and Treg-depleted (D) PBMC cultures from EN, MF and CP individuals. IFN-γ (A–B) and IL-13 (C–D) secretion is depicted for BmA- (left panel) and unstimulated (right panel) conditions. Connecting lines represent data points of one individual, for mock- and Treg-depleted cultures; tested by paired t-test *p≤.05 **p≤.01***p≤.001, p-values between 0.05 and 0.10 are indicated.</p

Study population characteristics.

*<p> <i>Pf Plasmodium falciparum; Pv Plasmodium vivax.</i></p

Association between skin reactivity to HDM or cockroach and potential risk factors for atopy in the semi-urban area^a.

a<p>association based on univariate logistic model. ^bMean and standard deviation.¹diagnosed by PCR. ²diagnosed by microscopy. The number of positives (n) of the total population examined (N). OR: Odds ratio, CI: Confidence intervals. *P<0.05.</p

Association between specific or total IgE and potential risk factors for atopy in the semi-urban area^a.

a<p>association based on univariate logistic model. ^bMean and standard deviation. The total population examined (N). ^#IgE to <i>Dermatophagoides pteronyssinus</i> (HDM). ¹diagnosed by PCR. ²diagnosed by microscopy. β (beta): estimate regression coefficients. CI: Confidence intervals. *P<0.05, **P<0.01, ***P<0.001.</p

Association between skin reactivity, specific IgE or total IgE and potential risk factors for atopy in the semi-urban area^a.

a<p>Multivariate model adjusted with age and sex. β (beta): estimate regression coefficients. CI: Confidence intervals. *P<0.05, **P<0.01, ***P<0.001, ^¶P<0.1.</p

Characteristics of population and allergic disorders in semi-urban and rural areas.

<p>SD: standard deviation. The number of positives (n) of the total population examined (N). ^#IgE to <i>Dermatophagoides pteronyssinus</i> (HDM).</p><p>The statistically significant results are given in bold. ^$P-value derived from Student t-test. ^∞P-value derived from Chi-Square test.</p

Immune parameters in soil-transmitted helminth uninfected and infected participants.

<p>Abbreviations: HsCRP = High sensitive C reactive protein, TNF = tumor necrosis factor, IL10 = interleukin 10, IgE = Immunoglobulin E. HsCRP, TNF, IL10 and IgE are log-transformed.</p><p># The difference is expressed as increase or decrease in the parameter per increasing number of infections per patient (maximum = 3).</p><p>Immune parameters in soil-transmitted helminth uninfected and infected participants.</p

Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

<div><p>Objective</p><p>Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects.</p><p>Design</p><p>We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections.</p><p>Methods</p><p>From 646 adults, stool samples were screened for <i>Trichuris trichiura</i> by microscopy and for <i>Ascaris lumbricoides</i>, <i>Necator americanus</i>, <i>Ancylostoma duodenale</i>, <i>and Strongyloides stercoralis</i> by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m²), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance.</p><p>Results</p><p>424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m², p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07).</p><p>Conclusion</p><p>STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone.</p></div