Genetically Determined MBL Deficiency Is Associated with Protection against Chronic Cardiomyopathy in Chagas Disease

<div><p>Chagas disease (CD) is caused by <i>Trypanosoma cruzi</i>, whose sugar moieties are recognized by mannan binding lectin (MBL), a soluble pattern-recognition molecule that activates the lectin pathway of complement. MBL levels and protein activity are affected by polymorphisms in the <i>MBL2</i> gene. We sequenced the <i>MBL2</i> promoter and exon 1 in 196 chronic CD patients and 202 controls. The <i>MBL2*C</i> allele, which causes MBL deficiency, was associated with protection against CD (P = 0.007, OR = 0.32). Compared with controls, genotypes with this allele were completely absent in patients with the cardiac form of the disease (P = 0.003). Furthermore, cardiac patients with genotypes causing MBL deficiency presented less heart damage (P = 0.003, OR = 0.23), compared with cardiac patients having the <i>XA</i> haplotype causing low MBL levels, but fully capable of activating complement (P = 0.005, OR = 7.07). Among the patients, those with alleles causing MBL deficiency presented lower levels of cytokines and chemokines possibly implicated in symptom development (IL9, p = 0.013; PDGFB, p = 0.036 and RANTES, p = 0.031). These findings suggest a protective effect of genetically determined MBL deficiency against the development and progression of chronic CD cardiomyopathy.</p></div

Distribution of MBL levels according to <i>MBL2</i> genotypes in controls and patients.

<p>Open circles indicate individuals with the <i>LYQC</i> haplotype. Medians in each group are given by a horizontal line. P values refer to Kruskal-Wallis test.</p

Hypothetical role of high MBL levels in heart Chagas disease.

<p>In the acute stage of <i>T</i>. <i>cruzi</i> infection, MBL molecules function as opsonins for the pathogen. Thus high MBL levels would increase phagocytosis of the parasite. In the chronic stage of the disease, MBL may bind to altered-cell molecular patterns expressed on myocardium of CD patients, activating the lectin pathway and leading to an increased secretion of RANTES and pro-inflammatory cytokines such as IL-9 and PDGF (in patients with the <i>MBL2*A/A</i> genotype), thereby promoting heart damage leading to chagasic chronic cardiomiopathy.</p

Distribution of cytokine/chemokine levels according to the presence of <i>MBL2*O</i> (<i>B</i>, <i>C</i> or <i>D</i>) alleles.

<p>A. IL9 distribution (P value refers to Mann-Whitney test; horizontal line indicates the median level). B. PDGF distribution (P value refers to an unpaired t-test; horizontal line indicates the mean level). C. RANTES distribution (P value refers to Mann-Whitney test; horizontal line indicates the median level). There were no <i>MBL2*O/O</i> homozygotes among those measured for the investigated cytokines/chemokines. Three outliers with inconsistent results were excluded from all comparisons. Due to small sample size, Bonferroni P values were not significant.</p

Distribution of MBL levels according to the functional classification of heart failure.

<p>Open circles indicate patients with the <i>YO</i> haplotype; open diamonds, patients with the <i>XA/XA</i> or <i>XA/YA</i> genotypes. Medians in each group are given by a horizontal line. MBL levels were not analyzed in patients classified within the “B2” class. P value refers to Kruskal-Wallis test.</p