Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 epression in monocyte-derived dendritic cells

Abstract

Patients after allogeneic stem-cell transplantation (alloSCT) have an increased risk for invasive aspergillosis (IA). Here, recipients of an allograft with IA (n ‫؍‬ 81) or without IA (n ‫؍‬ 58) were screened for 84 single nucleotide polymorphisms in 18 immune relevant genes. We found 3 markers in chemokine (C-X-C motif) ligand 10 (CXCL10, 4q21, 11 101 C > T, P ‫؍‬ .007; 1642 C < G, P ‫؍‬ .003; ؊1101A < G, P ‫؍‬ .001) significantly associated with an increased risk of developing IA. Furthermore, immature dendritic cells (iDCs) exposed to Aspergillus fumigatus germlings showed markedly higher CXCL10 expression, if carrying the wild type genotype, compared with the "CGAG" high risk haplotype. In addition, serum from patients with proven/probable IA showed increased serum levels of CXCL10, compared with immunocompromised patients without IA. Thus, polymorphisms in CXCL10 determine chemokine secretion by iDCs upon exposure to A fumigatus and most likely thereby genetically determine the risk of IA after alloSCT. IntroductionInfections with Aspergillus fumigatus are frequent and life threatening in patients after allogeneic stem-cell transplantation (alloSCT). 1 Several single nucleotide polymorphisms (SNPs) were described influencing the course and outcome of invasive aspergillosis (IA). Kesh and colleagues revealed an association of IA with polymorphisms in Toll-like receptor genes TLR1 and TLR6, whereas no association could be found for the TLR4 gene. 2 In addition, it has been shown that polymorphisms in mannan-binding lectin (MBL) contribute to the occurrence of allergic bronchopulmonary aspergillosis (ABPA) by influencing the MBL plasma level and protein activity. 3 Besides MBL, further SNPs in C-type lectins were investigated leading to the identification of an association between ABPA and variants of the surfactant protein A2 gene . 4 In contrast, alleles with a protective role in the pathogenesis of IA were discovered in the promoter region of IL10. 5 MethodsThis study was approved by the local ethics committees involved in the study (University of Innsbruck, Innsbruck, Austria; University of Graz, Graz, Austria; Karolinska University Hospital, Stockholm, Sweden; and Medical Hospital II, Tübingen, Germany). Patient and sampling dataAfter approval of the local ethics committees, each consecutive patient who underwent alloSCT and who showed complete donor chimerism at the time of blood collection (as determined by short tandem repeat markers 6 ) was asked for study participation. After informed consent was obtained in accordance with the Declaration of Helsinki, blood samples from 139 consecutive patients were collected between day ϩ20 and day ϩ50 after alloSCT. Patients suffered from acute myeloid leukemia (n ϭ 57), chronic myeloid leukemia (n ϭ 26), acute lymphatic leukemia (n ϭ 20), multiple myeloma (n ϭ 11), and other hematologic disorders (n ϭ 25). Sampling was performed at the University of Innsbruck, Innsbruck, Austria (n ϭ 16), University of Graz, Graz, Austria (n ϭ 26), Karolinska University Hospital...

Toll-Like Receptor 9 Modulates Immune Responses toAspergillus fumigatusConidia in Immunodeficient and Allergic Mice

“…In the present study we found significant changes in the levels of TNF-␣, CXCL10, and CCL2, all of which are significant mediators of inflammation during IPA infection. TNF-␣ plays an important role in the recruitment of neutrophils, CXCL10 promotes dendritic cell and macrophage recruitment, and CCL2 acts as a chemoattractant for macrophages (38,50). In our studies, we found that all three of these factors were decreased in TLR9 Ϫ/Ϫ mice at day 2 after challenge with resting conidia but increased in TLR9 Ϫ/Ϫ mice at day 4 after challenge with swollen conidia.…”

“…Investigations in the area of innate immune receptors and soluble factors that inhibit or enhance immune activation during IPA or ABPA have led to considerable progress in understanding its underlying mechanisms. In particular, inflammatory cytokines and chemokines such as tumor necrosis factor alpha (TNF-␣) (36,40,46), CCL2 (6), and CXCL10 (38) play critical roles in the activation and recruitment of immune cells such as dendritic cells and macrophages that further act to regulate inflammation at the site of Aspergillus infection. More recently, interleukin-17 (IL-17) has also been demonstrated to promote inflammation and infection during Aspergillus infection (58).…”

CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

“…Ϫ/Ϫ chimeric mice produced significantly higher CXCL10, a chemokine recently shown to render the host susceptible to invasive aspergillosis if inappropriately expressed (31). Additionally, both wild-type and CCR7 Ϫ/Ϫ chimeras showed similar expression of the potent antiinflammatory cytokine IL-10 after conidia challenge.…”

CCR7 impairs hematopoiesis after hematopoietic stem cell transplantation increasing susceptibility to invasive aspergillosis

“…Although it is not immediately clear why CXCL10 and CXCL9 were increased in the CCR7 Ϫ/Ϫ chimeric mice, it has been reported that high levels of CXCL10 correlate with decreased susceptibility to IA. 41 Thus, the balance of pro-and anti-inflammatory mediators produced in the CCR7 Ϫ/Ϫ 3WT chimeras after infection appears to enhance fungal clearance.…”