Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT

Abstract

A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P ¼ 0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be B0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression. Genes and Immunity (2005) The carbohydrate recognition domain of MBL binds to high mannose and N-acetyl-glucosamine oligosaccharides on various microorganisms, while the collagen-like domain is considered to bind to its receptors on phagocytes. 1,3 MBL activates complement independently of antibodies, which is a third pathway (lectin pathway) distinct from the classical and alternative complement activation cascade. It is therefore considered that MBL is an apical and important component of innate immunity of host defense. MBL has been shown to bind to a wide range of microorganisms including fungi, bacteria, protozoa, and viruses. 4 The serum level of MBL is dependent on various factors such as polymorphisms (in the coding region) and ethnicity and age (in the promoter region). [5][6][7] Of these factors, the structural polymorphisms at codons 52, 54, and 57 in the coding region are the most important determinants. All the three polymorphisms are caused by a single amino-acid substitution and result in the profound decrease of serum MBL in the individuals carrying the polymorphisms homozygously. Two polymorphisms in the promoter region at positions À550 and À221 also have additional, but less pronounced effects on the serum level of MBL. 5 Individuals carrying either of these three codon variants homozygously are common in different ethnic groups from 5 to 10%. 4 MBL deficiency is associated with infection in infants with immature immunity, 8,9 and patients with autoimmune disorders 10 and cystic fibrosis. 11,12 An association of MBL deficiency and infection is also reported in patients treated with conventional chemotherapy 13,14 or high-dose myeloablative chemotherapy followed by allogeneic stem cell transplantation, 15 which is not confirmed by others. 16,17 In the present study, we report an increased risk of major bacterial infection in patients carrying the MBL polymorphism when treated with high-dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). In ad...

MBL2 polymorphism and risk of severe infections in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation

“…Horiuchi et al 24 found that the low producing genotypes B/B and B/A were associated with a highly increased and significant risk of major bacterial infections in a series of patients with mixed malignancies. In 113 patients, they found a much lower occurrence of bacterial infections (n ¼ 10) than we did (n ¼ 29, documented pneumonia Table 3 Multiple logistic regression analysis of risk of (a) breakthrough fever a (b) proven septicaemia a The relation between MBL2 polymorphisms and the function of the MBL system is complex, as significant variation between serum levels is seen within each genotype, 17,18 and the association found in the present study might be stronger, if serum levels of MBL are measured as well.…”

“…The results indicated that highfunctioning MBL genes decrease the risk of major bacterial infections. 24 Only one of the earlier published studies was made on a uniform group of patients, namely patients with AML, 21 and new studies on the topic should probably relate to specific patient groups. In this study, we focus on the impact of MBL2 polymorphism on the risk of severe infections related to ASCT in patients with MM.…”

Antimicrobial therapy of febrile complications after high-dose chemotherapy and autologous hematopoietic stem cell transplantation—guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

“…Overall, the risk of fatal infectious complications is less than 5 % and may be even lower in experienced centres [17]. In the future, gene polymorphisms of components of the immune system may prove useful in refining the estimation of infection risks for individual patients [18]. While polymorphisms in Toll-like receptor [19] and cytokine genes are associated with the risk of invasive aspergillosis in allogeneic HSCT [20], mannose-binding lectin 2 gene polymorphisms are associated with severe infections in both allogeneic and autologous HSCT [21,22].…”

“…The incidence of febrile complications following HDC and auto-HSCT is 60-100 % [13,[16][17][18][19][20][21][22][23][24][25], whereas the majority is categorized as fever of unknown origin (FUO). One third of cases of documented infection [13,14] are mostly caused by bacteria.…”

Infections After High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation

“…In a series of 113 autologous HSCT for multiple myeloma, patients homozygous for wild-type mannose-binding lectin (MBL) 2 were at lower risk to develop septicemia compared with patients carrying the variant MBL2 [ 2 ]. In another study, MBL defi ciency was associated with higher risk of bacterial infections [ 3 ]. …”