Clinical manifestation of mannose-binding lectin deficiency in adults independent of concomitant immunodeficiency
Introduction
The mannose-binding lectin (MBL) belongs to the family of collectins and is involved in first-line defense against invading microorganisms [1], [2]. Circulating steady-state levels of functional MBL are subject to large interindividual variations, which are mainly determined by genetic polymorphisms within the coding and promoter regions of the MBL2 gene. The correlation between the MBL genotype and phenotype has been well established: (i) normal MBL plasma levels result from the wild-type A/A coding genotype, (ii) partial deficiency is caused by coding mutation heterozygosity (A/0 coding genotype, with “0” being B, C, or D alleles) in combination with certain promoter polymorphisms, and (iii) severe deficiency results from coding mutation homozygosity (O/O genotype) or coding mutation heterozygosity and low promoter haplotypes [1], [3]. The frequencies of the MBL variant alleles differ between ethnic groups and demographic areas [4]. In Caucasians, about 60% of individuals present with the wild-type coding genotype, 30% with coding mutation heterozygosity, and 10% with coding mutation homozygosity [4].
Whereas severe MBL deficiency has been associated with an increased susceptibility to infection in children 6 to 17 months old [5], [6], the clinical impact of MBL deficiency in adults remains controversial [1], [5]. Several studies have indicated that MBL deficiency becomes clinically relevant in adults only in individuals who are immunocompromised for other reasons (e.g., chemotherapy, iatrogenic immunosuppression, surgical stress) [1], [2]. To determine the clinical significance of MBL deficiency and its association with concomitant immunodeficiency in adults, we have analyzed the distribution of MBL deficiency and concomitant antibody or cellular immunodeficiency in a large cohort of unrelated Caucasian adults.
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Patients with a history of recurrent and/or severe infections
Two hundred twenty-eight patients with a history of recurrent and/or severe infection (Caucasians, 79.4% female, median age [range]: 40 [16–86] years) were recruited from patients referred to our immunodeficiency outpatient clinics between 2005 and 2008. Patients had been classified as having a history of recurrent and/or severe infections if they had reported four or more infections per year and/or at least one severe infection in the past (e.g., pneumonia). Classification was performed using
Significantly higher prevalence of severe MBL deficiency exists in patients with recurrent and/or severe infections
The distribution of MBL plasma levels in patients with recurrent and/or severe infections and control subjects is illustrated in Fig. 1. The median MBL plasma level over all study participants was 1536.8 (607.5–2665.1) ng/ml, with median values of 1236.8 (468.7–2127.8) ng/ml for patients and 1763.0 (824.1–2873.1) ng/ml for control subjects (p < 0.001 versus patients).
The frequency of individuals with severe MBL deficiency (MBL plasma levels ≤ 50 ng/ml) was significantly higher in patients with
Discussion
In this retrospective study, we reported a significantly increased frequency of severe MBL deficiency in adult patients with a history of recurrent and/or severe infections, and this association persisted even in the absence of concomitant humoral or cellular immunodeficiency. Our data corroborate previous findings indicating a causative link between MBL deficiency and increased susceptibility to infections in adults without suspected other immunodeficiencies [11], [12], [13], [14]. However,
Acknowledgments
The authors thank Sandra Hartfil, Christa Liebenthal, and Claudia Conert for excellent technical assistance, Elizabeth Wallace for accurately proofreading the manuscript, and Wolf-Dietrich Döcke for critically reading the manuscript.
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