Clinical manifestation of mannose-binding lectin deficiency in adults independent of concomitant immunodeficiency Conny Hoeflich a , Nadine Unterwalder a , Sabine Schuett b , Kathrin Schmolke a , Olaf Boenisch a , Markus Hammer a , Ramona Scheufele c , Dagmar Michael a , Hans-Dieter Volk a , Carmen Scheibenbogen a , Volker von Baehr b , Christian Meisel a, * a Institute of Medical Immunology, University Hospital Charitè, Berlin, Germany b Department of Immunology, Laboratory Center Berlin, Berlin, Germany c Institute of Biometry and Clinical Epidemiology, University Hospital Charitè, Berlin, Germany ARTICLE INFO Article history: Received 4 November 2008 Accepted 1 July 2009 Available online 4 July 2009 Keywords: Mannose-binding lectin MBL Immunodeficiency Infection Human ABSTRACT Mannose-binding lectin (MBL) mediates important functions within the innate immune system, and its deficiency was associated with infectious complications. However, in adults without concomitant immuno- deficiency the clinical relevance of MBL deficiency remains controversial. We analyzed the distribution of MBL deficiency and its association with concomitant immunodeficiency in 228 adult Caucasian patients with a history of recurrent and/or severe infections. Two hundred forty-one unrelated Caucasians without recur- rent or severe infections served as control subjects. The frequency of severe MBL deficiency (plasma levels  50 ng/ml) was significantly higher in patients with a history of recurrent and/or severe infections (p  0.05, odds ratio 2.1, 95% confidence interval 1.1– 4.1), and this association was independent of concomitant antibody or cellular immunodeficiency. Our data challenge the view that MBL deficiency in adulthood becomes relevant only in individuals who are immunocompromised for other reasons.  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. 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 het- erozygosity (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 geno- type, 30% with coding mutation heterozygosity, and 10% with cod- ing 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 con- troversial [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, iatro- genic 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 cellu- lar immunodeficiency in a large cohort of unrelated Caucasian adults. 2. Subjects and methods 2.1. 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., pneumo- nia). Classification was performed using a standardized classifica- tion protocol by experienced physicians (C.H., N.U.), who were blinded to the results of the MBL assay. The clinical spectrum of diseases in patients with recurrent and/or severe infections was heterogeneous and included recurrent common colds, isolated paranasal sinus infections, bronchitis, pneumonia, furunculosis, * Corresponding author. E-mail address: chr.meisel@charite.de (C. Meisel). Human Immunology 70 (2009) 809 – 812 Contents lists available at ScienceDirect 0198-8859/09/$32.00 - see front matter  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2009.07.003