Mannose-binding lectin (MBL) deficiency is relatively common occurring in ∼7% of the general population. Most individuals with MBL deficiency are clinically unaffected due to protective antibody adaptive immunity, and therefore never present for evaluation of recurrent infections. We sought to identify associated immunologic abnormalities in patients with MBL deficiency that may have influenced their clinical presentation and resulted in referral for evaluation. Retrospective chart review of all patients found to have MBL deficiency at Cardinal Glennon Children's Medical Center at Saint Louis University between 2000 and 2009. Twenty-two patients, 40% of 55 patients with MBL deficiency, were found to have concomitant selective antibody deficiency (SAD). At initial evaluation Streptococcus pneumoniae antibody titers were frequently nonprotective in both groups of patients. After S. pneumoniae vaccination, MBL-deficient patients with SAD developed protective antibody titers to 44% ± 13% of S. pneumoniae serotypes compared with 80% ± 15% in patients with isolated MBL deficiency (P = 0.0004). Patients with MBL deficiency and SAD had increased frequency of otitis media, pneumonia, and sepsis compared with patients with MBL deficiency alone. Prophylactic antibiotics were used more frequently in MBL deficiency with SAD compared with MBL deficiency, 90% versus 76%, as was intravenous immunoglobulin/subcutaneous gammaglobulin, 43% versus 6% (P = 0.002). CD27+ memory B cells were significantly decreased in MBL deficiency with concomitant SAD. SAD was identified in ∼40% of individuals with MBL deficiency. The large number of patients with MBL deficiency and concomitant SAD as well as the relative increase in recurrent otitis media, pneumonia, sepsis, and need for intravenous immunoglobulin seen in patients with both disorders strongly support evaluating for additional immunologic abnormalities in patients with MBL deficiency.
Get full access to this article
View all access options for this article.
References
1.
TurnerMW. Deficiency of mannan binding protein—a new complement deficiency syndrome. Clin Exp Immunol, 1991; 86,Suppl 1:53–56.
EisenDP, MinchintonRM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis, 2003; 37:1496–1505.
4.
DahlM, Tybærg-HansenA, SchnohrP, NordestgaardBG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med, 2004; 10:1391–1399.
5.
RoosA, GarredP, WildenbergME, LynchNJ, MunozJR, ZuiverloonTCM, BouwmanLH, SchlagweinN, van den HoutenFCF, Faber-KrolMC, MadsenHO, SchwaebleWJ, MatsushitaM, FujitaT, DahaMR. Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency. Eur J Immunol, 2004; 34:2589–2598.
6.
WorthleyDL, BardyPG, MullighanCG. Mannose-binding lectin: biology and clinical implications. Intern Med J, 2005; 35:548–555.
AittoniemiJ, KoskinenS, LaippalaP, LaineS, MiettinenA. The significance of IgG subclasses and mannan-binding lectin (MBL) for susceptibility to infection in apparently healthy adults with IgA deficiency. Clin Exp Immunol, 1999; 116:505–508.
9.
MullighanCG, MarshallSE, WelshKI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol, 2000; 51:111–122.
10.
LitzmanJ, FreibergerT, GrimbacherB, GathmannB, SalzerU, PavlíkT, VlčekJ, PostráneckáV, TrávníčkováZ, ThonV. Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency. Clin Exp Immunol, 2008; 153:324–330.
11.
GarredP, StrømJJ, QuistL, TaaningE, MadsenHO. Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis, 2003; 188:1394–1403.
12.
GarredP, VossA, MadsenHO, JunkerP. Association of mannose-binding lectin gene variation with disease severity and infections in a population based cohort of systemic lupus erythematosus patients. Genes Immun, 2001; 2:442–450.
13.
ThórarinsdóttirHK, LúdvíkssonBR, VíkingsdóttirT, LeópoldsdóttirMO, ÁrdalB, JónssonT, ValdimarssonH, ArasonGJ. Childhood levels of immunoglobulins and mannan-binding lectin in relation to infections and allergy. Scand J Immunol, 2005; 61:466–474.
14.
WolpertJ, KnutsenAP. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr Asthma Allergy Immunol, 1998; 12:183–191.
15.
BrouetJC, ChedevilleA, FermandJP, RoyerB. Study of the B cell memory compartment in common variable immunodeficiency. Eur J Immunol, 2000; 30:2516–2517.
16.
JacquotS, Macon-LemaitreL, ParisE, KobataT, TanakaY, MorimotoC, SchlossmanSF, TronF. B cell co-receptors regulating T cell-dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immuno-compromised patients. Inter Immunol, 2001; 13:871–876.
17.
BonillaFA, BersteinIL, KhanDA, BallasZK, ChinenJ, FrankMM, KobrynskiLJ, LevinsonAI, MazerB, NelsonRPJr, OrangeJS, RoutesJM, ShearerWT, SorensenRU. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol, 2005; 94:S1–S63.
18.
ParisK, SorensenRU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol, 2007; 99:464–464.
19.
BallochA, LicciardiPV, RussellFM, MulhollandEK, TangMLK. Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine. J Allergy Clin Immunol, 2010; 126:395–397.
20.
LandesmanSH, SchiffmanG. Assessment of the antibody response to pneumococcal vaccination in high risk patients. Rev Infect Dis, 1981; 3S:184–196.
21.
DouglasRM, PatonJC, DuncanSJ, HansmanDJ. Antibody response to pneumococcal vaccination in children younger than 5 years of age. J Infect Dis, 1983; 148:131–137.
22.
SumiyaM, SuperM, TabonaA, LevinskyRJ, AraiT, TurnerMW, SummerfieldJA. Molecular basis of opsonic defect in immunodeficient children. Lancet, 1991; 337:1569–1570.
23.
MadsenHO, GarredHO, HofmannB, SvejgaardA. Increased frequency of homozygosity of abnormal mannan binding protein alleles in patients with suspected immunodeficiency. Lancet, 1995; 346:941–943.
24.
SummerfieldJA, SumiyaM, LevineM, TurnerMW. Association of mutations in mannose binding protein gene in childhood infection in consecutive hospital series. BMJ, 1997; 314:1229–1232.
25.
SummerfieldJA, RyderS, SumiyM, ThurszM, GorcheinA, MonteilMA, TurnerMW. Mannose binding protein in gene mutations associated with unusual and severe infections in adults. Lancet, 1995; 345:886–889.
26.
CedzynskiM, SzemrajJ, SwierzkoAS, Bak-RomaniszynL, BanasikM, ZemanK, KilpatrickDC. Mannan-binding lectin insufficiency in children with recurrent infections of the respiratory system. Clin Exp Immunol, 2004; 136:304–311.
27.
RijkersGT, SandersEAM, BreukelsMA, ZegersBJM. Infant B cell responses to polysaccharide determinants. Vaccine, 1998; 16:1398–1400.
28.
KochA, MelbyeM, SørensenP, HomøeP, MadsenHO, MølbakK, HansenCH, AndersenLH, HahnGW, GarredP. Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA, 2001; 285:1316–1321.
29.
EisenDP, DeanMM, BoermeesterMA, FidlerKJ, GordonAC, KronborgG, KunJFJ, LauYL, PayerasA, ValdimarssonH, BrettSJ, IpWKE, MilaJ, PetersMJ, SaevarsdottirS, van TillJWO, HindsCJ, McBrydeES. Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin Infect Dis, 2008; 47:510–516.
30.
RoyS, KnoxK, SegalS, GriffithsD, MooreCE, WelshKI, SmarasonA, DayNP, McPheatWL, CrookDW, HillAVS. the Oxford Pneumococcal Surveillance Group. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet, 2002; 359:1569–1573.
31.
Garcia-LaordenMI, Sole-ViolanJ, Rodriguez de CastroF, AspaJ, BrionesML, Garcia-SaavedraA, RajasO, BlanquerJ, Caballero-HidalgoA, Marcos-RamosJA, Hernandez-LopezJ, Rodriguez-GallegoC. Mannose-binding lectin and mannose-binding lectin–associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults. J Allergy Clin Immunol, 2008; 122:368–374.
32.
HazlewoodMA, KumararatneDS, WebsterDB, GoodallM, BirdP, DahaM. An association between homozygous C3 deficiency and low levels of anti-pneumococcal capsular polysaccharide antibodies. Clin Exp Immunol, 1992; 87:404–409.
33.
SelanderB, WeintraubA, HolmströmE, SturfeltG, TruedssonL, MårtenssonU, JenseniusJC, SjöholmAG. Low concentrations of IgG antibodies to Salmonella serogroup C in C2 deficiency: suggestion of a mannan-binding lectin pathway-dependent mechanism. Scand J Immunol, 1999; 50:555–561.
34.
RusevaM, KolevM, Dagnaes-HansenF, HansenSB, TakahashiK, EzekowitzA, ThielS, JenseniusJC, GadjevaM. Mannan-binding lectin deficiency modulates the humoral immune response dependent on the genetic environment. Immunology, 2009; 127:279–288.
35.
TestST, MitsuyoshiJ, ConnollyCC, LucasAH. Increased immunogenicity and induction of class switching by conjugation of complement C3d to pneumococcal serotype 14 capsular polysaccharide. Infect Immunol, 2001; 69:3031–3040.
36.
HaasKM, ToapantaFR, OliverJA, PoeJC, WeisJH, KarpDR, BowerJF, RossTM, TedderTF. Cutting edge: C3d functions as a molecular adjuvant in the absence of CD21/35 expression. J Immunol, 2004; 172:5833–5837.
