Clinical manifestation of mannose-binding lectin deficiency in adults independent of concomitant immunodeficiency

doi:10.1016/j.humimm.2009.07.003

Human Immunology

Volume 70, Issue 10, October 2009, Pages 809-812

https://doi.org/10.1016/j.humimm.2009.07.003 Get rights and content

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 immunodeficiency 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 recurrent 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.

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.

Section snippets

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.

References (22)

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Mannan-binding lectin—a soluble pattern recognition molecule
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R. Steffensen et al.
Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers
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N.J. Klein
Mannose-binding lectin: do we need it?
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C. Hoflich et al.
Naturally occurring anti-IFN-γ autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans
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Improving the in vitro antigen specific T cell proliferation assay: the use of interferon-α to elicit antigen specific stimulation and decrease bystander proliferation
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Disorders of neutrophil function
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Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency
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J.A. Summerfield et al.
Mannose binding protein gene mutations associated with unusual and severe infections in adults
Lancet
(1995)
O. Neth et al.
Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study
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D.L. Worthley et al.
Mannose-binding lectin: biology and clinical implications
Intern Med J
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P. Garred et al.

Mannose-binding lectin and its genetic variants

Genes Immun

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Cited by (19)

Risk factors of laryngeal cryptococcosis: A case report
2019, Medical Mycology Case Reports
Cryptococcal infections are acquired by inhalation of encapsulated yeast cells or basidiospores. While Cryptococcus has a propensity to invade the lungs and central nervous system, other sites can be affected. Laryngeal cryptococcosis is rare with less than 30 previously reported cases, which commonly occurred in apparently immunocompetent hosts on inhaled corticosteroids. We present a case of laryngeal cryptococcosis with a long-term inhaled corticosteroid use, co-infection of pulmonary Mycobacterium avium-intracellulare, and mannose-binding lectin deficiency.
Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome
2015, Human Immunology
Citation Excerpt :
In the present study determining MBL levels with the same assay, a MBL deficiency [<100 ng/ml] was found in 15% (n = 43 of 293) of CFS patients in the first cohort and in 12% (n = 20 of 160) in the second cohort. The levels of MBL were lower in CFS patients with a median of 1115 ng/ml [ranging from <50.0 to 4897.5] ng/ml compared to 1763.0 [ranging from 824.1 to 2873.1] ng/ml as reported for our previous healthy control group [28]. Nearly half of the CFS patients with MBL deficiency (<100 ng/ml) reported an increased susceptibility to infections of the upper and lower respiratory tract (47%) in contrast to 30% of the patients with normal MBL concentrations in the 1st cohort (p = 0.038).
Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections. In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG₃ and IgG₄ subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG₂ in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.
Impaired thymic function and CD4+ T lymphopenia, but not mannose-binding lectin deficiency, are risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients
2013, Transplant Immunology
Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in kidney transplant recipients (KTR), but risk factors remain poorly defined. CD4 + T lymphopenia and mannose-binding lectin (MBL) deficiency are common immunodeficiencies in KTR. Here, we investigated whether CD4 + T lymphopenia and/or MBL deficiency would be risk factors for PCP in KTR. Furthermore, the role of thymic function in CD4 + T lymphopenia and outcome was studied by assessing CD45RA+CD31+CD4 + T cell numbers (RTE, recent thymus emigrants).
In 321 de novo KTR serial determinations of peripheral T lymphocyte subsets (n = 281, mean 4.2 times between days 0–365) and/or MBL levels (n = 112, mean 1.8 times between days 30–180) were performed. 22/321 patients developed a PCP episode on average at day 199 (107–398) post-Tx.
Age correlated inversely with RTE, CD4 + and CD8 + T-cell counts until day 180 post-Tx. RTE correlated with CD4 + T-cell counts at all time-points pre- and post-Tx. PCP patients had more CMV infections (p = 0.045) within the first 3 months compared to controls. Importantly, PCP patients were older (p = 0.008), and had lower RTE (p = 0.046) pretransplant, and lower CD4 + T-cell counts pretransplant (p = 0.017), at day 60 (p = 0.032) and for the average of all post-Tx values (p = 0.027) compared to controls. Though treatment with T-cell depleting antibodies was associated with consecutive CD4 + T lymphopenia in the whole cohort, the number of patients who received T-cell depleting antibodies was comparable between PCP and control patients (p = 0.754). A multivariate stepwise logistic regression model identified only pretransplant CD4 + T-cell counts (OR 0.011, p = 0.010) and acute rejection (OR 4.66, p = 0.023) as predictors of PCP.
In contrast, MBL levels and incidence of MBL deficiency (< 500 ng/ml) at days 30, 90 and 180 post-Tx were not different between PCP patients and controls.
In conclusion, PCP risk was associated with higher age and related to both thymic functional impairment and long-lasting CD4 + T-lymphopenia that started already before transplantation. Despite frequent occurrences in KTR, low levels of serum MBL were not associated with increased risk for PCP. CD4 + T-cell counts and function should be addressed in prospective studies for more individualized approaches to PCP prophylaxis.
Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis
2012, Human Immunology
Citation Excerpt :
In line with this concept it is also not surprising that children with HSE and a single mutation in TLR3 were not suffering from HL. The concept of a multigenic predisposition is in accordance with findings of deficiencies in other pattern recognition molecules, such as TLR5 and mannose-binding lectin; where defect-carriers have a mild phenotype, and the clinical consequences to infection only appear in a subset of people or under certain circumstances [1,32–34]. The potential relevance of TLR3 L412F polymorphism for HL susceptibility is further supported by studies showing its association with coxsackievirus and CMV infections [10,30] as described in the previous paragraph.
HSV-1 persistently infects almost 90% of our population; however, only 30% of the infected subjects suffer from recurrent herpes lesions, most frequently herpes labialis (HL). We hypothesized that variations in toll-like receptor (TLR) functions might contribute to HL susceptibility. In our study, the TLR-2/1,-3, and -7/8 responses of immune cell subsets derived from asymptomatic HSV-1 carriers were compared with responses of subjects with HL history. Remarkably, natural killer (NK) cells isolated from HL subjects showed significantly lower IFN-γ responses selectively to the TLR3 agonist poly(I:C). Furthermore, the TLR3 L412F genetic polymorphism was found to reduce NK cell TLR3-responsiveness and is associated with susceptibility to recurrent HL. The TLR3 response detected in HL total peripheral blood mononuclear cells (PBMCs), however, was not impaired, indicating restoration of NK cell TLR3-deficiency through co-stimulatory functions. In conclusion, our results suggest that decreased TLR3 response of NK cells is associated with HL susceptibility; and potentially explain why symptomatic outbreak of HL usually occurs after stress or prolonged UV light exposure, when host co-stimulatory functions are disturbed.
Mannose-binding lectin deficiency is not associated with increased risk for polyomavirus nephropathy
2012, Transplant Immunology
Citation Excerpt :
In all serum samples, functional MBL was measured using an MBL Oligomer enzyme-linked immunosorbent assay kit (Antibody Shop, Gentofte, Denmark) as described elsewhere [21]. In line with former studies, median post-Tx MBL concentrations lower than 500 ng/mL were classified as MBL deficiency and values below 1000 ng/mL as partial MBL deficiency [15,21,22]. Serum BKV-loads were measured by TaqMan real-time polymerase chain reaction (PCR) targeting the large T antigen.
Polyomavirus associated nephropathy (PVAN) affects up to 10% of kidney transplant recipients and is a major risk factor for graft loss. Mannose-binding lectin (MBL) is an important recognition molecule of the innate immune system, and its deficiency has been associated with susceptibility to various infections. In transplantation, on the other hand, high MBL levels have been associated with increased tissue damage in ischemia–reperfusion models and poorer graft and patient survival in solid organ transplant patients. To investigate the relation between MBL and BK virus infection, post-transplant (post-Tx) MBL levels were determined in a cohort of de novo kidney transplant patients with and without BK viremia.
41 de novo kidney transplant patients with high (n = 16, group 1) or low level BK viremia (n = 25, group 2) and 64 patients without BK viremia (group 3) were included. In every patient, functional MBL levels were determined at 1–3 time points (days 30, 90 or 180) post-Tx using an MBL oligomer ELISA.
MBL levels remained unchanged between days 30 and 180 post-Tx independent of BKV viremia. Frequencies of MBL deficiency (< 500 ng/mL) and MBL levels were not significantly different between the 3 groups. However, group 2 patients showed a trend towards lower MBL serum levels compared to group 1 patients, notably in patients without acute rejection (p = 0.076).
MBL deficiency was not associated with higher risk for BK viremia. In contrast, we hypothesize that BK virus replication in patients with low MBL levels might imply lower risk for progression towards PVAN compared to patients with high MBL levels. This view is supported by recent data demonstrating local complement activation in BK nephropathy.
A novel mutation in complement 2 accompanied by susceptibility variants in C3 glomerulonephritis: A case study
2019, Nefrologia
C3 glomerulonephritis is a rare, chronic disease characterized by C3c-dominant staining on renal biopsy and is caused by inherited or acquired alternative complement pathway dysregulation.
Here, we reported a 36-year-old man presenting with nephritic syndrome and normal renal function. Secondary causes were excluded by detailed clinical history and laboratory tests. His renal biopsy was consistent with C3 glomerulonephritis with a membranoproliferative glomerulonephritis pattern. To identify the etiology, we carried out genetic and autoantibody screening tests. The results showed he was negative for autoantibodies, while the next-generation sequencing revealed common variants of complement factor H (c.1204T>C; p.Tyr402His), (c.184G>A; p.Val62Ile) and thrombomodulin (c.1418C>T; p.Ala473Val), which have previously been reported to increase susceptibility to complement-mediated diseases. He also carried complement factor H (c.2808G>T; p.Glu936Asp) and mannose-binding lectin (c.161G>A; p.Gly54Asp), putting the patient at an increased risk of infections, which was an important trigger for C3 glomerulonephritis. A novel variant of complement 2 (c.53A>G; p.His18Arg) that might contribute to the occurrence of C3 glomerulonephritis when combined with these susceptibility variants was further identified. The patient was treated with ramipril and regular fresh frozen plasma infusion. He had a good response to treatment with well-controlled proteinuria, stable renal function and an increasing serum C3 level.
This case adds insight into the pathogenesis of C3 glomerulopathy by showing that a combination of susceptibility variants, genetic mutations and triggers might be responsible for the clinical and pathological phenotypes.
La glomerulonefritis C3 es una enfermedad rara y crónica caracterizada por tinción dominante en C3c en la biopsia renal y es causada por una desregulación de la ruta alternativa del complemento heredada o adquirida.
Informamos sobre un varón de 36 años que presenta síndrome nefrítico y función renal normal. Las causas secundarias fueron excluidas por la historia clínica detallada y las pruebas de laboratorio. Su biopsia renal fue consistente con glomerulonefritis C3, con un patrón de glomerulonefritis membranoproliferativa. Para identificar la etiología realizamos pruebas de cribado genéticas y de autoanticuerpos. Los resultados mostraron que era negativo para autoanticuerpos, mientras que la secuenciación de próxima generación reveló variantes comunes del factor del complemento H (c.1204T>C; p.Tyr402His), (c.184G>A; p.Val62Ile) y trombomodulina (c.1418C>T; p.Ala473Val), que previamente se había informado que aumentaban la susceptibilidad a las enfermedades mediadas por el complemento. También tuvo factor del complemento H (c.2808G>T; p.Glu936Asp) y lectina de unión a manosa (c.161G>A; p.Gly54Asp), que aumentaba el riesgo de infección para el paciente, y que fue un desencadenante importante para glomerulonefritis C3. Una nueva variante del complemento 2 (c.53A>G; p.His18Arg) que podría contribuir a la aparición de glomerulonefritis C3 cuando se combina con estas variantes de susceptibilidad fue identificado. El paciente fue tratado con ramipril e infusión regular de plasma fresco congelado. Tuvo una buena reacción al tratamiento con proteinuria bien controlada, función renal estable y un aumento de suero del nivel C3.
Este caso agrega una idea de la patogénesis de la glomerulopatía C3 al mostrar que una combinación de variantes de susceptibilidad, mutaciones genéticas y desencadenantes podría ser responsable de los fenotipos clínicos y patológicos.

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Human Immunology

Abstract

Introduction

Section snippets

Patients with a history of recurrent and/or severe infections

Significantly higher prevalence of severe MBL deficiency exists in patients with recurrent and/or severe infections

Discussion

Acknowledgments

References (22)

Mannan-binding lectin—a soluble pattern recognition molecule

Mol Immunol

Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers

J Immunol Methods

Mannose-binding lectin: do we need it?

Mol Immunol

Naturally occurring anti-IFN-γ autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans

Blood

Improving the in vitro antigen specific T cell proliferation assay: the use of interferon-α to elicit antigen specific stimulation and decrease bystander proliferation

J Immunol Methods

Disorders of neutrophil function

Blood Rev

Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency

Lancet

Mannose binding protein gene mutations associated with unusual and severe infections in adults

Lancet

Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study

Lancet

Mannose-binding lectin: biology and clinical implications

Intern Med J

Mannose-binding lectin and its genetic variants

Genes Immun

Cited by (19)

Risk factors of laryngeal cryptococcosis: A case report

Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome

Impaired thymic function and CD4+ T lymphopenia, but not mannose-binding lectin deficiency, are risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients

Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis

Mannose-binding lectin deficiency is not associated with increased risk for polyomavirus nephropathy

A novel mutation in complement 2 accompanied by susceptibility variants in C3 glomerulonephritis: A case study