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Keywords:

  • CVID;
  • FcRn;
  • genetic polymorphism;
  • IgG replacement;
  • primary immune deficiency

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An ‘efficiency’ index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

Common variable immunodeficiency disorders (CVIDs) are a group of diseases characterized by primary immune defects resulting in reduced serum immunoglobulin (Ig)G, IgA and/or IgM and a lack of protective antibodies [1]. CVID patients usually present with recurrent respiratory infections. Replacement immunoglobulin therapy is the standard treatment for patients with CVID, using either the intravenous (i.v.) or subcutaneous (s.c.) route. Efficacy was evidenced by studies showing infection prevention and raised serum trough IgG levels [2-4]. It has also been shown that each patient requires an individual dose to both maintain an individual target IgG level and prevent breakthrough bacterial infections [5]. Patients with CVID are also more susceptible to a range of complications, including autoimmune, gastrointestinal, lymphoproliferative and granulomatous diseases. Several classifications have attempted to improve characterization of subgroups of patients, according to the outcome or severity of the disease. A clinical classification based on distinct clinical phenotypes associated with different prognosis has been proposed [6] and confirmed recently with two independent cohorts [7]. In a previous study it was shown that doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0·2 to 1·2 g/kg/month. Furthermore, it has been shown that patients with s.c. IgG (SCIG) substitution required a lower IgG dose than patients receiving i.v. IgG (IVIG) to maintain given IgG trough levels [8, 9] and that patients with more severe clinical phenotypes or bronchiectasis required higher doses [5]. Thus it was important to confirm, in a large series of CVID patients, that a higher dose of IgG was used in patients with i.v. substitution and/or presenting with CVID complications to achieved satisfactory trough levels. To examine IgG efficiency in terms of IgG increment for a given dose of IgG, we defined an efficiency index that reflects the return of IgG to the serum resulting in an IgG increment over baseline on replacement therapy.

In addition, we postulated that genetic factors could influence IgG efficiency. The neonatal Fc receptor (FcRn) is a heterodimeric receptor composed of a non-classical MHC class I α-chain and β2-microglobulin that binds two ligands, IgG and albumin, and extends the catabolic half-lives of both proteins [10-12]. FcRn recycles an amount of albumin equivalent to that synthesized in a given time. For IgG, the receptor recycles four times the amount synthesized [13]. FcRn binds endocytosed IgG at an acidic pH within endosomes, diverts it from degradation and transports it back to the cell surface, where IgG is released at neutral pH [14]. Endothelial and haematopoietic cells are involved in the process but other cells, such as bronchial epithelial cells, also express FcRn, and may also play a role in recycling [15, 16]. A variable number of tandem repeats (VNTR) polymorphism influences the transcriptional activity of the FcRn gene promoter and these could support differences in IgG catabolism [17]. This genetic polymorphism was investigated in the present study alongside the efficiency of IgG.

Material and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

Patients

Patients were included into the French DEFI cohort study [18] and into the Oxford Primary Immune Deficiency (PID) cohort study [5]. The criteria used for the diagnosis of CVID were consistent with the European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency criteria [1]. These cohort studies have been approved by local ethic committees and all human participants gave written informed consent. Patients with stable (>6 months) IgG replacement were selected for the present study.

Data analysis

The DEFI study was started in 2004 and has collected clinical data and biological specimens from adult patients with primary hypogammaglobulinaemia in 46 centres. The Oxford PID database was set up in 1987 to collect demographic and infection data alongside details of therapies. Separate Excel spreadsheets were extracted from the two databases and merged for the purpose of the present analysis, having agreed the criteria of complications to define clinical phenotypes.

Clinical phenotypes were based on revised versions of the original criteria [5-7]. Four disease-related phenotypes were analysed: polyclonal lymphoproliferation with or without granulomatous disease, autoimmune cytopenia or enteropathy. Persistent unexplained enteropathy had to be biopsy proven with flat villi and increased intraepithelial lymphocytes and gluten-insensitive; the fourth group, ‘infection only’, or no disease-related complications, was defined by the absence of any of the complications that define the other three phenotypes. In addition, the complications of splenomegaly, chronic non-viral liver disease with portal hypertension usually related to nodular regenerative hyperplasia, lymphoma and bronchiectasis, were also analysed for possible correlations.

Treatment-related details used for analysis were: (i) route of immunoglobulin replacement (i.v. versus s.c.), (ii) serum residual IgG (level in serum before replacement; g/l), (iii) dose of IgG replacement calculated in grams per kilogram per week, (iv) serum IgG trough levels (g/l) once stable on therapy and (v) an ‘efficiency’ index covariate calculated as the ratio of serum IgG trough level minus IgG residual (g/l) to the average weekly dose of IgG infusion (g/kg/week). Serum albumin level was recorded at the time of trough level evaluation.

IgG Fc fragment receptor transporter alpha chain (FCGRT) VNTR promoter polymorphism

DNA was obtained from 302 patients. Polymerase chain reaction (PCR) assays were performed using primers encompassing the VNTR polymorphism of the FCGRT gene promoter described by Sachs et al. [17]. The 20-μl reaction mixture contained 10 ng of genomic DNA, 250 nM of sense (5′-GGAGCGAGGCTGAAGGGAAC-3′) and anti-sense (5′-CCCCTGAACTGGATCTCAGTTG-3′) primers, 200 μM of each dNTP (MBI Fermentas, St Leon-Rot, Germany), 1·5 mM MgCl2 and 0·5 U of Taq DNA polymerase in its buffer (Promega, Madison, WI, USA). PCR conditions comprised 5 min at 94°C followed by 40 cycles, each consisting of three steps at 94°C for 1 min, 64·4°C for 1 min and 72°C for 40 s. PCR complete extension was achieved for 5 min at 72°C. This amplification was performed on a MyCycler thermocycler (Bio-Rad, Marnes-la-Coquette, France). PCR products were resolved using 8% acrylamide gel (Invitrogen, Carlsbad, CA, USA) and visualized after ethidium bromide staining.

The VNTR polymorphism consists of one to five repeats of a 37-base pairs (bp)-long motif (VNTR1–5) in the promoter region of the FcRn gene. Alleles with three repeats (VNTR3) are most common in Caucasians.

Statistics

Summary statistics, i.e. mean ± standard deviation (s.d.), median and interquartile range (IQR) and percentages, were computed for quantitative and qualitative variables, respectively. Comparison of distributions according to specific subsets were based on non-parametric Wilcoxon rank sum tests, while Pearson's correlation coefficients were computed to assess correlation between variables. Finally, generalized linear models were used to summarize predictive information from univariable analyses with backward elimination, starting with all candidate variables and deleting those without statistical significance. Statistical analysis was performed using the sas 9·2 (SAS Inc., Cary, NC, USA) software package. All tests were two-sided, with P-values of 0·05 or less denoting statistical significance.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

Patient characteristics

A total of 380 adult patients, 275 from the French DEFI cohort and 105 from the Oxford cohort, were included into the study. Using the clinical phenotype classification, 230 (60%) patients had no disease-related complications (‘infections only’ group), while 150 (40%) had at least one disease-related phenotype: polyclonal lymphoid proliferation (26%), autoimmune cytopenia (17%) or unexplained enteropathy (7%). In addition, 139 (37%) developed splenomegaly, 14 (4%) lymphoma, 35 (9%) chronic non-viral liver disease and 156 (41%) bronchiectasis. The frequency of patients with CVID complications was similar in France (39·3%) and the United Kingdom (40%). However, the frequency of some complications was higher in the Oxford cohort than in the DEFI study (Table 1).

Table 1. Main clinical and biological characteristics in 380 common variable immunodeficiency (CVID) patients according to the route used for immunoglobulin (Ig)G replacement therapy and cohort origin.
 IVIGSCIGTotalDEFIOxford
 n = 307n = 73n = 380n = 275n = 105
Sex (male : female)138:16930:43168:212125:15043:62
Age (years, median)4546454541
IgG at diagnosis (g/l, median)1·82·01·81·81·4
Infection only (%)57·374·060·560·760·0
Lymphoid proliferation (%)29·015·126·327·323·8
AI cytopenia (%)18·911·017·414·923·8
Enteropathy (%)7·85·57·46·98·6
Splenomegaly (%)39·126·036·633·843·8
Lymphoma (%)4·21·43·72·95·7
Liver disease (%)10·15·59·26·915·2
Bronchiectasis (%)43·331·54137·849·5
Serum albumin (g/l, median)43·042·042·942·044·3

Patients treated with IVIG and SCIG were similar in terms of sex, age and serum IgG level at diagnosis. Patients on IVIG therapy were more likely to have presented with CVID complications than patients with SCIG (42·7% versus 26%; Table 1).

Lower IgG replacement efficiency in patients receiving IVIG versus SCIG

For the whole cohort of 380 patients, the mean (± s.d.) value for IgG efficiency was 54·1 (± 30·8) and the median (IQR): 51·9 (35·1–67·1). Most patients, 307 (81%), were treated with IVIG and 73 (19%) received SCIG.

IgG trough levels were slightly lower in the 307 patients with IVIG than in patients with SCIG (7·85 ± 2·47 versus 8·58 ± 2·35 g/l; P = 0·011), the mean dose used for IVIG was 22% higher than that used for SCIG (0·128 ± 0·054 versus 0·105 ± 0·041 g/kg/week; P < 0·001) and the efficiency index 29% lower in IVIG patients (50·2 ± 26·4 versus 70·7 ± 41·2; P < 0·001; Fig. 1). The efficiency index was similar in patients treated every 2 (n = 43), 3 (n = 115), 4 (n = 137) and 5 or 6 (n = 12) weeks.

figure

Figure 1. (a) Immunoglobulin (Ig)G efficiency index in common variable immunodeficiency (CVID) patients according to the route of replacement therapy or the presence of a disease-related complication (i.e. lymphoid hyperplasia, autoimmune cytopenia or enteropathy). (b) The most significant difference in efficiency was observed according to the route of substitution in patients belonging to the ‘infections only’ group. Data are represented as box-plots displaying medians, 25th and 75th percentiles as boxes, and 10th and 90th percentiles as whiskers. Difference between groups were compared by the Kruskal–Wallis test.

Download figure to PowerPoint

The most striking difference in efficiency between the two routes used for replacement was observed in patients from the ‘infections only’ group (75·3 ± 43·1 for SCIG versus 53·3 ± 28·1 for IVIG; P < 0·001). The difference in IgG efficiency was less important in patients with disease-related phenotypes (57·6 ± 32·7 for SCIG versus 45·9 ± 23·2 for IVIG; P = 0·02; Fig. 1).

Lower IgG replacement efficiency in patients with disease-related phenotypes

IgG trough levels were lower in patients with disease-related phenotypes when compared to those without (7·53 ± 2·66 g/l versus 8·26 ± 2·28 g/l; P = 0·002). However, IgG dose was higher (0·132 ± 0·058 versus 0·118 ± 0;048 g/kg/week; P = 0·008), and therefore the efficiency index was significantly lower (47·4 ± 24·8 versus 58·5 ± 33·5; P < 0·001) in patients with disease-related phenotypes compared to those without, as shown in Fig. 1 and Table 2. Table 2 also demonstrates the different approaches to immunoglobulin therapy between the two cohorts. DEFI patients are treated with sufficient IgG to reach a particular trough level (7·5–8 g/l), whereas the Oxford patients received sufficient doses of IgG to prevent bacterial infections regardless of clinical phenotype.

Table 2. Immunoglobulin (Ig)G replacement efficiency according to the absence or presence of disease-related phenotypes in 380 common variable immunodeficiency (CVID) patients.
Patients (nb)TotalDEFIOXFORD
Infections onlyDisease-related phenotypes Infections onlyDisease-related phenotypes Infections onlyDisease-related phenotypes 
230150P167108P6342P
  1. Efficiency: (IgG trough – IgG residual)/IgG dose). Numbers in bold denote statistical differences between the two groups.

IgG residual (mean; g/l)2·071·880·252·241·870·0451·641·910·31
IgG dose (mean; g/kg/week)0·1180·1320·0080·1160·140< 0·0010·1220·1150·41
IgG trough (mean; g/l)8·267·530·0027·967·540·0778·967·520·003
Efficiency (mean)58·547·4< 0·00156·348·80·01864·548·9< 0·001

Patients with disease-related complications were more likely to be treated with IVIG rather than with SCIG (Table 1). However, in a multivariate analysis, route of administration (P < 0·001) and clinical phenotype (P = 0·004) were associated independently with the values for IgG efficiency, although a disease-related phenotype was associated with lower efficiency in IVIG patients. However, no complications that make up the clinical phenotypes were individually associated significantly with lower efficiency (Table 3).

Table 3. Immunoglobulin (Ig)G replacement efficiency according to disease-related phenotypes in 307 intravenous immunoglobulin (IVIG) patients.
307 CVID patients 

Patients

(nb)

IgG efficiency

(mean ± SD)

P value
  1. Numbers in bold denote statistical differences between the two groups.

Disease-related phenotypeNo17653·3 ± 28·10·01
Yes13145·9 ± 23·2
EnteropathyNo28350·8 ± 26·60·12
Yes2442·8 ± 22·6
AI cytopeniaNo24951·6 ± 27·20·06
Yes5843·8 ± 21·3
Polyclonal lymphoid proliferationNo21851·7 ± 27·60·11
Yes8946·5 ± 22·7
LymphomaNo29450·0 ± 26·40·68
Yes1353·0 ± 25·9
SplenomegalyNo18751·2 ± 27·30·32
Yes12048·6 ± 24·9
Liver diseaseNo27650·6 ± 27·00·46
Yes3146·4 ± 20·2
BronchiectasisNo17450·6 ± 27·80·85
Yes13349·6 ± 24·5

Twenty-two patients from the DEFI cohort had been splenectomized at time of analysis. Efficiency was similar in these patients to the 253 non-splenectomized patients (mean ± s.d., 49·3 ± 34 versus 52·8 ± 33; P = 0·36).

Low serum albumin level was also associated with poor efficiency in patients with IVIG, but not in patients with SCIG (P < 0·001 and P = 0·42, respectively). In IVIG patients, the mean value for efficiency was 28·6 when serum albumin was below 36 g/l and 52·1 when above 36 g/l. Interestingly, this correlation observed in IVIG patients was still observed after exclusion of the patients with liver disease or enteropathy (P < 0·001).

IgG replacement efficiency according to lymphocyte phenotyping

By using the EUROClass classification of B cell phenotype in CVID, we could not find any differences in efficiency index according to the different phenotype groups: 53 ± 29 in patients with no circulating B cells (B), 51·9 ± 29·3 in patients with switched memory B cells below 2% (smB) and 53·9 ± 38·2 in patients switched memory B cells above 2% (P = 0·95). The 39 patients with associated severe T cell defects characterized by CD4+ naive T cells below 20 × 106/l were shown to have a similar efficiency index to patients with CD4+ naive T cells above 20 × 106/l: 50·6 ± 24·8 versus 52·9 ± 34·3 (P = 0·85).

Lower IgG replacement efficiency is associated with infrequent FCGRT polymorphisms

This study was restricted to the 302 patients with available DNA samples. The allelic frequencies observed for the two most frequent alleles, VNTR3 (89%) and VNTR2 (10%), were not different to those observed in 202 French controls (90 and 9%, respectively). Most patients (240, 79·5%) were homozygotes for the 3/3 genotype, while 54 (17·9%) were compound heterozygotes for the 2/3 genotype. The best efficiency for IgG replacement therapy was observed in patients with the 3/3 genotype when compared to patients with another genotype (55·3 ± 33·8 versus 43·4 ± 21·7; P = 0·01). Outliers analysis revealed that three of the six patients with very low efficiency (<10) exhibited a non-3/3 genotype (2/3 in two and 3/4 in one), while all seven patients with a very high efficiency index (>150) had the common 3/3 genotype. The difference regarding efficiency was significant in the 245 patients with IVIG: (51·0 ± 28·5 versus 39·8 ± 21·3; P = 0·01), but not in the 57 patients with SCIG (75·1 ± 47·2 versus 55·6 ± 18·7; P = 0·13).

IgG replacement efficiency in 245 IVIG patients

According to these results, and to the small number of patients treated with SCIG, we then focused the analysis on the 245 IVIG patients who have been genotyped for FCGRT_VNTR.

Analysis of these patients revealed that the 48 patients with an uncommon genotype (i.e. different from the 3/3 genotype) had lower IgG trough levels and lower IgG efficiency than the 197 patients with the VNTR_3/3 genotype (Table 4 and Fig. 2). No difference in the serum albumin levels could be demonstrated according to the FCGRT_VNTR genotype and there was no association between the clinical phenotype and the FCGRT_VNTR genotype (data not shown).

figure

Figure 2. (a) Immunoglobulin (Ig)G efficiency index in common variable immunodeficiency (CVID) patients treated with intravenous immunoglobulin (IVIG) according to the presence of a disease-related complication (i.e. lymphoid hyperplasia, autoimmune cytopenia or enteropathy) and to the genotype of the Fc fragment of IgG, receptor, transporter, alpha (FCGRT) variable number of tandem repeats (VNTR) promoter gene (VNTR3/3 versus VNTRnon-3/3). (b) A significant difference in efficiency was observed according to the FCGRT_VNTR genotype in patients presenting with a disease-related complication of CVID. Data are represented as box plots displaying medians, 25th and 75th percentiles as boxes, and 10th and 90th percentiles as whiskers. Difference between groups were compared by the Kruskal-Wallis test.

Download figure to PowerPoint

Table 4. Immunoglobulin (Ig)G efficiency according to Fc fragment of IgG, receptor, transporter, alpha (FCGRT) variable number of tandem repeats (VNTR) genotype in 245 intravenous immunoglobulin (IVIG) patients.
 FCGRT_VNTR 
 

3/3

n = 197

non 3/3

n = 48

P value
  1. Numbers in bold denote statistical differences between the two groups. s.d.: standard deviation.

IgG residual

g/l; mean ± s.d.

2·10 ± 1·462·05 ± 1·350·94

IgG dose

g/kg/week; mean ± s.d.

0·127 ± 0·0540·141 ± 0·0700·37

IgG trough level

g/l; mean ± s.d.

7·89 ± 2·387·23 ± 2·700·01

IgG efficiency

mean ± s.d.

50·9 ± 28·539·8 ± 21·3< 0·01

Serum albumin

g/l; mean ± s.d.

42·5 ± 4·941·7 ± 6·30·45

Efficiency was lower in the 101 patients with disease-related complications than in the 144 patients with the ‘infections only’ phenotype: 44·9 ± 24·7 versus 51·5 ± 29·2 (P = 0·044). When we analysed the impacts of the FCGRT_VNTR genotype and of clinical complications on IgG efficiency, we observed that the most significant difference in IgG efficiency was observed in patients with CVID clinical complications: 47·3 ± 24·6 in patients with VNTR3/3 versus 36·1 ± 23·5 in patients with a different genotype (P = 0·03; Fig. 2).

Multivariate analysis in 245 IVIG patients

A multivariate analysis was performed to predict IgG replacement efficiency in IVIG patients. The FCGRT_VNTR3/3 genotype (P = 0·008) and high serum albumin level (P < 0·001) were associated independently with high IgG efficiency, while disease-related complications and splenomegaly were no more predictive (P = 0·29 and P = 0·57, respectively). When we restricted the analysis to patients without liver disease or enteropathy, the FCGRT_VNTR3/3 genotype (P = 0·006) and high serum albumin level (P < 0·001) remained associated independently with high IgG efficiency. In the 57 SCIG patients, none of these covariates could predict IgG efficiency (data not shown and possible lack of power due to small number of patients).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

Replacement therapy with IgG is an essential intervention in patients with primary antibody deficiencies, as it reduces the frequency and severity of infections. The main goal of replacement therapy is to improve infection prevention. However, as high trough IgG levels are associated with a reduced risk of pneumonia or severe infection, it is widely accepted that IgG trough levels should reach a minimum of 6 g/l to be within the range found in normal healthy individuals [19-22]. Indeed, in most ongoing patient cohorts and in the present study, the IgG trough level is usually approximately 8 g/l [4, 5] or even higher [23]. It has also been suggested that the increment in the serum IgG level was more important than the trough level and that subsequently, in cases with relatively high residual IgG, higher trough levels should be targeted [24]. It has been recognized that the IgG dose required for infection prevention varies from one individual to another [5], and that two major factors are involved: (i) contrary to some advice, real-life data show that the s.c. route requires lower IgG doses to achieve trough levels similar to those achieved with the i.v. route [8, 9]; (ii) disease-related clinical phenotyes and some complications are associated with lower trough levels and/or require higher IgG doses to prevent bacterial infections [5]. Furthermore, although trough levels reached with IVIG and SCIG probably mean the same, the possible merit of a high peak level and different area under the curve (AUC) obtained with IVIG may have some impact on the clinical efficacy of Ig substitution. The present study was designed to confirm these data in a large series of patients enrolled into two prospective cohorts in France and the United Kingdom and to investigate possible genetic factors implicated in the efficiency of IgG replacement therapy.

In France, IgG trough levels were similar in patients with or without disease-related complications while the IgG dose was increased slightly in patients with disease-related phenotypes. In contrast, in the Oxford cohort, the IgG dose was similar, but the trough levels were slightly lower in the group with disease-related phenotypes. However, the ‘efficiency’ index was similar in both cohorts, with decreased indices in patients with disease-related phenotypes. This underlines the relevance of this index, which takes into account different management protocols for deciding the IgG dose for replacement: frequency of infections (Oxford) versus maintenance of a particular trough level (DEFI). This efficiency index reflects the average increment of serum IgG after parenteral IgG administration and should be considered as a biological efficiency index. Because of the study design, we could not evaluate possible correlations with infection prevention as these data were not collected for all patients. However, the correlations found in other studies, including a large meta-analysis, between trough levels and prevention of infectious episodes, suggest that the higher the efficiency index, the higher the protection for a given IgG dosage.

IgG replacement efficiency was higher in patients treated with SCIG than in patients treated with IVIG, and in both cohorts from the present study disease-related phenotypes were associated with a reduced efficiency of IgG replacement. The frequency of patients with disease-related complications was higher in the group of patients treated with IVIG than in patients with SCIG and could have biased the analysis regarding the impact of the replacement route on IgG efficiency. However, in a multivariate analysis, both route of administration and clinical phenotype were associated independently with IgG efficiency.

A trend for lower efficiency was noted for almost all disease-related complications, but the difference reached statistical significance only for the whole group of patients with at least one complication. These disease-related phenotypes may be associated with lymphocyte activation and with higher IgG turnover or protein loss. The correlation between low efficiency and low serum albumin in IVIG patients but not in SCIG patients could support the later hypotheses, but could also suggest increased catabolism or reduced recycling when high peak concentrations are achieved with i.v. infusions in contrast to the more stable levels with more frequent SCIG infusions.

Recycling of IgG is regulated by serum IgG concentration. In early studies it has been shown that, for hypogammaglobulinaemic patients, the median half-life of serum IgG was 38 days, with 3–9% of the intravascular pool catabolized per day, whereas in normal subjects the IgG half-life was 22 days, with 6–8% of the IgG catabolized per day [25]. In patients with chronic lymphocytic leukaemia and hypogammaglobulinaemia there was a similar finding [26], supporting the hypothesis that the catabolism of IgG is concentration-dependent [27]. Thus, as demonstrated in the IgG serum curve post-i.v. infusion, the higher the IgG serum level, the higher the catabolic rate.

The neonatal Fc receptor (FcRn) is a key regulator of IgG and albumin homeostasis, as it protects these proteins from catabolism and recycles them very efficiently. Lack of saturation of the FcRn in CVID patients as well as FcRn genetic differences might lead to longer half-lives of serum IgG and increased efficiency of IgG replacement therapy [28].

A polymorphism in the promoter region of the FCGRT gene consisting of a variable number of 37-bp tandem repeats (VNTR) has been described. The allele with two tandem repeats (VNTR2) is associated with decreased promoter activity and lower transcription compared with the most common VNTR3 allele. Monocytes from VNTR3/3 homozygote patients bind IgG more efficiently [17]. In our study, the best efficiency of IgG replacement was observed in VNTR3/3 patients. A significant difference in IgG efficiency according to the VNTR genotype was observed in patients with IVIG replacement but not in patients with SCIG therapy. FcRn might be saturated by the high serum IgG peak concentration observed after an i.v. infusion, and in such circumstances less efficient FcRn might fail to recycle a significant proportion of the infused IgG. Such an IgG peak in serum levels is not observed after s.c. infusion and therefore saturation of the receptor is unlikely. In a small series of CVID patients, no significant differences could be detected in IgG kinetics after i.v. infusion according to the VNTR polymorphism [29]; however, only a limited number of patients were available for this study, with lack of power in the analysis.

Quantitative analysis of FcRn mRNA expression was not available in the present study and would help in the understanding of the differences in IgG recycling according to FCGRT genotype. It has also been shown that FCGRT mRNA levels correlated negatively with the extent of bronchiectasis [28]. In the present study, although the frequency of bronchiectasis was similar in patients with the VNTR3/3 genotype and those with a different genotype, statistical analysis revealed that efficiency remained higher in VNTR3/3 patients without bronchiectasis (P = 0·04), whereas this increase was not significant in patients with bronchiectasis (P = 0·14). As the exact pathophysiology of bronchiectasis in CVID remains poorly understood, it could be interesting to investigate further the possible role of FcRn in the development of lung damage, although it is more likely that bronchiectasis interferes with IgG recycling through FcRn expression and local catabolism. Under either hypothesis, FcRn expression might be an interesting potential therapeutic target.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

The highest efficiency of IgG replacement therapy is observed in CVID patients with no disease-related complications and, independently, in those receiving s.c. substitution. In IVIG patients, a decreased efficiency was demonstrated in patients with an uncommon FCGRT genotype (i.e. different from the VNTR3/3 genotype) and with low serum albumin, although no correlation could be found between FCGRT genotype and serum albumin. These data suggest that, in the context of high serum IgG peak levels following i.v. administration, patients with an unfavourable FCGRT genotype would experience FcRn saturation and subsequent decreased IgG recycling.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

We are grateful to the Immunology Laboratory in Oxford for the serum measurements.

Disclosure

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group

The DEFI study was supported by a national program for clinical research (PHRC 2005) and by the National Center on Hereditary Immune Deficiencies (CEREDIH), by Laboratoire Français du fractionnement et des Biotechnologies (LFB) and Baxter BioScience. The present study was supported by CSL Behring. The Oxford study was supported by the NIHR Oxford Biomedical Research Centre, an unrestricted gift from Baxter Healthcare and Centre of Excellence awards from the Primary Immunodeficiency Association and the Jeffrey Modell Foundation.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group
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Appendix: DEFI study group

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure
  10. References
  11. Appendix: DEFI study group
  • Coordination: E. Oksenhendler, Hôpital Saint Louis, Paris.
  • Clinical Centres: Hôpital Saint Louis, Paris: C. Fieschi, M. Malphettes, L. Galicier, D. Boutboul, J.P. Fermand. Bordeaux: J.F. Viallard. Limoges: A. Jaccard. Tours: C. Hoarau, Y. Lebranchu. Hôpital Cochin, Paris: A. Bérezné, L. Mouthon. HEGP, Paris: M. Karmochkine, S. Georgin-Lavialle. Marseille: N. Schleinitz. Lyon Sud: I. Durieu, R. Nove-Josserand. Clermont-Ferrand: V. Chanet. Montpellier: V. Le-Moing. Roubaix: N. Just. Hôtel-Dieu, Paris: C. Salanoubat. Reims: R. Jaussaud. Hôpital Necker, Paris: F. Suarez, O. Hermine. Le Mans: P. Solal-Celigny. Lille: E. Hachulla. Perpignan: L. Sanhes. Angers: M. Gardembas, I. Pellier. Troyes: P. Tisserant. Lyon Armée: M. Pavic. Dijon: B. Bonnotte. Pitié-Salpêtrière, Paris: J. Haroche, Z. Amoura. Toulouse: L. Alric, M.F. Thiercelin, L. Tetu, D. Adoue. Nancy Vandoeuvre: P. Bordigoni. Lyon Croix Rousse: T. Perpoint. Lyon Hotel-Dieu: P. Sève. Besançon: P. Rohrlich. Strasbourg: J.L. Pasquali, P. Soulas. Hôpital Foch, Suresnes: L.J. Couderc, E. Catherinot. Montauban: P. Giraud. Hôpital Saint-Louis, Pédiatrie, Paris: A. Baruchel. Clermont-Ferrand 2: I. Deleveau. Kremlin-Bicêtre: F. Chaix. Hôpital Trousseau, Paris: J. Donadieu. Rouen: F. Tron. Bobigny: C. Larroche. Aix: AP Blanc. Nantes: A. Masseau, M. Hamidou. Nancy: G. Kanny, M. Morisset. Poitiers: F. Millot. Bondy: O. Fain. Hôpital Bichat, Paris: R. Borie. Rennes: A. Perlat. Clamart: V. Martinez. Caen: B. Bienvenu.
  • Laboratories: Pitié-Salpêtrière, INSERM U543, Paris: P. Debré, G. Mouillot, I. Théodorou. Saint-Louis, Immunologie, Paris: C. Rabian, M. Carmagnat. Saint-Louis, EA 3963, Paris: C. Fieschi, M. Malphettes, N. Vince, D. Boutboul, C. Bono.
  • Data Management: L. Gérard.