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Clinical Immunology (2007) 122, 156–162

Anti-IgA antibodies in Common VariableImmunodeficiency (CVID): Diagnosticworkup and therapeutic strategyJulia Horn a, Vojtech Thonb, Dana Bartonkova b,Ulrich Salzer a, Klaus Warnatz a, Michael Schlesier a,Hans-Hartmut Peter a, Bodo Grimbacher a,⁎

a Division of Rheumatology and Clinical Immunology, University Hospital Freiburg,Hugstetterstr. 55, D-79106 Freiburg, Germanyb Division of Clinical Immunology and Allergology, St. Anne University Hospital, Masaryk University, Brno, Czech Republic

Received 1 July 2006; accepted with revision 3 October 2006Available online 28 November 2006

⁎ Corresponding author. Present addlogy, Royal Free Medical School, UniveNW3, UK. Fax: +49 761 270 3531.

E-mail address: grimbacher@medsc

1521-6616/$ – see front matter © 200doi:10.1016/j.clim.2006.10.002

Abstract Common Variable Immunodeficiency (CVID) patients who are seropositive for anti-IgAantibodies have a predisposition for anaphylactoid reactions to intravenous immunoglobulinreplacement therapy (IVIG). Among 88 CVID patients, we identified eight with IgG anti-IgAantibodies (9%). All eight completely lacked IgA (<0.0009 g/l). Five of them had a history ofanaphylactoid reactions to IVIG. However, four of these five patients tolerated subcutaneousimmunoglobulin replacement therapy (SCIG). To identify predisposing factors for anti-IgAantibodies and related anaphylactoid reactions, we analyzed the clinical and immunologicalphenotype of affected patients. All eight IgG anti-IgA-positive patients lacked IgA+ B cells inperipheral blood. Moreover, CVID patients with retained class-switched CD27pos IgMneg IgDneg

memory B cells (Freiburg classification group II) and total IgA deficiency seem to have anincreased risk for developing anti-IgA antibodies. In seven of the eight patients, lymphoproli-feration was observed (most prominently nodular lymphatic hyperplasia), two had granuloma-tous disease, and two showed autoimmune phenomena.© 2006 Elsevier Inc. All rights reserved.

KEYWORDSIgG anti-IgA antibodies;Common VariableImmunodeficiency (CVID);IgA deficiency;IgA+ B cells;Class-switched CD27pos

IgMneg IgDneg memoryB cells;Freiburg CVIDclassification;Intravenousimmunoglobulinreplacement therapy(IVIG);Anaphylactoid reaction;Subcutaneousimmunoglobulinreplacement therapy(SCIG)

ress: Department of Immuno-rsity College London, London

h.ucl.ac.uk (B. Grimbacher).

6 Elsevier Inc. All rights reserved

Introduction

Anti-IgA antibodies occur in up to 40% of patients withselective IgA deficiency and are detected in 10 to 25% ofpatients with Common Variable Immunodeficiency (CVID)

.

157Anti-IgA antibodies in CVID

[1–4]. CVID is the most common symptomatic primaryimmunodeficiency characterized by low serum levels of IgG,IgA and variably IgM. Recurrent infections of the respiratoryand gastrointestinal tracts, autoimmune phenomena (∼20%),lymphoproliferation (∼10%), and granulomatous disease(∼10%) are typical for the clinical presentation of CVID[5,6]. Immunoglobulin G (IgG) replacement therapy repre-sents an effective prophylaxis for infections in most CVIDpatients. However, in any given IgG product, traces of IgA(0.05 to 6.0 mg/dl depending on the product) can be found.Therefore, patients with anti-IgA antibodies are at risk todevelop an anaphylactoid reaction to these IgG formulations,especially upon intravenous administration [7].

We studied the prevalence of IgG anti-IgA antibodies andrelated anaphylactoid reactions following immunoglobulininfusions in 88 patients with CVID because it is not under-stood why some patients with anti-IgA antibodies developanaphylactoid reactions and others do not. Moreover, weaddressed the question of other predisposing factors for IgGanti-IgA antibodies and related anaphylactoid reactions. Wefound that major predictors in our series of affected patientsare (1) the complete absence of serum IgA, and (2) theabsence of IgA-positive B cells, although these correlationsare not absolute. The use of markers of B cell maturation toclassify CVID is prognostically useful. Four of the five patientswith anaphylactoid reactions to IVIG were able to tolerateSCIG. We therefore conclude that CVID patients who haveanti-IgA antibodies may safely be treated with SCIG. Finally,we propose an algorithm for CVID patients with and withoutIgA deficiency in order to avoid anti-IgA-related anaphylac-toid reactions.

Materials and methods

Patients

Between 1991 and 2006, eighty-eight patients were diagnosedwith CVID based on the ESID/PAGID criteria (www.esid.org).Their follow-up corresponds to 481 patient years. The patients'records were studied retrospectively. The anaphylactoid reac-tions in the eight IgG anti-IgA-positive patients occurred bet-ween 1996 and 2004. The medical history of the eight anti-IgAseropositive CVID patients is summarized as case reports(individuals with anaphylactoid reactions to IVIG, #1–5) and inTable 1 (individuals #1–8). Written consent was obtained ac-cording to the ethics committee approved protocol BG239/99.

Immunoglobulin quantification

Immunoglobulins IgG, IgA and IgM in patients sera weremeasured by nephelometry using the BN2 Nephelometer(Dade Behring, Marburg) according to the manufacturer’sinstructions. Serum IgA concentrations below 0.06 g/l couldnot be measured nephelometrically. Sera of anti-IgA-positiveCVID patients were tested for low IgA content by a sensitiveIgA-specific ELISA as described previously [8].

ELISA for IgG anti-IgA antibodies

Micro-titer plates (MaxiSorp, Nunc, Wiesbaden, Germany)were coated with polyclonal highly purified IgA (IgA Calbio-

chem, San Diego, CA) at 4°C overnight. The remaining bindingsites were blocked by 1% bovine serum albumin (Serva,Heidelberg, Germany). At first the screening step for anti-IgAantibodies was performed. Coated plates were incubatedwith the samples and controls diluted 1:100, AlkalinePhosphatase Conjugate Rabbit Anti-Human IgG (DAKO,Glostrup, Germany) was added, and the reaction wassubsequently developed with p-nitro phenyl phosphate(SIGMA, Prague, Czech Republic, 1 g/l) and stopped with1 M sodium hydroxide. The absorbance was measured at405 nm. The specificity of detection of anti-IgA antibodiesfound in previous screenings was confirmed by an inhibitiontest with a mixture of sera with normal level of IgA andwithout anti-IgA antibodies and with a mixture of serawithout IgA and without anti-IgA antibodies. The amount ofanti-IgA antibodies was quantified by titration.

B cell and T cell phenotyping

B cell phenotyping of peripheral blood mononuclear cells(PBMCs) and T cell phenotyping of whole EDTA blood wereperformed as described previously [8]. The B cell phenotypewas determined according to the Freiburg CVID classifica-tion. The Freiburg CVID classification is based on class-switched CD27pos IgMneg IgDneg memory B cells and differ-entiates two major groups (type I and type II). Type I CVIDpatients show reduced class-switched memory B cells, i.e.<0.4% of peripheral blood mononuclear cells (PBMCs). Type IICVID patients show >0.4% of PBMCs [8].

TACI sequencing

Eight anti-IgA-positive CVID patients were sequenced formutations in TACI (TNFRSF13b) as described by Salzer et al.[9].

Statistical analysis

All statistical analysis was done by chi-square contingencytable analysis (χ2). Differences between groups wereconsidered significant at p<0.05. A chi-square value >3.841was considered as significant.

Case reports

The immunological and clinical phenotype of the eightpatients is summarized in Tables 1–3.

Patient #1In a 49-year-old female CVID patient, IVIG replacement(Octagam®, containing <0.1 mg/ml IgA) was initiated, butshe immediately developed acute dyspnea and hypotensionand the infusion was discontinued. Two weeks later, a newtherapeutic attempt with a different IVIG preparation(Sandoglobulin®) containing a maximum of 1.2 mg/ml IgAwas undertaken. Despite premedication with prednisoloneand anti-histamines, the patient developed a generalizedflush and acute dyspnea. The mean arterial pressuredecreased to 30 mm Hg necessitating adrenalin and volumesupport. One month later, Gammavenin® (a pepsin-digestedpreparation with Fab fragments of IgG, IgA, and IgM; without

Table 1 Summary data of patients with anti-IgA antibodies

Patients P#1–5 with anaphylactoid reactions are highlighted in gray.

158J.

Horn

etal.

Table 2 Serum immunoglobulinsa and IgG anti-IgA Titers

Pathological values are printed in bold, patients P#1–5 with anaphylactoid reactions are highlighted in gray.a IgG, IgA, and IgM values before treatment with immunoglobulins.b As determined by nephelometry.c As determined by ELISA.d Before IVIG therapy or at the time of anaphylactoid reaction.e Reassessment after start of SCIG or continuous IVIG therapy at different time points.

159Anti-IgA antibodies in CVID

the constant region (Fc) of Ig) was administered underintensive care conditions. This was carried out to evaluatewhether it is the Fc part of the Ig molecule to which thepatient reacted. Despite the premedication with dexa-methasone and anti-histamines, she reacted again withflushes, pruritus, and cough after a few milliliters. Theadministration of additional dexamethasone preventedcardiovascular instability. The search for anti-IgA antibodiesrevealed an IgG anti-IgA titer of 1:400. Because of persistingrecurrent infections, substitution therapy with subcuta-neous human immunoglobulins was initiated. Interestingly,the patient did not develop an anaphylactoid reaction to theSCIG infusion with Beriglobin® (IgA max 1.7 mg/ml).Reassessment of anti-IgA antibodies 12 months later resultedin undetectable anti-IgA titers.

Patient #2A 33-year-old woman with the diagnosis CVID given at age 29was referred to our outpatient clinic after she haddeveloped an anaphylactoid reaction to IVIG treatment(Intraglobin F®; IgA 2.5 mg/ml) which manifested withgeneral edema, acute despond, hypotension, cyanosis, andunconsciousness. She had recovered quickly followingadrenalin and corticosteroid administration. Analysis for

Table 3 B cell phenotype: IgA+ B cells and CVID classification

Pathological values are printed in bold; patients P#1–5 with anaphylac

anti-IgA antibodies revealed a titer of 1:1600 IgG anti-IgAantibodies. Our therapeutic attempt with a subcutaneous Igproduct (Gammanorm®; IgA max. 0.05%) was successful.Interestingly, even 1 year after initiation of the SCIGreplacement, the IgG anti-IgA titer of 1:1600 was unchangedand the patient still reports mild swelling of the uvula whenadministering the SCIG product.

Patient #3A 36-year-old woman – diagnosed with CVID at the age of29 – reacted to two different IVIG preparations (Endobulin®;IgA max. 0.05 mg/ml; and Pentaglobin®; IgA 6 mg/ml) withacute dyspnea, fever, and chills soon after start of the in-fusion despite premedication with anti-histamines. Duringher initial presentation in our outpatient clinic, 20 g of IVIG(Gamunex®; IgA max 0.084 mg/ml) was administered afterpremedication with prednisolone. At first she developedchest tightness, but when the infusion rate was lowered, shetolerated the application of this IVIG product. There were noside effects observed when she started with SCIG replace-ment therapy (Subcuvia®; IgA max. 1.7 mg/ml) 1 week later.The screening for IgG anti-IgA antibodies revealed a titer of1:400. After 2 months on SCIG, the IgG anti-IgA titer declinedto 1:200.

toid reactions are highlighted in gray. n.t., not tested.

160 J. Horn et al.

Patient #4In a 28-year-old male CVID patient with an asymptomaticinfection of Campylobacter, Salmonella and with Giardialamblia, IVIG therapy was initiated. The first infusion withOctagam® (containing <0.1 mg/ml IgA) resulted in a severeanaphylactoid reaction with a capillary leak syndrome and anacute renal failure and edema of the lung. A few weeks later,he again was treated with 20 g of IVIG (Polyglobin®; IgA0.16 mg/ml) under premedication with corticosteroids andanti-histamines. He showed no adverse events. Since then,the patient is regularly treated with Polyglobin® infusionswithout any side effects. At the time of the initial infusion,he had a very high IgG anti-IgA titer (IgG anti-IgA 1:6400).

Patient #5A 33-year-old female – diagnosed at the age of 14 with CVID–was started on 20 g Octagam® (containing <0.1 mg/ml IgA),but a few minutes after the start of the infusion, shedeveloped an anaphylactoid reaction consisting of anexanthema of the whole integument accompanied by anenanthema and an edema of the upper and lower respiratorytract. Intravenous infusion of prednisolone and antihista-mines resolved the anaphylactoid reaction. Just before thisfirst IVIG infusion, she had a pneumococcal pneumoniatreated by intravenous antibiotics. The analysis for anti-IgAantibodies showed a titer of 1:6400. We introduced SCIGtreatment (Gammanorm®; IgA max 0.05%) which wastolerated without any adverse side effects. One year afterinitiation of the SCIG therapy, the anti-IgA titer was 1:1600.

Results

Prevalence of IgG anti-IgA and relatedanaphylactoid reactions in CVID patients

Eight of 88 CVID patients (9%) carry IgG anti-IgA antibodies asdetermined by ELISA. Five of these eight patients (62.5%)developed anaphylactoid reactions upon IVIG replacement.Thus, the prevalence of anti-IgA-related anaphylactoidreactions accounts for 6% (5/88). In total, 7 out of 88 CVIDpatients developed anaphylactoid reactions upon IVIGreplacement. One out of 88 CVID patients reacted uponintramuscular immunoglobulin replacement therapy (IMIG).

Anti-IgA levels under subcutaneous Ig replacementtherapy

Four of the reported five patients (case reports) weresuccessfully switched to SCIG. SCIG has been reported toinduce reductions in anti-IgA antibody titers due to thebinding of anti-IgA by IgA from the preparation andsubsequent elimination of the complex [7]. However, onlyin one patient (#1), the introduction of SCIG resulted innegative anti-IgA titers. The titer was reduced in twopatients (#3, 5), and the level remained constant in onepatient (#2), after initiation of SCIG.

Immunoglobulin A levels

Anti-IgA antibodies are associated with very low or missingendogenous IgA levels [1,2]. As determined by nephelometry,

all eight patients with IgG anti-IgA antibodies had an IgAserum level below 0.06 g/l (normal values 0.7–4 g/l). Inorder to determine residual IgA production more precisely,we further analyzed the sera by IgA-specific ELISA. With thismost sensitive method, all eight patients exhibited extre-mely low IgA levels below 0.0009 g/l. In comparison, in theIgG anti-IgA-negative cohort, 24 patients (30%) had IgA levelsabove 0.22 g/l, nine patients (11%) between 0.22 g/l and0.06 g/l, and 41 (51%) had IgA levels of less than 0.06 g/l. Sixsamples (8%) with an IgA level <0.22 g/l were not availablefor detailed analysis.

Correlation to the B cell phenotype and theFreiburg CVID classification

All patients with anti-IgA antibodies had high total CD19+ Bcell counts (12.5% to 40.3%; normal values 6 to 15%). Fourpatients had reduced class-switched memory B cells classi-fied as CVID type I, and four patients were type II CVIDpatients with normal numbers of class-switched memory Bcells. Moreover, all eight patients lacked IgA+ memory B cells.In the anti-IgA-negative cohort (n=80), 60 patients were typeI, 13were type II patients, and 15 patients were unclassifiabledue to severely reduced CD19+ B cells. Interestingly, of 41anti-IgA-negative patients with total IgA deficiency (<0.06 g/l),only one patient fell into the Freiburg classification group II,whereas 4/8 patients with total IgA deficiency and anti-IgAantibodies cluster in group II (p<0.001; chi-square of 10.6).We therefore conclude that CVID patients with total IgAdeficiency and lack of IgA+ B cells have a higher risk ofdeveloping anti-IgA antibodies when they are type II patients.

Autoimmunity and lymphoproliferation in patientswith anti-IgA antibodies

Autoimmunity was observed in 25% (n=2) and lymphoproli-feration in 88% (n=7) of IgG anti-IgA-positive patients. Thefrequency of autoimmunity in these patients is similar to theanti-IgA-negative cohort of 80 CVID patients (32%, n=26).However, the frequency of lymphoproliferation is highercompared to the anti-IgA-negative cohort (46%, n=37). Inparticular, nodular lymphoid hyperplasia (NLH) was observedin 5/8 anti-IgA-positive patients. Compared to 10/80 CVIDpatients with NLH from the anti-IgA-negative cohort, wefound the coincidence of NLH and IgG anti-IgA to besignificant (chi-square=4.62; p<0.032).

TACI analysis in patients with anti-IgA antibodies

It has been shown that CVID patients who carry mutations inTACI (TNFRSF13b) are characterized by a high incidence oflymphoproliferation and autoimmune conditions [9,10].Interestingly, two of the eight IgG anti-IgA-positive patientshad the heterozygous mutation at position C104R inTNFRSF13b/TACI, but neither developed an anaphylactoidreaction to IVIG.

Discussion

Since 1968 approximately 40 cases of anti-IgA-relatedanaphylactoid reactions to blood transfusions, immunoglo-

161Anti-IgA antibodies in CVID

bulin replacement therapy and other plasma products havebeen published [11]. Reviewing the literature on CVIDpatients with an IgG anti-IgA-associated anaphylactoidreaction to IVIG, we identified only six cases reportedbetween 1987 and 2006 [2,12–14].

Here, we add five cases of IgG anti-IgA-related anaphy-lactoid reactions to IVIG. These five cases were detected in aCVID cohort of 88 patients, which is the largest CVID cohortever screened for IgG anti-IgA antibodies. In contrast toother studies, all positive IgG anti-IgA titers determined byELISA were confirmed by an inhibition test. Moreover, in ourscreen, IgG anti-IgA antibodies were not found in healthydonors or in CVID patients with IgA levels above 0.06 g/l. Thisfinding disputes the theory that anti-IgA antibodies alsooccur in healthy donors or patients with relatively low levelsof IgA (IgA >0.06 but <7.0 g/l). In these previous studies,anti-IgA antibodies were detected by hemagglutinationtechniques which are less specific than the ELISA appliedhere [15–17].

However, there are many unresolved questions concern-ing anti-IgA antibodies in CVID. What is the exact pathogenicmechanism of IgG anti-IgA-related anaphylactoid reactions?Why do some patientswith anti-IgA antibodies develop severeanaphylactoid reactions to IVIG while others do not? In ourapproach, we analyzed the clinical and immunologicalphenotype of affected patients in order to identify factorspredisposing to anti-IgA-related anaphylactoid reactions.The only previously identified predisposing factor for anti-IgA antibody development is total IgA deficiency below0.05 g/l [1,2]. In our eight anti-IgA-positive patients, weexcluded residual IgA levels as measured by ELISA. Inaddition, we found that all eight patients lacked circulatingIgA+ switched memory B cells. Herbst et al. were the first toshow that CVID patients with IgA deficiency may lack IgA-positive B cells but these patients have not been screened foranti-IgA antibodies [18]. With regard to the cohort of CVIDpatients with IgA levels <0.06 g/l, the lack of IgA+ B cells maybe a prerequisite, but alone is not sufficient for theproduction of anti-IgA antibodies.

An additional interesting finding was the correlationbetween anti-IgA antibodies and NLH. This observationmight be interesting with regard to the fact that IgAproduction by IgA plasma cells occurs in the lymphoid tissueof the intestine. Nodular lymphoid hyperplasia thereforemay be a predisposing factor or pathomorphological corre-late for anti-IgA antibody development.

CVID type II patients with normal numbers of class-switched memory B cells had been shown to produceswitched isotype antibodies such as IgG in vitro in contrastto type I patients with reduced numbers of class-switchedmemory B cells [8]. In our eight patients, four were CVID typeII patients, three of whom had anaphylactoid reactions.Interestingly, only 1 patient out of 41 anti-IgA-negativepatients with IgA levels <0.06 g/l had normal numbers ofclass-switched memory B cells (CVID type II). Thus, it appearsthat IgA-deficient CVID patients are more likely to have anti-IgA antibodies and related anaphylactoid reactions whenthey have retained switched memory B cells (CVID type II).

The search for a genetic marker in CVID patients withanti-IgA antibodies should also be considered in futurestudies. In 1983, Hammarstrom et al. postulated that inselective IgA deficiency anti-IgA antibodies seem to be

correlated with HLA-DR-3 [2]. Sequencing TACI in all eightanti-IgA-positive patients, we found two heterozygote C104Rmutations, neither associated with an anaphylactoid reac-tion. To analyze whether the mutation C104R in TNFRSF13bprotects anti-IgA-positive CVID patients from anaphylactoidreactions, larger cohorts of CVID patients with anti-IgAantibodies would need to be studied.

The therapeutic strategy of Ig replacement in CVIDpatients with anti-IgA antibodies is a critical issue. Firstattempts to overcome anti-IgA antibody mediated anaphy-lactoid reactions were the reduction or depletion of IgA inIVIG preparations [19]. In the 1990s, SCIG therapy becamemore popular in Europe. One large randomized, multicenter,open-label, crossover trial concluded that there are nosignificant differences in mild and moderate adverse reac-tion rates between SCIG and IVIG [20]. Gardulf et al. 1995showed that SCIG is a safe option for patients with previousmild or moderate reactions to IVIG. The same group reportedthat SCIG is also a safe therapeutic option in patients with ahistory of severe or anaphylactoid reactions to IMIG [21].However, Eijkhout et al. in 2003 were the first todemonstrate that IVIG-treated CVID patients with severe oranaphylactoid reactions can be safely treated with SCIG [14].They demonstrated the tolerance of SCIG in four out of eightCVID patients with a history of anaphylactoid reactions, ofwhom only one patient had anti-IgA antibodies. Likewise,seven of our CVID patients, with a previous anaphylactoidreaction to IVIG (four with anti-IgA antibodies), alsotolerated SCIG without side effects. Tolerance induction bySCIG might be explained by the gradual exposure to IgA dueto the slow resorption of the subcutaneous deposit ofimmunoglobulins into the circulation [7].

In conclusion, we would like to propose the followingalgorithm concerning screening for anti-IgA antibodies andchoice of immunoglobulin therapy in order to avoidanaphylactoid reactions: screening for IgG anti-IgA anti-bodies might be helpful only in patients lacking IgA and IgA-positive B cells who intend to use intravenous immunoglo-bulins. In particular, testing for IgG anti-IgA is useful in CVIDtype II patients lacking IgA. On the contrary, if SCIG isplanned, testing for IgG anti-IgA antibodies seems not to berequired.

Acknowledgments

Wewould like to acknowledge the contribution of all patientsfor providing blood samples.

We are indebted to Dr. Christine Scholz, Dr. Jens Thiel, Dr.Carla Rautenberg, Dr. Sigune Goldacker, Prof. Peter Vaith,and all other physicians who were involved in the care of thepatients. We thank Dr. Anne-Marie Eades-Perner for criticalreading of the manuscript.

Grant support: Deutsche ForschungsgemeinschaftSFB620C2; European Union grant #SP23-CT-2005-006411;Ministry of Health, Czech Republic, Grant No. NR9035-4.

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