Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)

Abstract

SIgAD, using 0.05 g/l of serum IgA as the upper limit for diagnosis in adults and a concomitant lack of secretory IgA, is the most common form of primary immunodeficiency (PID) in the western world and affects approximately 1/600 individuals [1]. However, there is a marked variability in the prevalence in different ethnic groups [2], with a lower frequency in Japanese (1/18 000) and Chinese (1/4000), suggesting a genetic basis for the disorder. The term ‘selective IgAD’ should be reserved for those individuals who do not have identifiable disorders which are known to be associated with low IgA levels (see below). However, in many cases a simultaneous change in the IgG subclass pattern is seen with a lack of specific anti-polysaccharide antibodies of the IgG2 subclass [3] or a total lack of serum IgG2 [4], IgG4 and IgE [5], reflecting a relative or absolute block in switching to genes downstream of the G1. CVID affects about 1/25 000 Caucasians, the patients having a marked reduction in serum levels of both IgG (usually < 3 g/l) and IgA (< 0.05 g/l); IgM is also reduced in about half the patients (< 0.3 g/l) [1]. Symptoms of recurring infection can start at any time of life, but there are peaks of onset during 1–5 and 16–20 years of age [6], with equal distribution between the sexes. The condition is clinically more complex than X-linked agammaglobulinaemia (XLA), with patients being prone to chronic inflammatory and autoimmune complications [6, 7]. Familial inheritance of either SIgAD or CVID occurs in about 20% of cases (Fig. 1). A different population prevalence in various ethnic groups, strong familial clustering of the disorder, a predominant inheritance pattern in multiple-case families compatible with autosomal dominant transmission, and a high relative risk for siblings suggest the involvement of thus far unidentified genetic factors in the pathogenesis of IgAD/CVID [8, 9]. In multiple-case families with a dominant transmission of CVID/IgAD, CVID was usually present in the parents accompanied by IgAD in descendants [9]. This is consistent with the hypothesis that CVID may develop later in life as a more severe manifestation of a common, complex genetic defect, most likely involving immunoglobulin class switching. This is supported by a description of a gradual decline of IgG levels that progressed at similar ages in affected siblings [10]. Furthermore, CVID may develop from IgAD [11–13] and occasionally vice versa [14]. In both diseases anti-IgA antibodies have been detected. Since the disease phenotype is persistent and the phenocopy rate is low, chromosome susceptibility loci underlying this complex trait should be detectable by genetic linkage analysis. The recurrence risk of IgAD was found to depend on the gender of parents transmitting the defect: affected mothers are more likely to pass the defect on to their offspring than affected fathers. This was accompanied by a preferential transmission of associated alleles in the MHC, suggesting a role for this region in the parent-of-origin penetrance differences [9]. The role of the MHC is further supported by a higher prevalence of anti-IgA antibodies among females transmitting the disease to their offspring than in female non-transmitters. Fig. 1. Three pedigrees are shown demonstrating the inheritance patterns for IgAD and CVID. Note that in some families there are relatives with minor IgG abnormalities. Our recent study involving a large number of multiple-case families supported the presence of a predisposing locus in the class II or class III region [ 9]. A significant increase in sharing of MHC alleles in affected members of our family dataset was consistent with previous allelic associations observed in case control studies, which appear to be much stronger for IgAD than CVID. It is possible that the gene(s) involved predispose to the production of IgA antibodies. A number of abnormalities in the cytokine network have been observed in SIgAD and CVID; however, attempts to find a defect in candidate cytokine genes have so far failed, including the available coding region of the cytokine genes in the MHC, such as lymphotoxin α and β (Vorechovsky et al., unpublished). Using the same family material, we were unable to confirm a susceptibility locus on chromosome 18, despite a number of anecdotal reports of patients with gross defects in the 18p region and SIgAD [ 15]. The finding of immunoglobulin deficiency in only one of two monozygotic twins suggests an environmental, possibly infectious agent as a triggering factor, but longer follow up of these twins is needed [16]. In SIgAD the defect is manifested at the stem cell level, since a bone marrow transplant from an IgA-deficient donor transfers the defect to the recipient [ 17], whereas bone marrow from a normal individual transplanted into an SIgAD patient will correct the defect [18]. The genes for α1 and α2 can readily be demonstrated in the genome of IgAD patients [19] and these ‘silent’ genes