Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age.
SIgAD is the most common primary immunodeficiency disease with an estimated incidence varying in Caucasians from 1:3000 to 1:150, depending on the study population. It is defined when IgA serum level is equal to or below 7 mg/dL with normal IgG and IgM levels, in patients older than 4 years of age with an otherwise normal immune system. When serum IgA level is more than 7 mg/dL, but <2 standard deviations (SD) for age, it is defined as partial or probable IgA deficiency.
Here, through this narrative review, we aim to examine and update readers on this important association between SIgAD and atopic disease.
Structure of Immunoglobulin A (IgA)
Understanding IgA
IgA is a class of immunoglobulins characterized by the presence of an alpha heavy chain. In humans, there are two subclasses of IgA-IgA1 and IgA2-that differ in the structure of the hinge region and in the number of the glycosylation sites. IgA1 is the predominant subclass in the serum, accounting for as much as 90%, while in mucosal tissue both subclasses are equally distributed.
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In humans, IgA present as monomeric, prevalent in the serum, and polymeric, found in secretions such as breast milk, sputum and bronchial and gastrointestinal fluids. Polymers of secretory IgA, mainly dimers, are covalently linked by a J-linking chain and secreted into the mucosal surface with their secretory complement, which protects them from the proteolysis of bacteria in the intestinal lumen.
As for all the Ig classes, IgA are produced by B lymphocytes that have differentiated into plasma cells. In mucosal areas such as the gastrointestinal, genitourinary and respiratory tracts, IgA is the most abundant antibody class, playing a key role in keeping a tight balance by tolerating commensals and harmless (as food) antigens on the one hand and providing protection against harmful pathogens on the other hand. Mucosal IgA protects the host by diversifying the microbiota and neutralizing toxins and viruses without causing inflammation, by the inability of activating the complement cascade. Moreover, it blocks colonization and penetration of pathogenic bacteria by binding with receptors on the fimbriae, clearing unwanted particles and promoting sampling of antigens.
In serum, IgA is the second most predominant antibody class after IgG. In contrast to mucosal IgA, the roles of serum IgA are relatively unknown. By binding the FcRα receptor on the phagocyte’s membrane, serum IgA allows the phagocytosis of the IgA-antigen immune complex.
Schematic function of IgA.
Diagnosis and Incidence of SIgAD
As stated by the European Society for Immunodeficiencies (ESID), the criteria for the definitive diagnosis of SIgAD include patients greater than 4 years of age who have serum IgA levels of less than 7 mg/dL (0.07 g/L) but normal serum IgG and IgM (also defined as isolated IgA deficiency), where other causes of hypogammaglobulinemia have been excluded, and there is normal IgG antibody response to vaccination. The diagnosis is “probable” when the serum IgA levels are at least 2 SD below normal for age with the same other criteria as for the definitive diagnosis.
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The incidence of SIgAD presents considerable variability when comparing different ethnic groups. In the Caucasian population SIgAD is the most common primitive humoral immunodeficiency with an incidence varying from 1:150 to 1:3000, while in Asian populations its incidence is significantly lower (1:4000 in China and up to 1:18,000 in Japan). However, since many patients affected by SIgAD are asymptomatic, and due to the lack of screening programs for immunodeficiency, the real incidence of SIgAD can be highly underestimated.
Pathogenesis of SIgAD
Although SIgAD is rather common, the underlying pathogenetic mechanism remains largely unexplored. SIgAD is a heterogeneous disorder with the underlying pathogenetic mechanism remaining largely unexplored. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. Intrinsic defects in the class switch recombination (CSR) mechanism and in the maturation of B cells have been reported, with decreased levels of peripheral class-switched memory B cells who cannot differentiate into IgA-secreting plasma cells.
IgA CSR occurs by engagement of different receptors, transcription factors and cytokines such as the toll-like receptor, B cell receptor (BCR), nitric oxide (NO), retinoic acid (RA), IL-6, TACI, BAFF, A proliferation-inducing ligand (APRIL) and thymic stromal lymphopoietin. In addition to intrinsic maturation defects of B lymphocytes, dysfunction of T helper (th) and regulatory T lymphocytes (T regs) has also been observed in SIgAD. Indeed, defective antibody production may be related to a decreased or compromised T helper activity as evidenced by a recent study where adult and pediatric patients had reduced Th1 and Th17 cells compared to controls. Moreover, T regs expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis, including the regulation of humoral immunity. Among them, T-follicular regulatory cells (Tfr), a specialized subset of T regs, help in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. A decreased number of T regs could contribute to pathogenesis of SIgAD.
The genetic basis of IgA deficiency remains to be clarified. SIgAD generally occurs sporadically, but autosomal recessive, autosomal dominant and sporadic transmission patterns have all been observed. Among identified genetic defects, mutations in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI, TNFRSF13B) have been reported in 7-10% of Common Variable Immunodeficiency (CVID) patients and 13% of SIgAD carried at least one mutated TNFRSF13B allele. TACI, a B-cell surface ligand for BAFF and APRIL, has a role in B-cell function, development and tolerance. The same TACI mutation may be present in individuals with either IgA deficiency or CVID in the same family. However, it is controversial whether TACI mutations have a cause-effect relationship with IgA deficiency or CVID.
With regard to MHC associations, a predisposing locus was found on chromosome 6 in the MHC region of classes II and III and the DR/DQ locus was reported as the most involved in the genetic predisposition to the disease. The set of these findings could be at the basis of both ethnic differences and the association with autoimmune diseases (frequently found in patients with SIgAD). Indeed, some studies have shown that subjects with autoimmune diseases have a higher frequency of HLA B8. In line with this, SIgAD patients with autoimmune disorders (B lymphocytes or T reg lymphocytes) and severe infections (also linked to IgG subclass deficiency or specific antibody deficiency) are at a higher risk of developing CVID.
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In 2010 an association was found between SIgAD and an amino acid variant of the IFIH1 gene, associated with diabetes mellitus 1 (DM1) and systemic lupus erythematosus (SLE), supporting the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of SIgAD.
Clinical Manifestations of SIgAD
Patients with SIgAD clinically range from asymptomatic patients, who are diagnosed coincidentally during a laboratory screening, to symptomatic patients with heterogeneous clinical phenotypes and severity of the disease: recurrent infections, mainly of the respiratory and gastrointestinal tract, are the most common finding. Allergy is a quite common clinical complication affecting more than 30% of patients. Finally, autoimmune diseases are associated with SIgAD in up to 20% of subjects.
This heterogeneity in clinical symptoms may be related to the different combination of etiological agents. The lack of serious infection in some patients may in some cases be due to a compensatory increase in secretory IgM. The clinical course of the disease is generally favorable in most patients, being influenced by the clinical manifestation. The most frequent and relevant clinical manifestations are recurrent infections, especially those affecting the respiratory system and the gastrointestinal tract.
Infections in adults occur more frequently as rhinosinusitis or lung infections while otitis media is less common, whereas in children the main infections are pharyngotonsillitis, otitis, bronchitis, sinusitis and, less frequently, pneumonia. Impaired antibody response to vaccinations are considered exclusion criteria for SIgAD. Recurrent infections of the intestinal tract are also common due to alteration of the protective IgA-mucosal barrier of the gastro-intestinal tract, which facilitates the adhesion of pathogens to the epithelium leading to proliferation and establishment of the parasitosis, mainly Giardia Lamblia.
IgA deficient patients are also more susceptible to non-infective gastrointestinal diseases such as lactose intolerance, celiac disease, inflammatory bowel disease, nodular lymphoid hyperplasia and tumors. Malabsorption can also occur, usually secondary to the structural damage of the intestinal villi or the onset of celiac disease. In some patients the presence of anti-IgA antibodies that can cause anaphylactic reactions in those receiving blood product transfusions has also been found.
Patients with IgA deficiency have been reported to be at higher risk for malignancies, especially gastric and colon adenocarcinoma and lymphoproliferative diseases. However, recent studies do not confirm the data between SIgAD and malignancy, making the association still not conclusive.
SIgAD and Allergy: A Closer Look
Allergy is a hypersensitivity reaction of the immune system to a specific allergen and can be considered a deregulated form of immunity. It is widely accepted that SIgAD is associated with allergy and various atopic manifestations including allergic rhino-conjunctivitis, asthma, urticaria, food allergy and atopic dermatitis (AD).
However, there is still controversy on the true prevalence of allergy and its manifestations in SIgAD, arguing whether it can be considered a comorbidity or a consequence of the disease. Moreover, the hypothesis of a higher risk for allergy in SIgAD patients in comparison to the general population is difficult to demonstrate due to the high prevalence of both these clinical conditions. Studies analyzing allergy on SIgAD patients showed prevalence ranging from 13 to 84% (Table 1), supporting in most of the cases the relationship between SIgAD and allergic diseases.
In an earlier study, Buckley et al. reported the frequency of atopy in children and adults with SIgAD accounting for 58%. In more recent studies, allergic manifestations were recorded in 43.2% of 118 Turkish children with SIgAD. It is worth mentioning that in many cases allergy is the first symptom of SIgAD, and, in some cases, it is the only symptom of disease. Indeed, it is also reported that up to 25% of SIgAD patients are diagnosed during an allergology clinical assessment.
The association between SIgAD and allergy was found for various allergic manifestations, the most commonly described of which are asthma, allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis and food allergy, even if the exact prevalence of each symptom and of one clinical manifestation or another varies among the studies reported. Among the most recent studies with a larger sample, on 39 over 103 pediatric patients Moschese et al. found allergic rhinitis in 18.45%, atopic dermatitis in 12.6% and allergic asthma in 10,67%. In the study of Erkoçoğlu et al. involving 81 pediatric patients, 45.7% had an allergic disorder of whom 34.6% had asthma, 27.2% had allergic rhinitis and 11.1% had eczema. Similarly, in the study of Živković et al. there was a higher prevalence of allergic diseases, specifically allergic rhinitis (59%), asthma (57,9%) and atopic dermatitis (15,8%) in children with low IgA compared to controls.
With respect to the type of sensitization to skin prick test (SPT), only two studies were found reporting the type of allergen involved in the allergic manifestations of patients with SIgAD. Moreover, in one of them the specific type of symptoms that relate to the SPT positivity are not even defined. It is known that the prevalence of a specific allergen varies among countries, however, in both studies, Dermatophagoides was the main allergen identified.
Mechanisms of Allergic Reactions
Type I hypersensitivity (IgE-mediated hypersensitivity) - causes, symptoms, pathology
| Study | Number of Patients | Prevalence of Allergy |
|---|---|---|
| Buckley et al. | Not specified | 58% |
| Turkish Children Study | 118 | 43.2% |
| Moschese et al. | 103 | 39% with various allergic manifestations |
| Erkoçoğlu et al. | 81 | 45.7% with allergic disorder |
| Živković et al. | Not specified | Higher prevalence compared to controls |
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