What is the role of the mucosal response in the pathophysiology of immunoglobulin A deficiency (IgAD)?

Updated: May 15, 2018
  • Author: Marina Y Dolina, MD; Chief Editor: Michael A Kaliner, MD  more...
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The ability of many patients with SIgAD to avoid respiratory infections may relate to compensatory mechanisms at the respiratory mucosal surface and/or compensatory increases in IgG. Nasal lavage samples obtained from patients with SIgAD compared to normal control show 10-fold higher median IgM levels and 3-fold higher median IgG levels. [28] An elevated nasal lavage level of the inflammatory cytokine IL-8 but not eosinophilic cationic protein (ECP) or TNF-α indicates a level of subclinical inflammation in these patients.

Nasal biopsy specimens from patients with SIgAD analyzed by Brandtzaeg et al associated a lower incidence of respiratory tract infections and an elevated ratio of IgM-producing cells to IgD-producing cells in the mucosa. [29] Patients with recurrent acute rhinosinusitis, otitis media, and tonsillitis had a dominance of the IgD over the IgM isotype, leading the investigators to conclude that immunoregulatory events favoring a dominant local IgD response did not support mucosal defense. Rose's data showed a wide range of IgM levels among patients with IgAD patients (0.87-5.2 μg/mL) but did not provide correlative clinical information. [28]

Structural lung disease such as chronic obstructive pulmonary disease (COPD) was previously thought not to associate with the ability to generate antigen-specific IgA. Studies of acute exacerbations of chronic bronchitis show that new mucosal IgA to surface-exposed epitopes of the infecting Moraxella catarrhalis isolate developed in sputum supernatants after 42% of exacerbations, [30] and significant increases in mycoplasmal-specific IgA occurred in 85% of a group of 34 patients hospitalized for acute exacerbations of COPD. In a prospective study of 250 hospitalizations for acute exacerbations of COPD, the geometric mean serum titer for IgG and IgA against Chlamydia pneumoniae was higher, with 33% meeting criteria for chronic infection. [31] In another series from India, serum and sputum IgA levels were higher in subjects with COPD than in control subjects. [32]

Recent studies, however, suggest that the mucosal IgA response is impaired in COPD with deficient transport of IgA across the bronchial epithelium, possibly involving degradation of the Ig receptor involved in transepithelial routing. [33] Like IgA deficiency, COPD/chronic bronchitis is a heterogeneous disorder, and some cases of primary defects in mucosal function (eg, cystic fibrosis) may actually be associated with increased IgA in the secretions.

Observations that SIgAD is associated with an increased prevalence of atopy suggest a possible role for IgA in asthma pathogenesis. A protective role of IgA has been seen in murine models of asthma. [33] It seems likely that in the absence of IgA, mucosal antigen exposure is increased, which may lead to increased IgE against inhalants or food antigens.

A case control study evaluated bronchial hyperresponsiveness in children with SIgAD (n = 20), children with normal IgA levels but sensitized to aeroallergens (n = 70) and children with normal IgA levels and negative skin prick tests (non-atopic) (n = 102). The children with SIgAD had lower forced vital capacity (FVC) but similar forced expiratory volume in 1 second (FEV1) values. Bronchial hyperreactivity was present in 30-35% of the children in the first 2 groups but in only 6% of the control group. The bronchial hyperreactivity among the children with SIgAD correlated with dust mite allergy but not with general atopy. [34]

Patients with partial IgAD can have diseases in which IgA is central to the pathogenesis. For example, a screening project identified 3 cases of partial IgA deficiency in patients with dermatitis herpetiformis, with IgA endomysial and tissue transglutaminase antibodies present in 2 of the patients. The authors conclude that pathogenically directed IgA antibodies were sufficient for cutaneous IgA deposition despite low serum IgA levels. [35]

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