Non-allergic Hypersensitivity Reactions to Immunoglobulin Preparations in Antibody Deficiencies: What Role for Anti-IgA IgG and Complement Activation?

Abstract

The presence of IgG anti-IgA in the serum of primary immunodeficiency (PID) patients has long been considered responsible for hypersensitivity (HS) to immunoglobulin preparations (IgPs), but this link is increasingly being questioned. The aim of this work was to describe the prevalence of IgG anti-IgA and its association with HS, and to explore a new pathophysiological hypothesis involving the complement system. We measured IgG anti-IgA, using a standardised commercial technique, in controls and PID patients, and compared our results to a systematic literature review. We measured complement activation in PID patients before and after IgP infusion, and in vitro after incubation of IgP with serum from controls and PID patients. IgG anti-IgA was detected in 6% (n = 2/32) of PID patients, 30% (n = 3/10) of selective IgA deficiency patients and 2% (n = 1/46) of healthy controls. In the literature and our study, 38 PID patients had IgG anti-IgA and HS to IgPs and 9 had IgG anti-IgA but good tolerance to IgPs. In our patients, we observed a constant complement activation after IgP infusion compared to baseline. In vitro, IgP induced significant complement activation with all sera from tested individuals. IgA immunisation is not rare in PID, higher in selective IgA deficiency, but may also occur in healthy controls. Our results question the clinical relevance and pathophysiological implication of IgG anti-IgA in the context of HS with IgPs. Complement activation-related pseudoallergy could explain the clinical characteristics and natural history of HS symptoms.

Keywords: Anaphylaxis; Anti-IgA IgG; CARPA; Complement; Intravenous immunoglobulins; Primary immunodeficiency.

Fig. 1

Anti-IgA IgG prevalence in primary immunodeficiency patients and in healthy controls. We performed anti-IgA IgG dosage using a fluorescent enzyme immunoassay on CVID and selective IgA deficiency patients managed at our centre and on 46 healthy controls. The prevalence of anti-IgA IgG in our cohort is presented at the top of the graph. We compared our results with those of studies in the literature which used various anti-IgA IgG assessment methods, and various positivity thresholds. Minimum and maximum prevalence for each group found in the literature are presented at the bottom of the graph. CVID, common variable immunodeficiency; FEIA, fluorescent enzyme immunoassay

Fig. 2

Association between IgP-HS and anti-IgA IgG presence. We studied all the patients who were tested for anti-IgA IgG in our laboratory and systematically collected the presence of IgP-HS in the medical records for each patient. We also performed a literature review about anti-IgA Ab and IgP-HS in the Pubmed electronic database. We report here the number or percentage of patients with (1) IgP-HS without anti-IgA IgG (left), (2) with IgP-HS and anti-IgA IgG (middle), and (3) with anti-IgA IgG without IgP-HS (right). FEIA, fluorescent enzyme immunoassay; IgP-HS, hypersensitivity to immunoglobulin preparations

Fig. 3

In vitro complement activation tests. Serum samples of healthy controls, anti-IgA-negative and -positive PID patients, and PID patients with or without IgP-HS were incubated with a negative control (PBS) or with an IgP (Clairyg®) for 30 min at 37 °C. The complement split product sC5b9 was dosed to assess the activation of the complement pathway, in healthy controls (A) and in PID patients (B). A paired Wilcoxon test was used to compare sC5b9 levels after incubation with PBS and with IgP. The increase in sC5b9 levels was assessed after incubation with IgP compared to PBS, according to the presence or absence of a history of HS (C) or according to presence or absence of anti-IgA IgG (D). Results are presented as fold changes between IgP and PBS experiments (individual values and their median). Mann–Whitney test was used to compare these fold changes in both comparisons, with a significance threshold at 0.05. IgP-HS, hypersensitivity to immunoglobulin preparations; PID, primary immunodeficiency. *p ≤ 0.05; **p ≤ 0.01

Fig. 4

In vivo complement assessment before and after IgP infusion. Plasma samples were collected from 11 PID patients just before and just after an IgIV infusion. Eight patients had no adverse effect (black dots) and three had signs of IgP-HS (mild HS symptoms, orange dots; moderate HS symptoms, red dots). Complement activation was assessed by dosing CH50, C3, C4 and the complement split products sC5b9 and Bb. Individual values before and after the IgP infusion were compared using a paired t test. IgP-HS, hypersensitivity to immunoglobulin preparations