The Very Low IgE Producer: Allergology, Genetics, Immunodeficiencies, and Oncology

Abstract

Opposite to other immunoglobulin (Ig) classes and subclasses, there is no consensus on the definition of normal levels of serum total IgE. However, longitudinal studies on birth cohorts produced growth charts of total IgE levels in helminth-free and never atopic children and defining the normal ranges of total serum IgE concentration at the individual, rather than population, level. Accordingly, very ‘low IgE producers’ (i.e., children whose tIgE level belong to the lowest percentiles) became atopic while keeping their total IgE levels in a range considered ‘normal’ if compared to the general age-matched population but ‘abnormally high’ if projected on the tIgE growth chart against the trajectory of that child’s own percentile levels. In ‘low IgE producers’, the IgE-specific activity, i.e., the ratio between allergen-specific and total IgE, is more important than the absolute specific IgE levels to confirm causality between allergen exposure and allergic symptoms. Patients with allergic rhinitis or peanut anaphylaxis but low or undetectable allergen-specific IgE levels must therefore be reconsidered considering their total IgE levels. Low IgE producers have been also associated with common variable immunodeficiency, lung diseases, and malignancies. A few epidemiological studies have shown a higher risk of malignancies in very low IgE producers, leading to a debated hypothesis proposing a novel, evolutionistic-relevant function for IgE antibodies for antitumor immune surveillance.

Various clinical manifestations of 223 patients with IgE deficiency in a tertiary hospital in China: A cross-sectional study

“…[ 7 ] However, the prevalence of ultra-low IgE had rarely been reported in Asian countries, and the real prevalence of ultra-low IgE is unclear. [ 13 ] Our study showed that the prevalence of ultra-low IgE is 0.35% in a single university hospital. And the resident population of Wenzhou in China was 9.645 million in 2021 which equal to a European country.…”

A Food Matrix Triggers a Similar Allergic Immune Response in BALB/c Mice Sensitized with Native, Denatured, and Digested Ovalbumin

“…However, individuals with very low allergen-specific IgE levels can trigger IgE-mediated allergic manifestations [ 24 , 25 ]. These individuals have been categorized as IgE responders with high specific activity [ 26 ]. Therefore, it has been suggested that the specific activity of IgE be assessed before we rule out a case of allergy rather than relying solely on the serum levels of IgE [ 26 , 27 ].…”

Reply to comment on: Unexpectedly high prevalence of primary immune deficiency in fibromyalgia: serologic features and clinical correlates

“…Recent studies have suggested a role for the distal ileum, an area of the gut protected by IgA, particularly IgA subclass 1, and IgG subclass 1, in the generation of several autoimmune diseases (reviewed in greater detail in our paper's Discussion section (2)) and our data demonstrated a positive correlation be-tween serum total IgA, IgA subclass 1, and IgG subclass 1 vis-a-vis epidermal nerve fiber density (ENFD), an important peripheral marker recently described in FM (6). Additionally, IgE deficiency (we defined this as < 7 IU / ml) may be used as a clue to the presence of PID, as it often accompanies that condition (11,12). Inan et al are mistaken when they dismiss mannose binding lectin (MBL) deficiency as irrelevant to our FM cohort evaluation because it is seen in "up to 5%" of the general population.…”