Serologic IL-18 increase with B-cell IL-18R loss characterizes selective IgA deficiency.

INTRODUCTION: Selective IgA deficiency (sIgAD) is the most common primary antibody deficiency in Western populations and is associated with increased risks of respiratory infections, atopy, and autoimmunity. However, the serologic and B-cell-intrinsic pathways underlying this immune dysregulation remain poorly defined. We sought to characterize a population-based adult sIgAD cohort clinically and immunologically and to identify soluble and transcriptional signatures that link cytokine milieu to B-cell dysfunction.

METHODS: We studied 61 adults with sIgAD and 73 age- and sex-matched healthy controls from the Icelandic sIgAD cohort. Participants completed standardized questionnaires on infections, atopy, and autoimmune disease. Serum immunoglobulins and autoantibodies (ANA, ENA, RF, CCP) were quantified, and a 65-plex Luminex cytokine/chemokine panel was measured in a subset of sIgAD individuals without active inflammatory disease and healthy controls. Purified CD19⁺ B cells from adults with sIgAD and controls were profiled by bulk RNA-seq at baseline and after 48 h TLR9 stimulation with CpG ODN 2006. Unsupervised analyses, differential expression, and correlation networks integrated clinical, serologic, and transcriptional data.

RESULTS: Clinically, adults with sIgAD had an airway-predominant infectious burden (notably increased sinusitis and pneumonia), a skin-skewed atopic pattern (eczema and urticaria), and frequent ANA/ENA positivity despite normal IgG and IgM. Immunoglobulin measurements showed very low IgA, increased total IgG and IgG1, and selectively reduced IgG4. Serum profiling revealed a coherent five-analyte signature, IL-18, sCD40L, TSLP, CCL3, and TWEAK, elevated in sIgAD and associated with higher IgG, lower residual IgA, and ANA/ENA positivity. This pattern was not reproduced in CpG-stimulated B-cell supernatants, indicating a non-B-cell origin. RNA-seq of purified B cells demonstrated diagnosis-dependent transcriptional programs at baseline and after CpG, with prominently reduced expression of IL-18 receptor components in sIgAD B cells.

DISCUSSION: Adult sIgAD is characterized by a blood-measurable endotype in which a systemic IL-18-centered soluble signature coexists with reduced IL-18 receptor expression and altered signaling programs in B cells. This IL-18-IL-18R axis aligns with ANA/ENA-associated immune dysregulation and an IgG-skewed class-switch profile, nominating IL-18-related mediators and B-cell IL-18R expression as candidate biomarkers and mechanistic targets in a subset of adults with sIgAD.