Abstract
In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of human serum IgA especially on neutrophil function were unraveled. Therefore, the aim of our work is to investigate functional aspects of the trimodulin IgA component, a new plasma-derived polyvalent immunoglobulin preparation containing ~56% IgG, ~23% IgM and ~21% IgA. The functional role of IgA was investigated by analyzing the interaction of IgA with FcαRI, comparing trimodulin with standard intravenous IgG (IVIG) preparation and investigating Fc receptor (FcR)-dependent functions by excluding IgM-mediated effects. Trimodulin demonstrated potent immunomodulatory, as well as anti-pathogenic effects in our neutrophil model (neutrophil-like HL-60 cells). The IgA component of trimodulin was shown to induce a strong FcαRI-dependent inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) signaling, counteract lipopolysaccharide-induced inflammation and mediate phagocytosis of Staphylococcus aureus. The fine-tuned balance between immunomodulatory and anti-pathogenic effects of trimodulin were shown to be dose-dependent. Summarized, our data demonstrate the functional role of IgA in trimodulin, highlighting the importance of this immunoglobulin class in immunoglobulin therapy.
Highlights
In humans, immunoglobulin A (IgA) is produced in higher amounts than all other immunoglobulin isotypes together
We tested the functional role of IgA and trimodulin in the context of several antibody functions: (1) facilitation of immune homeostasis, (2) immunomodulation, (3) anti-pathogenic effects and (4) immunoglobulin concentration as a critical parameter for the balance between these effector functions
We want to unravel the functional role of IgA in trimodulin
Summary
Immunoglobulin A (IgA) is produced in higher amounts than all other immunoglobulin isotypes together. IgA is the most abundant antibody on mucosa (~74%). The second most abundant in serum (15%) [1,2,3,4]. A large heterogeneity of IgA is observed: besides the monomeric form with two subclasses (IgA1 and IgA2), dimers and higher-order multimers (mainly tetramers), secretory forms and different glycoforms are known [2,4,5,6]. As known for IgM, multimeric IgA species have an enhanced avidity, increased antigen binding and effector functions [7,8]. In vitro data demonstrate a 15-fold stronger capacity of IgA dimers in neutralizing SARS-CoV-2 compared to monomeric IgA [9]
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