A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

Abstract

Inflammatory lung diseases represent a persistent burden for patients and the global healthcare system. The combination of high morbidity, (partially) high mortality and limited innovations in the last decades, have resulted in a great demand for new therapeutics. Are therapeutic IgA antibodies possibly a new hope in the treatment of inflammatory lung diseases? Current research increasingly unravels the elementary functions of IgA as protector against infections and as modulator of overwhelming inflammation. With a focus on IgA, this review describes the pathological alterations in mucosal immunity and how they contribute to chronic inflammation in the most common inflammatory lung diseases. The current knowledge of IgA functions in the circulation, and particularly in the respiratory mucosa, are summarized. The interplay between neutrophils and IgA seems to be key in control of inflammation. In addition, the hurdles and benefits of therapeutic IgA antibodies, as well as the currently known clinically used IgA preparations are described. The data highlighted here, together with upcoming research strategies aiming at circumventing the current pitfalls in IgA research may pave the way for this promising antibody class in the application of inflammatory lung diseases.

Keywords: IgA; SIgA; immunoglobulin preparation; immunomodulation; inflammation; mucosal immunity; neutrophils; respiratory disease.

Figure 1

Functions of SIgA in lung infection and inflammation. During infection, SIgA induces potent anti-pathogenic effects (left): (A) SIgA can efficiently agglutinate bacteria and virus, (B) neutralize pathogenic toxins and enzymes and (C) activate FcαRI dependent inflammatory effector functions on immune effector cells. These include ROS generation, degranulation or the release of inflammatory cytokines. Furthermore, SIgA-FcαRI cross-linking on neutrophils mediates the release of LTB4, which leads to recruitment of neutrophils to the lung. On the other hand, SIgA can induce various immunomodulatory effects during lung inflammation (right): Binding of SIgA to FcαRI on immune effector cells can reduce the release of ROS and inflammatory cytokines. SC alone can reduce inflammatory cytokines (D). In case of allergic inflammation, SIgA can prevent binding of allergens to the mucosa and reduces FcεRI dependent degranulation of mast cells via FcαRI binding (E). SIgA can also interact via DC-SIGN with dendritic cells, thereby modulating inflammatory cytokine release and T-cell responses (F). SIgA, Secretory Immunoglobulin A; FcαRI, Fc alpha-receptor I; ROS, Reactive oxygen species; LTB4, leukotriene B4; SC, secretory component; IgE, Immunoglobulin E; FcεRI, Fc epsilon-receptor I; DC-SIGN, Dendritic cell-specific ICAM-3-grabbing non integrin; DC, Dendritic cell; Th17, T-helper 17 cell; FOXP3, Forkhead-Box-Protein P3; RORγt, RAR-related orphan receptor gamma-t; Treg, T-regulatory cell.