Interleukin 5 is produced by TH2 cells, mast cells, CD34+ progenitor cells, invariant NK cells, type 2 innate lymphoid cells (ILC2), eosinophils or endothelial cells and, together with IL-4, IL-9, IL-13 and IL-21, is part of the type 2 immune response, which protects against helminths (endoparasitic worms), neutralizes toxins or regulates wound healing and tissue regeneration after infection or injury. Structurally, however, IL-5 is grouped together with IL-3 and GM-CSF in the beta common (βc) family, as their receptors all contain the β common chain. The IL-5 receptor pairs with the IL-5Rα subunit and is expressed by eosinophils, basophils and some B cells. However, the biologically active form of IL-5 – an intertwined homodimer of 30kDa – first binds the IL5Rα subunit, forming a binary complex before the βc subunit is recruited and formed into an active signaling complex.
Signaling by this complex induces eosinophil differentiation in the bone marrow via JAK2/STAT5 and Ras-MAP kinase pathway, as well as their recruitment and activation to peripheral inflammatory sites. On the other hand, IL-5 induces the terminal differentiation of B cells via Btk activation and increases their synthesis and secretion of immunoglobulins.
Dysregulation of the cytokine response can lead to a wide variety of diseases. In the context of IL-5, these are primarily eosinophil-dependent diseases, as IL-5 acts as their growth and survival factor, as already mentioned. This has also been described in research with transgenic mice. The loss of IL-5 signaling led to deficits in the development and function of eosinophils and also B cells, while the overproduction of IL-5 led to an increase in B-1 cells with additionally increased serum antibody levels, as well as an increase in the number of eosinophils in the blood and their infiltration into various tissues. In humans, eosinophilia can have a wide variety of causes. It can arise, for example, through clonal expansion as a result of a mutation in the hematopoietic stem cell. Polyclonal expansion in secondary (reactive) eosinophilia, on the other hand, can result from IL-5 overproduction (usually by TH2 cells or ILC2) and is involved in a wide variety of diseases such as eosinophilic asthma, organ-specific diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), or in immunodeficiencies such as Omenn’s syndrome. Overstimulation of the eosinophils is harmful to the body in the long term due to the toxins contained in the granules of the eosinophils.
Anti-drug antibodies such as mepolizumab, reslizumab (monoclonal antibody against IL-5) or benralizumab (monoclonal antibody against IL-5Rα) attempt to counteract pathological expansion and are already used in eosinophilic asthma or EGPA.
The determination of eosinophilopoietic cytokines such as IL-5, but also IL-3 and GM-CSF in serum can be helpful for the diagnosis of reactive eosinophilia.