Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases for almost 40 years. Numerous cells are involved in the innate immune response, such as monocytes/macrophages, neutrophils, dendritic cells (DC), mast cells, basophils, eosinophils, natural killer (NK) cells, and innate lymphoid cells (ILCs). Many studies have examined the mechanisms by which IVIg down-modulates inflammation and autoimmune processes of innate immune cells. Questions still remain regarding the mechanism of action in autoimmune or inflammatory conditions. In this work, the aim was to review the immunomodulatory effect of IVIg on human innate immune cells. A narrative review approach was chosen to summarize key evidence on the immunomodulatory effects of commercially available and unmodified IVIg on humane innate immune cells. Computerized bibliographic searches of PUBMED was supplemented with a manual search of reference lists. Only English-language studies were included. 559 articles were identified in PubMed. Finally, there were 65 articles included for the current review. Four Studies were duplicated because they examined different immune cell lineages and are each listed separately with the cell lineage in question.

Thus, studies based only on animal models were not included. One study for mast cells, two for basophils, one for eosinophils, thirteen for neutrophils, eighteen for NK cells, seventeen for monocytes/macrophages, fifteen for DC and one for ILCs were included in this review. Numerous different immunomodulatory effects of IVIg were reported, with sometimes very distinct effects depending on the immune cell type and the disease. Several limitations of the different studies have been identified. Of the 64 studies reviewed, 35 (53.8%) dealt with auto- or inflammatory diseases. Otherwise, the immunomodulatory effects of IVIg have been studied only in healthy donors using an in vitro experimental approach. Some of the documented effects showed a disease-specific effects as seen in Kawasaki disease. Different methodological limitations were also discovered, which may reduce the validity of some studies. As further insights have been gained into the various inflammatory cascades activated in immunological diseases, interesting insights have also been gained into the mechanism of action of IVIg. We are still far from having discovered all the immunomodulatory mechanisms of IVIg.