Immunoglobulin G (IgG) isolated from pooled human serum has been used clinically to treat many autoimmune neuropathies such as Guillain–Barré syndrome. However, the mechanism underlying the observed benefits from intravenous IgG treatment is unclear. Many immunomodulating mechanisms for IgG have been proposed, and the exact one could potentially be a combination of many mechanisms. IgG preparations have been demonstrated to contain agonist anti-Fas antibodies, which induce monocyte and lymphocyte apoptosis via a caspase-dependent pathway [
18]. IgG preparations also contain autoantibodies toward the sialic acid-binding immunoglobulin-like lectin-9 that can induce neutrophil apoptosis via caspase-dependent pathways and pathways dependent on ROS [
19]. In addition, IgG has been demonstrated to inhibit the production of MMP-9 in cultured macrophages via its Fc and F(ab´)
2 fragments [
20]. IgG also has been demonstrated to bind neutrophil chemotactic factors C3a and C5a at low affinity via the constant region of the F(ab´)
2 fragment [
21]. C5a is a potent chemotactic factor for neutrophil and macrophage recruitment and activation [
22]. Recently, it has been suggested that the IgG immunomodulating mechanism is achieved through the regulation of the expression levels of Fcγ receptors FcγRIIIA and FcγRIIB. [
23] These receptors have low affinity for the Fc domain of the IgG molecules, and they are coexpressed on the surface of neutrophils, macrophages, mast cells, B-lymphocytes, and natural killer cells (for a detailed review, see [
23]). These Fcγ receptors work antagonistically to maintain a constant balance between stimulatory and inhibitory signals in the immune system. The upregulation of the activating FcγRIIIA receptor has been linked to immune-complex diseases and autoimmune disorders, including Arthus reaction, rheumatoid arthritis, glomerulonephritis, systemic lupus erythematosus, and immune thrombocytopenic purpura [
23]. Specifically, the sialylated
N-linked glycan on the Fc fragment of IgG is required for the Fc fragment to bind to the SIGN-R1 (mice)/DC-SIGN (human) receptor on regulatory macrophages, which then upregulate the expression of immune inhibitory FcγRIIB receptors on effector macrophages [
24]. The sialic acid residue is part of a glycan, which is linked to the Fc fragment at the asparagine at position 297.