**5. Physiopathology**

In recent years, considerable progress has been made in understanding the physiopathology of IgAN. The multi-hits hypothesis is now recognized [66]. The first hit comprises the increased level of circulating galactose-deficient (Gd)-IgA1, influenced by

both environmental and genetic factors. Second, antibodies (IgA or IgG) recognizing Gd-IgA1 are produced or already present, possibly attributable to molecular mimicry. The formation of Gd-IgA1-containing immune complexes is thirdly mediated by complement factors and IgA receptors as the soluble IgA Fc alpha receptor (FcαR/sCD89), transglutaminase2 (TG2) and transferrin receptor (TfR/CD71) and fourth, Gd-IgA1 containing immune complexes deposit in the mesangium, hereby inducing a proliferation of mesangial cells and an overproduction of extracellular matrix components, cytokines (Interleukins, tumor necrosis factor-alfa (TNF-α), tumor growth factor-beta-1 (TGFβ-1)) and chemokines (monocyte chemotactic protein-1 (MCP-1)), which ultimately leads to renal dysfunction (Figure 3).

**Figure 3.** Physiopathology mechanism.

Other pathophysiological pathways are currently being studied, in particular with the aim to develop new treatments. The Toll-like receptors (TLRs) family plays a critical role in the mammalian innate immune system, particularly with regard to the mucosal immunity, which plays a key role in initiating the pathogenic process in IgAN, and it is the first line of host defense against invading pathogens. Activation of TLR-mediated signaling pathways induces gene expression of inflammatory cytokines and type I interferon [67,68]. The complement system, as well, is part of the innate immune system which can enhance the clearance of microorganisms. Skin and mesangial deposits in IgAV and IgAN contain the complement components C3 and C5-C9. Serum levels of activated C3 and mesangial C3 deposition correlate with loss of renal function. The degree of complement activation is also important and have been shown to have prognostic value [69–73].
