Fig. 2. Schematic of the implicated routes leading to anti-drug antibody (ADA) production by protein aggregates. On the left panel, the T cell dependent route is initiated by innate immune cells, such as immature DCs (iDCs), which associate protein aggregates with danger, possibly via PRRs. This leads to aggregates being taken up, processed and peptides (antigens) presented on MHC II, as part of DC maturation. Mature DCs also secrete cytokines and have up-regulated expression of co-stimulatory molecules, such as CD40, CD80 and CD86. Antigen-specific T cells become activated upon recognition of all three signals and in turn aid antigen-specific B cell activation and differentiation into ADA-producing plasma cells. Th cells also aid antibody class switching and the development of high-affinity antibodies via somatic mutations. The right panels depict T cell independent routes. In the top panel cross-linking of antigen-specific BCRs, along with PRR recognition, leads to activation and differentiation into ADA producing plasma cells, which are restricted to low-affinity IgM antibodies. In the bottom right panel, antigen presentation by innate immune cells, such as DCs, is implicated in activating MZ B cells, which upon PRR recognition, activate and differentiate into ADA producing plasma cells. Abbreviations: BCR, B cell receptor; CD, cluster of differentiation; DC, dendritic cell; MHC II, major histocompatibility complex class II; MZ, marginal zone; PRR, pattern recognition receptor; TCR, T cell receptor; Th, T helper. Servier Medical Art PowerPoint image bank was used to construct this diagram.