Dendritic cells (DCs) are professional antigen presenting cells that play a pivotal role in the initiation of immune responses. DCs ingest antigens and then present these antigens to T cells to initiate T cell activation and polarization. DCs receive signals both from environment and from endogenous molecules. DCs in the immune system constantly interact with immunoglobulins (or antibodies) and a substantial amount of these immunoglobulins are natural. We found that natural antibodies have a key role in regulating the DC functions and that CD40-reactive natural antibodies constitute one of the endogenous molecules that provide maturation-associated signals to DCs in physiology. In this chapter, we describe the isolation of anti-CD40 natural antibodies from pooled normal immunoglobulin preparations (intravenous immunoglobulin, IVIg) and their biological effects on human DC maturation and functions. © Springer Science+Business Media New York 2014.