During gene rearrangement the B-cell determines, guided by cytokines in its environment, which (sub)class of immunoglobulin is later produced by the respective plasma cells.

First of all the Fc-part determines the human (sub)class of the immunoglobulin: IgA (IgA1 and IgA2), IgD, IgE, IgG (IgG1, IgG2a, IgG2b, IgG3, and IgG4) and IgM. The Fc-part of immunoglobulins is relevant at three different levels. After the antibody binds the antigen via the variable regions, the constant region of the immunoglobulins denoted as Fc part can be recognized by other immune cells and facilitate the immune response ( 2– 4). For the purpose of this review it suffices to say that this variable part enables specific binding to antigens beyond the common patterns recognized by the innate immune system. The underlying mechanisms for this rearrangement has been reviewed elsewhere ( 1). These molecules contain an antigen-specific variable region brought about by gene rearrangement in B-cells. Immunoglobulins have evolved during evolution as a link between the antigen-specific adaptive immunity and the molecular pattern driven innate immune system. The inside-out control of FcRs is an interesting target for novel therapy by therapeutical antibodies as it can potentiate or decrease the functionality of the response to the antibodies depending on the mechanisms of the diseases they are applied for. Inside-out control can be achieved at different levels by modulation of: (i) receptor affinity, (ii) receptor avidity/valency, (iii) interaction with signaling chains, (iv) interaction with other receptors and (v) localization in functionally different membrane domains.

This concept is clearly described for the regulation of integrin receptors.

The function of IgG (FcγR's) and IgA (FcαR) recognizing receptors is controlled by cellular signals evoked by activation of heterologous receptors in a process generally referred to as inside-out control. Different FcRs are specifically recognizing and binding the different classes of immunoglobulins, transmitting different signals into the cell.

Receptors recognizing the Fc-part of immunoglobulins (FcR) are important in the engagement of phagocytes with opsonized micro-organisms, but they also play a major role in the pathogenesis of chronic inflammatory diseases.

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