The therapeutic implications of activated immune responses via the enigmatic immunoglobulin D.

Immunoglobulin D (IgD) is an enigmatic antibody and the least appreciated member of the immunoglobulin (Ig) family. Since its discovery over half a century ago, the essence of its function in the immune system has been somewhat enigmatic and less well-defined than other antibody classes. Membrane-bound IgD (mIgD) is mostly recognized as B-cell receptor (BCR) while secreted IgD (sIgD) has been recently implicated in 'arming' basophils and mast cells in mucosal innate immunity. Activations of immune responses via mIgD-BCR or sIgD by specific antigens or anti-IgD antibody thereby produce a broad and complex mix of cellular, antibody and cytokine responses from both the innate and adaptive immune systems. Such broadly activated immune responses via IgD were initially deemed to potentiate and exacerbate the onset of autoimmune and allergic conditions. Paradoxically, treatments with anti-IgD antibody suppressed and ameliorated autoimmune conditions and allergic inflammations in mouse models without compromising the host's general immune defence, demonstrating a unique and novel therapeutic application for anti-IgD antibody treatment. Herein, this review endeavored to collate and summarize the evidence of the unique characteristics and features of activated immune responses via mIgD-BCR and sIgD that revealed an unappreciated immune-regulatory function of IgD in the immune system via an amplifying loop of anti-inflammatory Th2 and tolerogenic responses, and highlighted a novel therapeutic paradigm in harnessing these immune responses to treat human autoimmune and allergic conditions.

Harnessing Newton's third-law paradigm to treat autoimmune diseases and chronic inflammations.

PURPOSE: It paradoxically seems counter-intuitive to consider treatments that activate the immune systems as a method to treat autoimmune diseases and chronic inflammations when these inflammatory conditions are themselves manifested by dysregulated activations of the immune responses. However, according to Newton's Third-Law of fundamental physics which formally states "For every action, there is an equal and opposite reaction", it can be reasonably argued that "For every activated pro-inflammatory response, there is an opposite and intrinsic anti-inflammatory response to follow." Therefore, harnessing these intrinsic self-regulated negative-feedbacks of anti-inflammatory and tolerogenic responses by activating the immune systems represents a novel therapeutic paradigm. METHODS: This review endeavoured to examine and discuss the current clinical and experimental evidences and therapeutic potentials of activating the innate and adaptive immune systems via their classical cell receptors, namely Toll-like receptors (TLRs), T-cell receptors (TCRs), and B cell receptors (BCRs), to modulate and suppress pathogenic inflammations. RESULTS: The evidence presented in this review illustrated the therapeutic potentials and the caveats of  recent approaches and advances in harnessing this unorthodox therapeutic paradigm in the treatments of autoimmune diseases, allergic and chronic inflammations. It highlighted the promising potentials of targeting BCR-activated tolergenic responses as a new approach in this new therapeutic paradigm.