ABSTRACT
The 'hygiene hypothesis', or lack of microbial and parasite exposure during early life, is postulated as an explanation for the recent increase in autoimmune and allergic diseases in developed countries. The favored mechanism is that microbial and parasite-derived products interact directly with pathogen recognition receptors to subvert proinflammatory signaling via T regulatory cells, thereby inducing anti-inflammatory effects and control of autoimmune disease. Parasites, such as helminths, are considered to have a major role in the induction of immune regulatory mechanisms among children living in developing countries. Invoking Occam's razor, we believe we can select an alternative mechanism to explain the hygiene hypothesis, based on antibody-mediated inhibition of immune responses that may more simply explain the available evidence.
Subject(s)
Antibodies/immunology , Autoimmune Diseases/immunology , Hygiene Hypothesis , Hypersensitivity/immunology , T-Lymphocytes, Regulatory/immunology , Adaptive Immunity/immunology , Animals , Antigen-Antibody Complex/immunology , Child , Developed Countries , Developing Countries , Humans , Hypergammaglobulinemia/complications , Hypergammaglobulinemia/immunology , Models, Immunological , Parasites/immunology , Parasitic Diseases/immunologyABSTRACT
The success of Fc-fusion bio-therapeutics has spurred the development of other Fc-fusion products for treating and/or vaccinating against a range of diseases. We describe a method to modulate their function by converting them into well-defined stable polymers. This strategy resulted in cylindrical hexameric structures revealed by tapping mode atomic force microscopy (AFM). Polymeric Fc-fusions were significantly less immunogenic than their dimeric or monomeric counterparts, a result partly owing to their reduced ability to interact with critical Fc-receptors. However, in the absence of the fusion partner, polymeric IgG1-Fc molecules were capable of binding selectively to FcγRs, with significantly increased affinity owing to their increased valency, suggesting that these reagents may prove of immediate utility in the development of well-defined replacements for intravenous immunoglobulin (IVIG) therapy. Overall, these findings establish an effective IgG Fc-fusion based polymeric platform with which the therapeutic and vaccination applications of Fc-fusion immune-complexes can now be explored.
