Evidence is reviewed that complementary proteins and peptides form complexes with increased
antigencity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody),
which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of
myelin basic protein and muramyl dipeptide (“adjuvant peptide”), which form a complex that induces experimental
allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component
individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its
antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus
haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity.
Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the
components against proteolysis, altering fragmentation and presenting novel antigens to the immune system.
Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that
produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple
Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive
immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced
antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using
information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide
libraries; or using antisense peptide strategies to design complements.
Keywords: Altered antigen processing, antigenic complementarity, antisense peptides, molecular mimicry, synergism, therapeutic
autoimmunity, toll-like receptors, vaccines.
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