How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy

Abstract

Evidence is reviewed that complementary proteins and peptides form complexes with increased antigenicity 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.

Intrinsic disorder in protein sense‐antisense recognition

“…What, then could be the molecular mechanism for the sense-antisense complementarity at the protein/peptide level? Since sense and antisense peptides can interact with each other with increased probability, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] one can assume the presence of some binding specificity. This specificity was described as "amphipathic recognition" for a hydrophilic-hydrophobic mechanism of sense-antisense peptide binding.…”

“…Curiously enough, what seems to be entirely nucleic acid-specific sense-antisense complementarity has found its way into the protein world too. In fact, multiple studies indicated that sense and antisense peptides can interact with each other with increased probability, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] with the length of known interacting sense-antisense peptides being varied between 4 and 19 amino acids. [17][18][19] Here, the amino acid sequence of a sense peptide is encoded by the nucleotide sequence (read 5 0 !…”

Synergistic Activation of Toll-Like and NOD Receptors by Complementary Antigens as Facilitators of Autoimmune Disease: Review, Model and Novel Predictions

“…Additional examples of enhanced immunogenicity and autoimmunity associated with complementary antigen complexes are reviewed in [ 136 ]. These include a diphtheria toxin-antitoxin (antibody) complex that induces an autoimmune polyneuritis similar to Guillain-Barré syndrome [ 137 , 138 , 139 ], the induction anti-insulin antibodies in type 1 diabetes by an insulin-glucagon complex [ 140 ] and improved antigen presentation to macrophages and dendritic cells by heat shock protein-viral antigen complexes [ 141 ].…”

“…In sum, for a number of AD with well-defined animal models and/or molecular targets, including two AD featured here—AM and MS—evidence exists that initiating antigens exhibit complementarity towards each other by binding directly to each other and/or by inducing immune responses that have idiotype–anti-idiotype characteristics. Notably, antigen presenting cells are known to process such antigen complexes differently than are their individual antigenic components (reviewed in [ 136 ]). Antigenic complexes are more stable than their components to proteolytic and oxidative degradation and thus more likely to be perceived by the immune system as antigenic; they are digested into different fragments by the proteasome than are their individual components; and such complexes can be perceived by the immune system as distinctly novel antigens that differ significantly from their individual components [ 136 ].…”

<strong>A General Theory of Autoimmune Disease Causation: Integrating Innate and Adaptive Immunity, Altered Antigen Processing, Sex and Genetic Predispositions, and Microbiome Effects</strong>

“…It is well known that molecules to which the immune system is tolerant can be made antigenic through chemical or physical alteration and that non-antigens can be made antigenic by chemically coupling them to an antigen or hapten (e.g., Landsteiner and van der Scheer, 1936;Eisen, et al, 1952). The formation of complementary antigen complexes can have the same effects (reviewed in Root- Bernstein, 2015).…”