Discovery of Natural Bispecific Antibodies: Is Psoriasis Induced by a Toxigenic Corynebacterium simulans and Maintained by CIDAMPs as Autoantigens?

The high abundance of Corynebacterium simulans in psoriasis skin suggests a contribution to the psoriasis etiology via cell envelope components, which may cause skin inflammation and immune responses. This hypothesis was tested in an exploratory study, where Western Blot (WB) analyses with extracts of heat-treated C. simulans and psoriasis serum-derived IgG exhibited a single 16 kDa- WB-band. Proteomic analyses revealed, among others, ribosomal proteins as candidate C. s.-antigens. A peptidomic analysis unexpectedly showed that psoriasis-serum-derived IgG already contained 31 immunopeptides originating from Corynebacteria ssp., suggesting the presence of natural bispecific antibodies (BsAbs). Moreover, peptidomic analyses revealed 372 "DECOY"-peptides with similarity to virus- and phage proteins, including Corynebacterium diphtheriae phage, and similarity to diphtheria toxin. Strikingly, upon a peptidomic analysis for peptides of human origin, 64 epitopes of major psoriasis autoantigens were identified, which originated from the spacer region of filaggrin, from hornerin repeats, SPINK9, keratin 9, caspase 14, desmoplakin, suprabasin, keratin 2, keratin1, keratin 6C, apolipoprotein A1, a Selene-binding protein, H1.8 linker histone, and the transcription factor BCLAF3. Most identified antigens represent potential "Cationic Intrinsically Disordered Antimicrobial Peptides (CIDAMPs)", which are generated within the fully differentiated epidermis. These may form complexes with bacterial disordered protein regions, representing chimeric antigens containing discontinuous epitopes. In addition, among 128 low-abundance immunopeptides, 48 are putatively psoriasis-relevant such as epitopes of IL-12, and the receptors of PGE2, vitamin D3, and IL-10. Further, 47 immunopeptides originated from tumor antigens such as CT47A, SDCCAG3, BRCA2, MAGEA6, RNASE4, and the endogenous retrovirus HERV-K. I propose that persistent infection with a toxigenic C. simulans initiates psoriasis, which is exacerbated as an autoimmune disease by CIDAMPs as autoantigens. The discovery of natural BsAbs allows the identification of antigen epitopes from microbes, viruses, autoantigens, and tumor-antigens, and may help to develop epitope- specific peptide-vaccines and therapeutic approaches with antigen-specific regulatory T cells to improve immune tolerance in an autoimmune disease-specific-manner.