Discovery of natural bispecific antibodies: Is psoriasis induced by a toxigenic Corynebacterium simulans and maintained by CIDAMPs as autoantigens?

Abstract

AbstractThe high abundance of Corynebacterium simulans in psoriasis skin suggests a contribution to the psoriasis aetiology. 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 ribosomal proteins as candidate C. s.‐antigens. A peptidomic analysis unexpectedly showed that psoriasis serum‐derived IgG already contained 31 immunopeptides of Corynebacteria ssp., suggesting the presence of natural bispecific antibodies (BsAbs). Moreover, peptidomic analyses gave 372 DECOY‐peptides with similarity to virus‐ and phage proteins, including Corynebacterium diphtheriae phage, and similarity to diphtheria toxin. Strikingly, a peptidomic analysis for human peptides revealed 64 epitopes of major psoriasis autoantigens such as the spacer region of filaggrin, hornerin repeats and others. Most identified immunopeptides represent potential cationic intrinsically disordered antimicrobial peptides (CIDAMPs), which are generated within the 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 epitope peptides of PGE2‐, vitamin D3‐ and IL‐10‐receptors. Further, 47 immunopeptides originated from tumour antigens, 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 tumour‐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.