The elusive case for a role of mimicry in autoimmune diseases.
The notion that mimicry between a self and a microbial peptide antigen can trigger or aggravate autoimmune pathology remains a popular hypothesis in autoimmunity research. Tremendous recent progress in our understanding of the interface between the T cell receptor (TCR) and peptide/MHC complexes has revealed a vast potential for degenerate recognition of numerous structurally similar pMHC complexes by each T lymphocyte. Moreover, functional and structural studies have confirmed that structural similarity between unrelated pMHC complexes is frequently sufficient for recognition by a single TCR. However, despite clear evidence that vaccination with mimetic microbial antigens has the potential to activate autoreactive T cells, crucial evidence for triggering of autoimmunity by mimetic sequences in natural pathogens is wanting. Antigen spreading, i.e. the fact that the number of self antigens targeted by a chronic autoimmune response tends to increase with its duration, does not facilitate the task of proving initial triggering, or subsequent acceleration, of autoimmune conditions by mimetic microbial antigens. Moreover, considering that activation rather than presence of autoreactive T cells is the hallmark of autoimmune disease, the creation of an environment resulting in failure of tolerance and regulatory mechanisms, rather than emergence of novel microbial antigenic determinants, may well be at the root of autoimmunity. Based on these considerations, we contend that the mimicry concept remains largely hypothetical, and that novel carefully designed animal models are needed to make a convincing case for a role of mimicry in autoimmune diseases.
Fourneau
Jean-Marie
JM
INSERM U580, Necker Institut, 161 rue de Sèvres, 75015 Paris, France.
Bach
Jean-Marie
JM
van Endert
Peter M
PM
Bach
Jean-François
JF
D000941:Antigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens