Imitation, the highest form of flattery: The Mimicry of T1D

Imitation, the highest form of flattery: The Mimicry of T1D

By: Cassidy Myhre

The concept of molecular mimicry is something that has long been noted as a potential trigger for autoimmunity. Molecular mimicry is when a foreign antigen shares sequence or structural similarities with self-antigens, typically characterized on an antibody or T cell level. 

Based on the knowledge that one of the earliest markers of T1D autoimmunity is the development of islet autoantibodies against autoantigens, like insulin (IAA), a study explored whether exposure to a microbial insulin epitope mimic could stimulate an autoimmune response initiating T1D onset. Focusing on the main insulin epitope, insulin B-chain 9-23 (insB:9-23), here are the findings:

  • A microbial insB:9-23 mimic of Parabacteroides distasonis stimulates non-obese diabetic (NOD) mouse T cells specific to insB:9-23. 
  • Immunization of NOD mice with either the bacterial mimic peptide or insB:9-23 further verified the cross-reactivity in vivo.
  • Modeling P. distasonis peptide revealed a potential pathogenic register 3 binding.
  • P. distasonis colonization of the female NOD mice gut accelerated T1D onset.
  • SCID recipients conferred the enhanced disease phenotype.
  • P. distasonis peptide is not present in the gut microbiota in the first year of life of human infants that eventually develop T1D. 
  • P. distasonis peptide can stimulate human T cell clones specific to insB:9-23, and T1D patients demonstrated a stronger humoral immune response to P. distasonis than controls. 

These findings conclude that Parabacteroides distasonis accelerates T1D in the NOD mouse model and involves expression of an insulin B:9-23 epitope mimic, supporting a potential disease mechanism involving molecular mimicry. There have been additional discoveries throughout the past few decades supporting the causative role of molecular mimicry in autoimmune responses by:

  • Associations between sequence homology and T and B cell cross-reactivity between selected host antigens have been identified as essential for the development of autoimmune diseases.
  • Microbial agents strongly support a causative role for molecular mimicry in that process. 
  • A current survey of PubMed reveals such associations for a plethora of diseases that afflict the central nervous system, endocrine and gastric organs, as well as eyes, heart and other organs.

Taken together, these studies define a potential molecular mimicry link between T1D pathogenesis and the gut microbiota. Identifying the infectious agent, the host “self” determinants and the pathogenic mechanisms involved may offer hints for future strategies to treat and prevent autoimmune disorders. 

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