Potential role of molecular mimicry between human U1-70kDa and fungal proteins in the development of T-cell mediated anti-U1-70kDa autoimmunity

Abstract

Context: Molecular mimicry between human and microbial antigens is a possible trigger of autoimmunity. The possible role of this mechanism in the onset of autoimmunity against the human autoantigen U1-70kDa, typical of mixed connective tissue disease, is not fully elucidated.

Objective: We aimed to identify microbial proteins highly similar to U1-70kDa and potentially triggering anti-U1-70kDa autoimmunity.

Materials and methods: We compared in silico the amino acid sequence of human U1-70kDa and those of all the sequenced fungal, viral and bacterial proteins.

Results: Human U1-70kDa shares highly significant (E<10⁻²⁰) amino acid sequence homology, spanning a segment containing T-cell epitopes, with 13 fungal (but no viral or bacterial) proteins, belonging to human pathogens. Nine of these proteins include the amino acid sequence VLVDVERGRTV, identical to the most frequent U1-70kDa T-cell epitope in anti-U1-70kDa positive patients, and sequences highly similar to the epitope DAFKTLFVARVN (identical residues or conservative residue substitutions in positions crucial for epitope binding).

Discussion and conclusion: Cross-reactivity between human U1-70kDa and microbial proteins was demonstrated for B-cell epitopes, but never investigated before for T-cell epitopes. Our data identify some fungal proteins as possible triggers of anti-U1-70kDa autoimmunity via molecular mimicry. Research in this field could improve the understanding of the mechanisms leading to anti-U1-70kDa autoimmunity, with potential consequences on prevention.

Keywords::

• Autoantigen U1-70kDa
• autoimmunity
• fungi
• mixed connective tissue disease
• molecular mimicry