Tuesday, August 16, 2016

Cross-reactivity to fungal antigen drives acquired IFN-γ auto-antibody mediated mycobacteria susceptibility

Inherited genetic deficiency in IFN-γ signaling underlies susceptibility to weakly virulent mycobacteria, such as bacille Calmette-Guérin (BCG) vaccines and nontuberculous mycobacteria. Here, new study in Nature Medicine reported group of patients with acquired susceptibility to mycobacteria due to presence of neutralizing anti-IFN-γ auto-antibodies that could have been results of its cross-reactivity to fungal Aspergillus antigens.

Molecular mimicry hypothesis suggests that if foreign [nonself] antigen shows antigenic similarity to self antigen, then immune response to such nonself antigen could lead to autoimmune diseases due to shared, cross-reactivity. Here, the authors showed that set of patients with mycobacteria infection expressed neutralizing anti-IFN-γ auto-antibodies.

Next, the authors found that conserved KRKR motif of IFN-γ, known to be crucial for the protein’s bioactivity, showed homology to amino acids 105–113 of the ribosome assembly protein Noc2 of Aspergillus terreus.

Indeed, sera from patients with neutralizing anti-IFN-γ auto-antibodies reacted with Noc2 antigen from Aspergillus.

In summary, this study suggested that immune response to Aspergillus in certain individuals carrying specific HLA polymorphism (HLA class II molecules HLA-DRB1*15:02–HLA-DQB1*05:01 and HLA-DRB1*16:02–HLA-DQB1*05:02) could lead to generation of cross-reactive neutralizing anti-IFN-γ auto-antibodies and acquisition of mycobacteria susceptibility.

David Usharauli

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