Initiation of autoimmune disease is still an immunological mystery. Some forms of autoimmune diseases are results of genuine genetic defects in signaling molecules within immune system. Other forms show strong linkage to certain HLA haplotypes that present antigenic epitopes. More recently scientists focused on the role of gut commensals in autoimmune diseases.
A new study in Jounral of Experimental Medicine showed that cross-reactivity at the epitope level between gut commensal Fusobacteria-derived magnesium transporter and β islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) contributed in autoimmune diabetes development in IGRP-specific CD8 T cell transgenic, CD8+ TCR NY8.3 NOD mice.
Initially, the authors observed that unlike MyD88KO NOD mice, MyD88KO CD8+ TCR NY8.3 transgenic NOD mice showed accelerated diabetes development (though unlike the authors, I don't find this surprising).
Interestingly, when co-housed with WT NOD mice, MyD88KO TCR NY8.3 transgenic NOD mice showed enhanced protection against diabetes, suggesting dominant role of fecal bacteria present in WT NOD mice in providing this protection.
Since it is known that NOD mice susceptibility to diabetes is commensal-dependent, the authors sequenced fecal microbiome in MyD88KO NY8.3 NOD mice to determine its composition. Not surprising, certain families of commensals underwent changes on MyD88KO background.
When the authors compared the IGRP206–214 peptide sequence against bacterial protein sequences in the nonredundant protein sequence database, they found several hits shared strong homology with IGRP206–214 peptid, the native autoantigen detected by NY8.3 CD8+ T cells. One such peptide, W15944, was derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal.
Indeed, W15944 stimulated NY8.3 CD8+ T cells could transfer diabetes in NOD mice.
Finally, introduction of L. goodfellowii into WT NY8.3 NOD mice accelerated diabetes development, further suggesting role of L. goodfellowii in this process (while in general, this paper is of high quality, it lacks some of the crucial experiments such as, for example, (1) introduction of L. goodfellowii into NY8.3 NOD mice on germ-free background and (2) experiments with L. goodfellowii lacking cross-reactive W15944 peptide).
In summary, the author showed that in this artificially constructed NOD mice, IGRP-specific CD8 T cells could be activated by commensal-derived cross-reactive peptide and initiate autoimmune destruction of β cells (it is remains to be seen why Foxp3+ regulatory T cells are incapable of preventing such T cell attack).
David Usharauli
Initially, the authors observed that unlike MyD88KO NOD mice, MyD88KO CD8+ TCR NY8.3 transgenic NOD mice showed accelerated diabetes development (though unlike the authors, I don't find this surprising).
Interestingly, when co-housed with WT NOD mice, MyD88KO TCR NY8.3 transgenic NOD mice showed enhanced protection against diabetes, suggesting dominant role of fecal bacteria present in WT NOD mice in providing this protection.
Since it is known that NOD mice susceptibility to diabetes is commensal-dependent, the authors sequenced fecal microbiome in MyD88KO NY8.3 NOD mice to determine its composition. Not surprising, certain families of commensals underwent changes on MyD88KO background.
When the authors compared the IGRP206–214 peptide sequence against bacterial protein sequences in the nonredundant protein sequence database, they found several hits shared strong homology with IGRP206–214 peptid, the native autoantigen detected by NY8.3 CD8+ T cells. One such peptide, W15944, was derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal.
Indeed, W15944 stimulated NY8.3 CD8+ T cells could transfer diabetes in NOD mice.
Finally, introduction of L. goodfellowii into WT NY8.3 NOD mice accelerated diabetes development, further suggesting role of L. goodfellowii in this process (while in general, this paper is of high quality, it lacks some of the crucial experiments such as, for example, (1) introduction of L. goodfellowii into NY8.3 NOD mice on germ-free background and (2) experiments with L. goodfellowii lacking cross-reactive W15944 peptide).
In summary, the author showed that in this artificially constructed NOD mice, IGRP-specific CD8 T cells could be activated by commensal-derived cross-reactive peptide and initiate autoimmune destruction of β cells (it is remains to be seen why Foxp3+ regulatory T cells are incapable of preventing such T cell attack).
David Usharauli
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