Background and Aims

Naturally-occurring autoantibodies to certain components of autophagy processes have been described in a few autoimmune diseases, but their fine specificity, their relationships with clinical phenotypes, and their potential pathogenic functions remain elusive.

Methods

We explored IgG autoantibodies reacting with a panel of cytoplasmic endosomal/lysosomal antigens and individual heat-shock proteins, all of which share links to autophagy.

Results

Sera from autoimmune patients and from MRL/lpr and NZB/W lupus-prone mice reacted with the C-terminal residues of lysosome-associated membrane glycoprotein (LAMP)2A. No cross-reaction was observed with LAMP2B or LAMP2C variants, with dsDNA or mononucleosomes, or with heat-shock protein A8. Moreover, administering chromatography-purified LAMP2A autoantibodies to MRL/lpr mice accelerated mortality. Furthermore, flow cytometry revealed elevated cell-surface expression of LAMP2A on MRL/lpr B cells.

Conclusions

These findings reveal the involvement of a new class of autoantibodies targeting the C-terminus of LAMP2A, a receptor for cytosolic proteins targeted for degradation via chaperone-mediated autophagy. These autoantibodies could affect the autophagy process, which is abnormally upregulated in lupus. The data presented support a novel connection between autophagy dysregulation, autoimmune processes and pathophysiology in lupus.

Ref. Wilhelm, M., Bonam, S.R., Schall, N., Bendorius, M., Korganow, A.-A., Lumbroso C. & Muller, S. (2021) Implication of a lysosomal antigen in the pathogenesis of lupus erythematosus. J. Autoimmunity 120, 102633

Background and Aims

Safe and targeted medicines to effectively treat inflammatory bowel diseases (IBDs) are still awaited. Autophagy, a vital self-eating process involved in cellular homeostasis, provides a potential avenue for treating IBDs as several autophagy-related genes are associated with IBD risk. The therapeutic peptide P140 developed in our team is currently being evaluated in phase III clinical trials for lupus. It targets key elements of chaperone-mediated autophagy, which is hyperactivated in lupus. The “correcting” effect of P140 on autophagy results in weaker signaling of autoreactive T and B cells, leading to an improvement of pathophysiological conditions. Hence, we aim to analyze the therapeutic effects of P140 in animal IBD models.

Methods

Susceptible mice have been induced with dextran sulphate sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) colitis and treated with P140 peptide following therapeutic protocols. The clinical course of the colitis has been monitored and animals were sacrificed for pathological and molecular analyses.

Results

Treatment with P140 peptide alleviates the clinical activity markers and repair the intestinal histo-morphological damages in DSS and TNBS colitis.

Conclusions

P140 exerts protective effects on the clinical course of chemically induced colitis. The molecular and cellular mechanisms behind this protection are currently investigated, with a special focus on autophagy.