Autophagie, auto-immunité et maladies auto-immunes

Abstract

Les maladies auto-immunes comme le lupus érythémateux disséminé sont la conséquence d’une réponse immune contre l’organisme lui-même, anormalement considéré comme étranger. Elles se caractérisent par un état inflammatoire et des dommages cellulaires et tissulaires parfois graves. Des défauts de l’autophagie qui touchent les lymphocytes de souris et de patients lupiques ont été mis en évidence. Le peptide synthétique P140/Lupuzor qui cible les voies autophagiques, notamment celles impliquant les protéines chaperonnes, est un candidat-médicament efficace qui ne présente pas d’effet indésirable. Il réduit la sur-activation de certaines voies autophagiques et la présentation de peptides antigéniques aux lymphocytes T autoréactifs.

Autoimmune diseases such as systemic lupus, are the consequence of immunity directed against the organism itself. The immune system abnormally recognizes self-components as foreign and produces antibodies targeting normal cells and tissues. We and others have discovered a number of failures affecting autophagy pathways in the lymphocytes of model mice and patients with lupus. While the current treatments are mainly based on immunosuppressive drugs that can lead to important side effects, the synthetic phosphopeptide P140/Lupuzor, which targets chaperone-mediated autophagy and displays no side effects, holds a lot of promise as a drug candidate. P140, which is currently evaluated in a phase III clinical trial, targets chaperone-mediated autophagy that is hyperactivated in lupus mice, and reduces antigenic peptides presentation to autoreactive helper T cells. Remarkably, we showed in lupus mice that upon treatment with P140, a number of immunological abnormalities affecting the pool of T and B cells as well as many biological and clinical features no longer occur.