regulatiOn of autoreactive b Cells by T lymphOcytes in the pathophysiology of PemphigUS – -OCTOPUS-
Pemphigus vulgaris (PV) is a chronic and life-threatening autoimmune disease. This pathology is characterized by the production of auto-antibodies (auto-Ab) directed against two desmosomal proteins: Desmoglein (Dsg)1 and Dsg3. In most patients, B-cell depletion using rituximab (RTX, an anti-CD20 Ab) leads to remission. However, there are around 30% relapsing patients. Additional RTX infusions are used to prevent and to treat relapses but can lead to serious side effects, including anti-infectious immunity that definitively contra-indicate their long-term use. Longitudinal assessment of anti-Dsg3 and anti-Dsg1 serum Abs are used to predict PV relapses, despite a poor correlation with disease severity. Consequently, there is an unmet medical need in order to predict and to cure PV relapses.
B cell responses are positively controlled by a particular subset of T lymphocytes, called follicular CD4+ T cells (Tfh). Presence of blood Tfh is a diagnostic biomarker of vaccination effectiveness or autoimmunity. In addition to Tfh, the T Follicular regulatory cells (Tfr) are also major players of B cell regulation and Ab-mediated autoimmunity.
We identified Dsg3-specific Tfh in PV patients. We found that RTX induces a major decrease of their representation and a correlated sustained depletion of memory autoreactive B cells. Our working hypothesis is that the accumulation and activation of Tfh participate in the severity of PV and that relapses could be linked to the conservation of activated functional Tfh, which sustain the autoreactive B cell pool. Conversely, control of disease could be due to the emergence of Tfr. Tfh and Tfr cell types are thus potential therapeutic targets. Our objective is to test this hypothesis and the causal and mechanistic role of Tfh and Tfr in the outcome of PV in pre-clinical PV mouse models deficient for each of these T cell populations and in an unique longitudinal cohort of PV patients treated with RTX.
Project coordination
NICOLAS FAZILLEAU (Institut Toulousain des Maladies Infectieuses et Inflammatoires)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
INFINITy Institut Toulousain des Maladies Infectieuses et Inflammatoires
PANTHER PHYSIOPATHOLOGIE, AUTOIMMUNITE MALADIES NEUROMUSCULAIRES et THERAPIES REGENERATRICES
Help of the ANR 558,055 euros
Beginning and duration of the scientific project:
October 2023
- 36 Months