"Sarcoidosis is an inflammatory disease characterized by the presence of coalescing,
tightly clustered, non-necrotizing granulomas. The diagnosis is based on three major
criteria: a compatible clinical presentation, the presence of non-necrotizing
granulomatous inflammation, and the exclusion of alternative granulomatous diseases. A
wide range of clinical phenotypes are observed depending on the location of the
granulomatous lesions which can affect any organ, with the lungs being the most affected
site. Sarcoidosis shares many similarities with tuberculosis, in which granuloma
formation is triggered by Mycobacterium tuberculosis (M. tb). These phenotypic
similarities between the two diseases present many challenges for diagnosis, clinical
management and therapy.
Our understanding of the factors that contribute to sarcoidosis development, granuloma
formation and maintenance remains limited. Part of this challenge is that granuloma
development may involve both environmental and genetic factors, which contribute to the
recruitment of immune cells to form the granuloma. Immune cells involved in the granuloma
include (1) CD4 Th1 and Th17 T cells and their associated cytokines (e.g, IFNγ, TNFα,
IL-17, IL-2); and (2) monocytes (Mo) and macrophages (Ma) including proinflammatory M1
and pro-fibrosis M2 types. However, the specific factors that contribute to granuloma
maintenance and evolution remain to be identified. Among them, we can hypothesized that
trained immunity, persistence of the antigen, or the microenvironment are involved in
this chronic dysregulated immune response. Such an improved understanding of the
pathophysiology of the disease may allow development of new treatments, as currently
corticosteroids remain the mainstay of therapy.
Our main hypothesis is that granuloma formation and maintenance mainly relies on the
overactivation of monocytes (Mo) and macrophages (Ma). To this end, the study aims (i) to
define MoMa systemic signature in sarcoidosis, (ii) to characterize this signature in
situ on tissue samples, and (iii) to identify causative factors that participate to the
MoMa chronic overactivation. Thus, a cohort of sarcoidosis patients will be compared with
tuberculosis patients. The MoMa systemic signature will be defined on whole blood
(TruCulture model) and then in situ through different methods (multi-parameter spectral
flow cytometry, RNA-seq, Luminex, imaging mass cytometry). The epigenome of monocytes
will be studied thanks to CUT&Tag. The MoMa systemic signature will be defined ex vivo at
different time points (M0, M6 and M12) during the course of the disease with phenotypic,
transcriptomic, cytokine and functional approaches. The previously identified signature
will be studied in situ and completed by the characterization of granuloma architecture
and microenvironmental interactions, which could be modulated by epigenetic
modifications. Hence, the epigenome of monocytes will be analyzed in two groups
(sarcoidosis and tuberculosis). These results would allow to better understand
sarcoidosis physiopathology and, in fine, may raise new therapeutic strategies. Finally,
the study could challenge the dogma on innate immunity/auto-inflammation versus adaptive
immunity/auto-immunity/memory."
