MoMa Signature During Granulomatosis (MOSAR)

Role of Monocytes (Mo) and Macrophages (Ma) in Sarcoidosis and in Tuberculosis

Sarcoidosis is a systemic inflammatory disease characterized by unspecific granuloma formation. Our 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 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.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis; Sarcoidosis
• Intervention / Treatment: Other: blood sample

Detailed Description

"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."

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Karim Sacre, MD-PhD, PU-PH; Phone Number: +33 0140256019; Email: karim.sacre@aphp.fr
• Study Contact Backup: Name: Darragh DUFFY, PhD; Phone Number: +33 0144389334; Email: darragh.duffy@pasteur.fr

Study Locations

• France
  • Paris, France, 75018
    • Recruiting
    • Hopital Bichat
    • Contact: Karim SACRE, MD, PhD; Email: karim.sacre@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients diagnosed with sarcoidosis or tuberculosis

Description

Inclusion criteria:

1. Male and female > 18 years old
2. Diagnosis of sarcoidosis and of tuberculosis
3. Affiliated to medical insurance

Exclusion criteria:

1. HIV infection
2. pregnant or breastfeeding woman
3. Patient under legal protection, guardianship or curators
4. Absence of signed consent" Secondary exclusion criteria Other causes of granulomatosis ultimately identified as sarcoidosis or tuberculosis

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sarcoidosis; patients diagnosed with sarcoidosis	Other: blood sample; blood sample collection
Tuberculosis; patients diagnosed with tuberculosis	Other: blood sample; blood sample collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
macrophage activation in sarcoidosis measured by epigenomic	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
monocyte activation in sarcoidosis measured by epigenomic	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
monocyte activation in sarcoidosis measured by transcriptomic	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
macrophage activation in sarcoidosis measured by transcriptomic	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
macrophage activation in sarcoidosis measured by cytokine measurement	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
monocyte activation in sarcoidosis measured by cytokine measurement	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
macrophage activation in sarcoidosis measured by spatial transcriptomics	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.
monocyte activation in sarcoidosis measured by spatial transcriptomics	performed on peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood	up to 12 months of follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
monocyte activation in tuberculosis measured by epigenomic		up to 12 months of follow-up.
Identification of a pathogen that triggers sarcoidosis development by metagenomic study		Samples collected before treatment/at diagnosis
identification of epigenetic modifications of monocytes by CUT&Tag method	CUT&Tag-sequencing, also known as cleavage under targets and tagmentation, is a method used to analyze protein interactions with DNA	12 months of follow-up.
Identification of a diagnostic test to discriminate sarcoidosis and tuberculosis	measurement of IFNγ secretion by whole blood in response to stimulation by tuberculosis antigen	Samples collected before treatment/at diagnosis
real-time analysis of oxidative phosphorylation of monocyte	By Seahorse methode	up to 12 months of follow-up
real-time analysis of glycolysis of monocytes	by seahorse method	up to 12 month of follow up

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Karim SACRE, MD-PhD, PU-PH, Assistance Publique Hopitaux De Paris

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2024
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: May 17, 2023
• First Submitted That Met QC Criteria: June 14, 2023
• First Posted (Actual): June 23, 2023

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: tuberculosis; monocytes; sarcoidosis; macrophages; granuloma
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Infections; Hypersensitivity; Lymphatic Diseases; Lymphoproliferative Disorders; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Hypersensitivity, Delayed; Actinomycetales Infections; Mycobacterium Infections; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Sarcoidosis; Tuberculosis; Granuloma; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: APHP230273; 2022-A02637-36 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No