Mechanisms Underlying the Immune Paradox in Sarcoidosis

About This Grant

Project Summary/Abstract: Sarcoidosis is a rare and understudied disease. It is characterized by a strong genetic predisposition, with risk often conferred by Major Histocompatibility (MHC) class II genes and a dysregulated immune response against an unidentified inhaled antigen. Antigenic exposure triggers interactions between antigen-presenting cells (APCs) and naïve CD4+ T-cells within lymph nodes (LNs), leading to a polarized Th1 response and granulomatous inflammation primarily observed in the lungs and LNs. Persistence of this heightened inflammatory immune response results in chronic sarcoidosis, with up to 40% of pulmonary cases progressing to irreversible and possibly end-stage fibrotic disease. Disease progression is associated with reduced quality of life, significant morbidity, higher mortality, and increased healthcare costs. Despite the negative impact, the exact immunological mechanisms driving persistent inflammation in sarcoidosis and progression to end stages have not been fully elucidated and pose a barrier to developing effective therapies. Our recent observations and those of other researchers indicate that up to 50% of sarcoidosis patients exhibit paradoxical peripheral lymphopenia, accompanied by CD4+ T-cell anergy and exhaustion, even in the early stages of the disease. This is associated with increased inflammatory activity, severe organ involvement, and disease progression. Loss of CD4+ effector T-cell function is thought to impair immune surveillance, leading to unmitigated inflammation and persistent granulomatous infiltration of affected tissues. Our prior research utilizing bulk RNA-seq analysis of peripheral immune cells suggests that compromised lymphocyte function and survival stem from aberrant, cell-specific, transcriptomic networks and interactions between lymphocytes and hyperactive innate APCs in lymphopenic sarcoidosis. Utilizing single-cell omic analyses, our novel preliminary data expands on this notion and reveals that peripheral naïve CD4+ T-cells from individuals with lymphopenic sarcoidosis possess a genetically imprinted, aberrant transcriptional program with multiple dysregulated immunoregulatory biological pathways that are involved in cell proliferation and death, predisposing them to impaired function and survival. Furthermore, we find an association between lymphopenia and MHC class II genes, and via single-cell RNA-seq of intrathoracic LNs fine needle aspirates, we find evidence that cDC1s in lymphopenic sarcoidosis have a limited ability to process and present antigens underscoring their crucial role in orchestrating adaptive immune responses. Thus, this research aims to elucidate the underlying mechanisms driving paradoxical peripheral lymphopenia in early sarcoidosis. We propose to utilize high-throughput analyses, such as single-cell RNA-seq and ATAC-seq, along with conventional immunology techniques to investigate how naïve CD4+ T-cells and cDC1s contribute to T-cell dysfunction and impaired survival. Focusing on these immune cell subsets will allow us to uncover intrinsic and extrinsic factors that influence immune dysregulation in lymphopenic sarcoidosis and provide critical insights for developing targeted therapies to mitigate disease progression.