Zaida G. Ramirez-Ortiz

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder arising from the convergence of genetic susceptibility, epigenetic remodeling, environmental exposures, and dysregulated immune networks. Although traditionally characterized by autoantibody production and immune complex mediated tissue injury, advances in genomics, systems immunology, and multi-omics profiling have revealed that lupus represents a multilayered failure of immune homeostasis driven by interconnected molecular circuits. Genetic variants enriched in regulatory immune enhancers establish a permissive transcriptional landscape that sensitizes innate nucleic acid sensing pathways and interferon signaling. Epigenetic remodeling further amplifies inflammatory transcriptional programs, while environmental triggers such as ultraviolet radiation and viral infection initiate bursts of nucleic acid release and immune activation. Defective apoptotic cell clearance, mediated in part by scavenger receptor dysfunction and complement abnormalities, increases the availability of immunogenic nucleic acids that engage pattern recognition receptors and drive chronic type I interferon production. This interferon-dominated environment rewires immune cell metabolism, alters differentiation trajectories of T and B lymphocytes, and sustains autoreactive immune circuits. Emerging multi-omics studies reveal distinct molecular endotypes defined by interferon signatures, metabolic states, and immune cell composition, highlighting the heterogeneity of disease mechanisms across patients. In this review, we integrate genetic, epigenetic, metabolic, and immunological insights to propose a systems-level model of lupus pathogenesis in which defective debris clearance, nucleic acid sensing, interferon amplification, and metabolic reprograming form a self-reinforcing pathogenic network. Understanding this integrated molecular architecture provides a foundation for biomarker-guided therapeutic strategies and precision medicine approaches aimed at disrupting the key nodes that sustain chronic autoimmunity in SLE.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease known for its heterogeneity in both manifestation and presentation. Recent evidence has increasingly implicated the gut microbiome within immunomodulation and autoimmunity. This study aims to characterize the intestinal inflammation and microbial profile associated with autoimmune diseases, particularly SLE, and to identify unique biomarkers and shared microbial signatures for potential therapeutic measures. Our lab identified scavenger receptor class F, member 1 (SCARF1, SREC-1) as an efferocytosis receptor essential for the clearance of apoptotic debris, and its deficiency results in the development of lupus-like disease. SCARF1 is crucial in immune homeostasis, and defects in efferocytosis lead to inflammation. However, the role of SCARF1 in gut homeostasis remains to be elucidated. To answer our question, we analyzed and compared the metagenomic datasets generated through whole genome shotgun sequencing between our Scarf1^−/− lupus-prone mouse model and healthy counterparts. We found that Scarf1^−/− mice had significantly lengthened intestines, elevated immune cell infiltration, and structural changes in the colon. Microbiome analysis revealed gut dysbiosis, including reduced alpha diversity and increased Firmicute/Bacteroidetes ratio. Notably, beneficial taxa such as Akkermansia muciniphila was absent in Scarf1^−/− mice. Linear regression analysis identified positive associations between lupus disease severity and increased abundances of Alistipes, Lachnospiraceae, and Clostridium. Function analysis of the gut microbiome in Scarf1^−/− mice indicated downregulation of multiple pathways related to cell proliferation. These findings highlight the role of SCARF1 involvement in the gut microbiome and immune regulation in the context of inflammation and SLE.

Scavenger receptors (SRs) play an important role in the innate immune response by recognizing and binding a variety of ligands to initiate the removal of both altered self- and non-self-antigens. Over the last two decades, SRs have become a forefront for their role influencing and contributing to inflammatory disease pathways. The findings discussed in this review show that the immunological role SRs play is (1) found in multiple organ systems and not limited to one disease or subset of symptoms; (2) part of both the innate and adaptive immune response in addition to influencing inflammatory signaling via non-immune cell subtypes; (3) both pro- or anti-inflammatory depending on which SR class or cell signaling pathway is being observed; (4) potentially useful for the development of therapeutics and diagnostic or prognostic biomarkers for autoimmune disease pathology. Understanding the role of SRs in the context of inflammation and autoimmunity will shed some light on the comprehension of heterogeneous diseases, such as Systemic Lupus Erythematosus.

Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE. In this article, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+ dendritic cells initiates an IL-10 anti-inflammatory response mediated by the phosphorylation of STAT1 and STAT3. Unexpectedly, there was no significant difference in SCARF1 expression in samples of patients with SLE compared with healthy donor samples. However, we detected anti-SCARF1 autoantibodies in 26% of patients with SLE, which was associated with dsDNA Ab positivity. Furthermore, our data show a direct correlation of the levels of anti-SCARF1 in the serum and defects in the removal of ACs. Depletion of Ig restores efferocytosis in SLE serum, suggesting that defects in the removal of ACs are partially mediated by SCARF1 pathogenic autoantibodies. Our data demonstrate that human SCARF1 is an AC receptor in dendritic cells and plays a role in maintaining tolerance and homeostasis.