Our research interest focuses on understanding the mechanisms by which toll-like receptor and cytokine signaling pathways promote B cell responses in extrafollicular antibody-forming cell (EF-AFC) and follicular germinal center (FO-GC) pathways in the context of autoimmune disease lupus and protective immunity. 

Our research interest focuses on elucidating the molecular and cellular basis for the loss of immune self-tolerance, which promotes B cell responses in an autoimmune disease systemic lupus erythematosus (SLE or lupus). My lab is interested in understanding the mechanisms that drive B cell differentiation in the extrafollicular antibody-forming cell (EF-AFC) and follicular germinal center (FO-GC) pathways in the generation of pathogenic and somatically mutated antinuclear antibody (ANA) production in SLE. My lab has pioneered in identifying the cell-intrinsic roles and mechanisms of autoimmunity-driven and spontaneously developed AFCs (Spt-AFCs) and germinal centers (Spt-GCs) in developing autoreactive B cells, autoantibody production and SLE pathogenesis using several SLE mouse models. We have generated various tissue-specific conditional and inducible conditional knockout systems on the SLE-prone mouse background to better understand the cell-intrinsic mechanisms by which various signaling pathways promote autoimmune B cell responses during systemic autoimmunity development. 

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression in immunity and autoimmunity, although many miRNAs remain poorly characterized. One such miRNA, miRNA-21 (miR-21), is upregulated in systemic lupus erythematosus (SLE) patients and promotes various diseases in mouse models. We found that TLR7 overexpressing SLE-prone B6.Sle1b^Yaa mice deficient in miR-21 (Sle1b^YaamiR-21^-/-) had reduced germinal center (GC) B cell, T follicular helper (Tfh) cell and plasma cell (PC) responses. These responses in Sle1b^YaamiR-21^-/- mice were strongly associated with reduced autoantibody, and splenic and bone marrow autoantibody-producing antibody forming cell (AFC) responses. Additional findings revealed increased extracellular acidification (ECAR) and oxygen consumption (OCR) rates in Sle1b^Yaa B cells overexpressing TLR7 compared to Sle1b B cells, indicating a more energetic phenotype in response to TLR7 signaling. Conversely, Sle1b^YaamiR-21^-/- B cells exhibited reduced ECAR and OCR compared to Sle1b^Yaa B cells. We hypothesize that miR-21 promotes TLR7-driven systemic autoimmune responses and SLE disease by regulating TLR7-NF-kB signaling and metabolic reprogramming in B cells. The goal of this project is to identify B cell-intrinsic mechanisms of miR-21-promoted inflammatory signaling and metabolic reprogramming in B cells, leading to autoimmunity. This will fill gaps in knowledge and may help discover an urgently needed targeted therapy for SLE, a debilitating disease that affects millions of Americans and people world-wide

Millions of Americans and people worldwide are afflicted by the complex autoimmune disease systemic lupus erythematosus (SLE), that predominantly affects women. Immunosuppressive agents widely-used for treating SLE predispose patients to severe infection and morbidity, including emerging threats such as SARS-CoV2 virus. To date, only one drug (Belimumab) with modest efficacy is FDA approved for SLE treatment. The bottleneck for developing effective targeted therapeutics for autoreactive B cells with no or reduced complications is our incomplete understanding of the differential mechanisms that promote autoimmune versus protective responses. Increased metabolic activity was shown to promote SLE autoimmunity in studies that primarily focused on the role of various T cell metabolic pathways. Several reports also highlighted the role of diverse metabolic pathways in B cell activation, proliferation and differentiation using in vitro (i.e., LPS, BCR, CD40) and in vivo induced systems. A detailed understanding of B cell metabolic networks that differentially promote protective B cell and autoreactive B cell development in the AFC and GC pathways remains unclear which is the focus of this project.  

Peli1, also known as Pellino-1, is a member of the E3 ubiquitin-protein ligase family. Peli1 facilitates the ubiquitination processes that negatively regulate pro-inflammatory and autoimmune responses. Peli1 is a dual-regulating protein with two opposite functions. Depending on its ubiquitin linkage, Peli1 can tag proteins for degradation or stabilize them for activation. This has been well-studied downstream of SLE-related inflammatory signaling pathways, such as Toll-like receptor (TLR) and interleukin-1 (IL-1). Specifically, K63-linked polyubiquitination is crucial for the activation of various downstream signaling molecules and transcription factors, such as IRAK1 and RIPk1, which perpetuate SLE-like inflammatory responses. Recent studies indicated that Peli1 may contribute to lymphomagenesis through the stabilization of B-cell lymphoma 6 (Bcl6) protein by mediating its K63-linked polyubiquitination. Bcl6 is the master transcription factor that regulates germinal center (GC) reactions. Peli1 regulation of Bcl6 suggests its regulatory functions at the peripheral B cell tolerance checkpoints, which has implications for autoimmune pathogenesis.

Our lab, along with others, previously showed that toll-like receptor 7 (TLR7), an endosomal single-stranded RNA sensing receptor, plays a central role in positively regulating the spontaneous formation of GCs and EF-AFCs. Our findings suggest that deficiency in the TLR7-MyD88 signaling pathway leads to impaired B cell proliferation and survival. Overexpression of TLR7 accelerates SLE disease development. TLR7 signaling can result in potent activation of the NF-kB pathway, which, if not tightly controlled, can drive immune cell dysregulation and autoimmune disease development. Peli1 has been identified as a negative regulator of the non-canonical NF-κB signaling pathway, inhibiting the activation of NF-κB by altering the K48-linked polyubiquitination of NIK in T cells. Although PELI1 is believed to support the TRIF-dependent TLR signaling pathways, current literature lacks a comprehensive elucidation of Peli1's influence on MyD88-dependent pathways in B cells and how that relates to autoreactive B cell differentiation in the GC and EF-AFC pathways. The relationship between TLR7 signaling and B cell fate is complex, and we are particularly interested in the regulatory capacity of Peli1. Our preliminary data shows that Peli1 expression is increased upon TLR7 stimulation, which suggests a responsive interaction between these molecules. Our goal in this project is to test the hypothesis that Peli1 operates downstream of TLR7 signaling to regulate the fate of B cells differentiating via the GC and/or EF-AFC pathways to produce autoantibodies.