Rahman Research


Position: Professor, Department of Microbiology & Immunology
Organization: Sidney Kimmel Medical College

233 S. 10th Street
BLSB 731
Philadelphia, PA 19107

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. 

Research Projects

Mechanisms of toll-like receptor (TLR) signaling-promoted autoimmune B cell responses in SLE

Representative images of spleen sections SLE-prone mice showing GL7+ GC B cells (green) and CD4+ GC-Tfh cells (red) within the GC.

Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that disproportionately affects women. Altered regulation of B and T cell responses and tolerance promote the development of autoreactive B cells and pathogenic autoantibodies, leading to inflammation and tissue injury, including lupus nephritis (LN). Mechanisms that promote the development of autoreactive B cells and SLE are incompletely understood. Yet this knowledge is essential for developing targeted therapies that would be preferable to currently available SLE treatment options that globally suppress the immune system, resulting in recurrent infections and increase disease-associated morbidity and mortality. 

We and others previously demonstrated a B cell intrinsic requirement for TLR7 in promoting autoimmune GC and extrafollicular antibody-forming cell (EF-AFC) responses and systemic autoimmunity. Stimulation of endosomal TLRs by nucleic acids, such as TLR7 by single-stranded RNA, activates NF-κB family members, and interferon regulatory factor 5 (IRF5) and 7 (IRF7). To date, numerous studies have characterized the involvement of IRF5 and IRF5 risk variants in SLE in mice and humans. Although IRF7 is implicated in the development of SLE, IRF7-expressing cell type(s) and mechanisms by which IRF7 regulates autoreactive B cell differentiation through the EF and GC pathways, leading to autoantibody-secreting plasma cells (PCs) and autoantibody production in SLE remain unknown. IRF7 is long thought to contribute to SLE by regulating type 1 interferon (T1-IFN) production by plasmacytoid dendritic cells (pDCs), although IRF7 is also expressed in B cells and monocytes. Whether and how IRF7 may regulate autoimmune GC- and EF-derived PC responses and systemic autoimmunity through functioning in cell types other than pDCs is not known. It is also unclear whether IRF7 transcriptionally controls SLE-promoting gene programs in B cells other than T1-IFN genes. Using mouse models of SLE that promote both EF-PC and GC responses, our goal is to identify the mechanisms by which IRF7 promotes autoimmune PC and GC responses and SLE-like disease. We have developed a novel conditional and inducible mouse model on a SLE-prone background to temporally control tissue-specific deletion of IRF7 in B cells; this will help demonstrate a B cell-intrinsic requirement for IRF7 in the progression and maintenance of autoimmune GC and PC responses. Our goal in this project is to delineate T1-IFN-indpendent functions for IRF7 in regulating B cell transcription, translation, and metabolism, breaching peripheral tolerance, and promoting autoimmune GC and PC responses in SLE.

MicroRNA regulation of autoimmune B cell responses in SLE

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.Sle1bYaa mice deficient in miR-21 (Sle1bYaamiR-21-/-) had reduced germinal center (GC) B cell, T follicular helper (Tfh) cell and plasma cell (PC) responses. These responses in Sle1bYaamiR-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 Sle1bYaa B cells overexpressing TLR7 compared to Sle1b B cells, indicating a more energetic phenotype in response to TLR7 signaling. Conversely, Sle1bYaamiR-21-/- B cells exhibited reduced ECAR and OCR compared to Sle1bYaa 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

Differential regulation of autoimmune and protective B cell responses by metabolic reprogramming in B cells

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.  

Regulation of autoimmune B and T cell responses by E3 ubiquitin ligase Peli1

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.