Imagine two different diseases-Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)-that appear at first glance to affect completely different organs and systems. MS disrupts the central nervous system, while T1D damages the insulin-producing cells of the pancreas. Yet, despite these differences, both diseases share a common underlying problem: the body’s own immune system mistakenly attacks healthy tissue. Scientists call these disorders autoimmune diseases. In both MS and T1D, overactive immune cells drive inflammation that can significantly impact patients’ quality of life.

One type of immune cell, the B cell, has attracted considerable research attention in recent years. B cells are commonly known for their ability to produce antibodies, but emerging studies suggest they also play a crucial role in how other immune cells-especially T cells-become active against the body’s tissues. Intriguingly, treatments that target or deplete B cells have shown significant clinical benefits in both MS and T1D. This is a major clue that B cells are critical to how these diseases develop and progress.

In this project, we want to uncover the full story behind B cells’ contribution to autoimmune disease. By carefully examining the genetic factors that make someone more likely to develop MS or T1D, we can begin to piece together the complex chain of events leading to autoimmunity. Most genetic changes linked to these diseases occur in the non-coding regions of our DNA. Instead, these variations often affect how and when genes turn on or off.
Understanding these subtle shifts can help scientists identify precisely which immune functions are going awry in each disease.

Using cutting-edge single-cell RNA sequencing (scRNA-seq), we will look at B cells one cell at a time. This enables them to see exactly which genes are active in each B cell subtype and how that activity might differ in healthy people compared to those with MS or T1D. By focusing on differences at this very detailed level, we aim to explain why some people’s immune systems seem to break tolerance and start the destructive process.

Beyond merely finding these differences, the study also aims to connect these discoveries with potential new targets for therapy. Once we know which genes or pathways are crucial for triggering the harmful immune reactions, we can start to think about designing medications or interventions that specifically inhibit those pathways. For example, if a particular B cell subtype is found to be too good at “training” T cells to attack healthy tissue, blocking the signals that allow this training to happen might reduce or prevent disease.

Ultimately, this research could transform how we treat and potentially even prevent autoimmune disorders like MS and T1D. By illuminating the common immunological threads and the distinct features of each condition, the project sets the stage for new, more tailored therapies. And because both diseases share certain genetic underpinnings, understanding them side by side offers a unique chance to learn general principles of autoimmune disease that could be applied to many other conditions as well.

Multiple Sclerosis (MS) and Type 1 Diabetes (T1D) are both T cell-mediated autoimmune diseases in which tissue- specific damage is closely tied to B cell functionality. Mounting evidence suggests that B cells serve as critical antigen-presenting cells (APCs), priming autoantigen-reactive T cells that orchestrate central nervous system (CNS) demyelination in MS and pancreatic 1 cell destruction in T1D. While anti-B cell therapies (e.g., rituximab, ocrelizumab) have demonstrated clinical efficacy in both disorders, the underlying molecular and genetic drivers that differentiate or unify MS and T1D are not well elucidated. Preliminary data suggest that in MS, B cells exhibit dysregulated expression of transcription factors such as TCF4 and diminished TIGIT expression, possibly leading to enhanced APC capacity or reduced immune regulation. In contrast, T1D we observed different B cell tolerance checkpoint failures and a distinct transcriptional signature. In both disorders, environmental factors such as EBV infection appear to modulate B cell phenotypes, though in a manner likely shaped by disease-specific genetic contexts. This project’s overarching goal is to elucidate the functional impact of autoimmune-associated genetic variants on B cell regulation in MS and T1D, using single-cell transcriptomics (scRNA-seq/BCR-seq) and advanced bioinformatic pipelines. Aim 1 focuses on comprehensive B cell profiling in adult-onset MS and T1D patients, paired with age- and sex-matched controls. Specifically, we will isolate peripheral B cells from patients, sequence them at single-cell resolution, and apply our established nonnegative matrix factorization framework for gene program extraction. This approach will reveal distinct B cell subtypes and the transcriptional pathways that correlate with disease status, including putative pathogenic subsets such as switched memory B cells and atypical B cells. Aim 2 employs ReapTEC, a specialized method to identify bidirectionally transcribed enhancers (btcEnhs) across B cell subtypes at single-cell resolution. As the majority of autoimmune disease-associated variants are found in non- coding cis-regulatory elements, determining variant overlap with btcEnhs is a critical step toward pinpointing disease-specific regulatory mechanisms. We will integrate these data with existing genome-wide association study results for MS and T1D, highlighting where each disease’s risk loci converge or diverge at the enhancer level.

Further downstream computational analyses using neural network-based tools such as BPNet and functional assays including base editing, massive parallel reporter assays will validate the regulatory impact of select variants in the future. By leveraging single-cell analytics, this project will offer a high-resolution map of how B cell subsets drive autoreactive T cell activation in MS and T1D, identifying targets for next-generation immunotherapies.