The Cerosaletti lab is engaged in translational research to identify key mechanisms in the development of autoimmunity and allergy. We take two approaches:
- Genotype/phenotype studies that characterize the functional impact of disease-associated genetic variants in order to pinpoint immune pathways dysregulated in autoimmune diseases or allergy
- Single-cell analyses of autoreactive T cells in type 1 diabetes using high-dimensional flow cytometry and RNA-sequencing to identify disease-related features of these cells.
The goal of our research is to discover biomarkers that can predict or monitor disease progression, stratify patients for therapy, or that may be novel targets for treatment.
Genetics of autoimmunity and allergy
Autoimmune diseases and allergy are complex disorders, with both environmental and genetic components. Genome wide association studies have identified a large number of genetic variants that contribute susceptibility to many autoimmune diseases and allergic conditions, but little is known about the functional consequences of these single nucleotide polymorphisms (SNPs). We perform cellular and molecular analyses of primary immune cells from genotyped healthy control subjects and autoimmune/allergy patients available through the BRI Registry and Repository to identify how SNPs alter the function of disease-relevant immune pathways, leading to the loss of self-tolerance in autoimmunity and promoting allergy. A focus of our research to date has been on autoimmune-associated SNPs in genes that function in cytokine signaling pathways, including PTPN2, IL2RA, IL6R, TYK2, IFIH1. In collaboration with Drs. Jane Buckner and Alice Long, we demonstrated that disease-associated SNPs in these genes limit the development and stability of regulatory T cells, and promote inflammatory cytokine responses.
Current projects in the lab are investigating genetic variants in the IL-33 pathway for a role in the development of food allergy. Our collaborator Dr. Steve Ziegler identified IL-33 is a key driver of gastrointestinal allergy in a murine model. We are characterizing the functional consequences of SNPs in the IL33 gene and its receptor ST2 (IL1RL1) that are associated with asthma and atopic dermatitis to determine how they might impact gastrointestinal allergy. A second project extends our studies of coding SNPs in the BANK1 gene that are associated with susceptibility to systemic lupus erythematosus (SLE) in collaboration with Dr. Rich James at Seattle Children’s Research Institute. BANK1 is a B cell scaffolding protein that regulates B cell signaling. Our research demonstrated altered B cell signaling with a parallel expansion of memory B cells in the blood of BANK1 risk subjects. Our current study investigates the role of the BANK1 risk variants in regulating terminal B cell differentiation and will test small molecule inhibitors to normalize this process in B cells carrying the risk alleles.
Single cell RNA-sequencing of autoreactive T cells in T1D
The lab is also studying autoreactive CD4 T cells in patients with type 1 diabetes using high dimensional flow cytometry coupled with single cell RNA sequencing, with the goal of identifying unique subsets of islet reactive CD4 T cells related to disease. Type 1 diabetes is considered a T cell mediated disease in which CD4 and CD8 T cells specific for beta cell proteins destroy the islets in the pancreas, leading to insulin dependence. In collaboration with Dr. Peter Linsley, we found expanded clones of islet reactive CD4 T cells in patients with established type 1 diabetes with a distinct transcriptional phenotype. Our current studies are investigating this unique subset of cells during disease initiation and longitudinally after diagnosis, to relate them to disease progression.
Read more about our research
- Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients.
- The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.
- The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans.
- Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes.