Silverman Laboratory

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The Silverman Lab aims to understand the mechanisms of immune system variation and to discover novel approaches to predict and prevent immune-mediated diseases, specifically the microbial and developmental factors that lead to T1D. Current research studies in the lab involve the genetic and microbiota impacts on T1D; pediatric gnotobiotic mouse model; and selective IgA deficiency (SIgAD).

Specifically, transgenic expression of the MHCII E molecule in NOD mice (Eα16/NOD)completely prevents T1D, mirroring dominant HLA protection from T1D in humans. Using these Eα16/NOD mice as a model of dominant genetic protection from T1D, the Silverman Lab demonstrated that protection from autoimmunity operates by the immune system shaping the early-life commensal microbiota. The lab’s ongoing project in this area aims to discover the mechanisms by which the host immune system impacts the development of commensal microbiota, and further, how commensal microbes educate the immune system to prevent autoimmunity. Modeling of HLA class II dominant protection from T1D supports the lab’s long-term goal of developing early-life microbiota-based therapies to prevent T1D in humans

The Silverman Lab has collaborated with Paul Planet, MD, PhD, attending physician in the Division of Infectious Diseases at CHOP, to generate the first gnotobiotic mouse model of the pediatric microbiome, which we call Pediatric Community or “PedsCom.” PedsCom is a consortium of 8 bacterial strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. These mice are unique and powerful tools to define the “rules of engagement” between the host and their commensal microbes.

Finally, the lab has recently defined the microbiome from pediatric patents lacking IgA. The team’s ongoing research aims to determine the mechanism for the increased incidence of autoimmune disease in patients with SIgAD.  The lab developed a technique (mFLOW-SEQ) to tag microbes with a patient’s own serum IgG antibodies followed by metagenomic sequencing to define those microbes which activate, and in some cases, over-activate their immune systems.

Project Highlights

  • Early-life microbial and genetic protection from T1D. This ongoing project aims to discover the mechanisms by which the host immune system impacts the development of commensal microbiota, and further how commensal microbes educate the immune system to prevent autoimmunity. Exploring the development and antigen-specificity of microbe-induced regulatory T-cells is an area of focus. Modeling of HLA class II dominant protection from T1D supports the lab’s long-term goal of developing early-life microbiota-based therapies to prevent T1D in humans.
  • Modeling early-life host microbiome interaction using the first gnotobiotic mouse model of the pediatric microbiome (PedsCom). A gnotobiotic mouse model with a small, defined community is a powerful tool to study the complex and dynamic host-microbiota interactions. However, the currently available consortia (e.g. Altered Schaedler’s Flora) were not designed to model the unique composition and function of the pediatric microbiome. The lab developed a simplified community of bacteria derived from pre-weaning mice that recapitulates the composition and function of the early-life microbiome.
  • Defining the microbiome and immune system response to commensal microbes in patients with selective IgA deficiency. The Silverman Lab recruited 16 families with one child with selective IgA deficiency and one healthy control. The lab uses fecal samples to define the impact of IgA deficiency on the intestinal microbiome composition. Further, the lab team predicts that these patients will have poor intestinal barrier function resulting in microbial translocation and induction of a systemic immune response including elevated IgG antibody response against commensal microbes. The lab developed a technique called mFLOW-SEQ to assess the degree of anti-commensal antibody binding and to identify the specific microbes inducing this systemic response.
  • Leveraging the host antibody responses to screen for immunomodulatory microbes using microbial flow cytometry coupled with metagenomic sequencing. For this project, the lab uses diabetes-susceptible NOD and diabetes-resistance Eα16/NOD mice to identify fecal microbes that specifically induce a systemic IgG response in Eα16/NOD compared to NOD mice. Candidate immunomodulatory microbes are then introduced into germfree NOD and Eα16/NOD mice and assessed for induction of regulatory T cells and development of autoimmune diabetes.