McDuffie, Marcia J.

Marcia J. McDuffie

Primary Appointment

Professor,

Contact Information


Telephone: 434-924-1707
Email: mjm7e@virginia.edu

Research Interests

Genetic analysis of autoimmunity

Research Description

Research in my laboratory is focused on the development of mouse models for identifying

genes controlling complex human diseases, particularly those resulting from abnormalities

of the immune system. Using both linkage analyses and classical recombinational

genetics, we have localized such genes in three distinct models of autoimmunity,

including insulin-dependent (“juvenile”) diabetes, systemic lupus erythematosus,

and Crohn’s-like inflammatory bowel disease. We are currently using molecular

and computational approaches, as well as detailed studies of immune function,

to define the structural differences in disease-associated alleles and to characterize

their function in both mice and humans.

Type 1 diabetes (T1D):

T1D results from T cell-dependent inflammatory destruction of insulin-producing

pancreatic islet cells. Our studies have shown that the development of full-blown

disease requires sequential expression of defects in antigen presentation to

T cells, control of T cell activation to self antigens from the islets, and

the response of pancreatic islet cells to the resulting local inflammation initiated

by self-antigen-specific T cells. Each step in the disease process can be controlled

by a unique set of genes, resulting in an extremely complicated polygenic susceptibility.

However, disease can be blocked by normalizing gene function at several discrete

steps. We have identified abnormalities in key regulatory genes that control

the differentiation and activation of both CD8+ T cells and myeloid antigen

presenting cell subsets (macrophages and dendritic cells) in non-obese diabetic

(NOD) mice, a well-established model of human T1D. These genes include a member

of the Runt family of transcriptional regulators, as well as key members of

the GM-CSF signaling pathway. Current work in the laboratory seeks to identify

the specific targets of these genes that are required for maintaining normal

tolerance in the T cell population and preventing the development of organ-specific

autoimmune disease. We are also testing whether the same pathways are defective

in human T1D and attempting to identify small molecule inhibitors and activators

of these gene products as potential therapeutic agents.

Systemic lupus erythematosus (SLE):

In SLE, T cells appear to interact with B cells to produce antibodies that recognize

self nuclear polynucleotide/protein antigens. Immune complexes, formed when

such antibodies interact with circulating debris from necrotic or apoptotic

cells, deposit in tissues and induce inflammatory damage in kidneys, skin, and

other target organs. Using the NZM2328 mouse, an inbred model of human SLE,

we have localized two genes which control the development of pathological autoantibodies

and target damage to the kidney. We are currently attempting to identify these

genes by traditional positional cloning methods and by functional characterization

of the effector cell populations.

Crohn’s disease (CD)

We have also completed a genetic analysis of a new spontaneous mouse model of

inflammatory bowel disease, the SAMP1/Yit mouse. Although T lymphocytes may

play a significant role in the initiation or progression of CD, it is clear

that the innate immune system and the intestinal epithelial cells themselves

are the most important factors in the development of this disease, allowing

us to contrast the genetic susceptibility in this disorder with those for SLE

and T1D. We have recently demonstrated that rare variants of the peroxisome

proliferator-activated receptor gamma (PPAR-g) can block genetic predisposition

to Crohn's disease in both humans and mice. PPAR-g has been shown to down-regulate

inflammatory responses, and loss of PPAR-g expression in mouse models is associated

with rapid induction of destructive intestinal inflammation in response to chemical

or immunological damage. Using the SAMP1/Yit mouse, we were able to show that

protective alleles of PPAR-g are characterized by high levels of expression

in the crypts of the small intestine. This tissue contains the essential stem

cell populations for continuous repopulation of the absorptive and protective

mature epithelial cells. We are currently determining the mechanism by which

this crypt-specific expression controls disease susceptibility and investigating

several promising therapeutic strategies for enhancing protective levels in

individuals genetically susceptible to development of CD.

Techniques routinely used in our laboratory include polymerase chain reaction

amplification of DNA (PCR), methods for quantifying gene expression, enzyme-linked

immunosorbant assays (ELISA), flow cytometry, and cell culture, as well as computational

methods for performing linkage analysis and sequence comparisons.

 

Additional Responsibilities & Affiliations:

Advisor, Medical Microbiology

Pediatric Endocrinology/Diabetes

Director, DERC Mouse Genetics Core

Selected Publications