Production of autoantibodies is the hallmark of many autoimmune diseases. To understand how these antibodies are controlled, we previously generated immunoglobulin transgenic mice where the majority of B cells express lupus-associated anti-DNA antibodies. We have shown that anti-DNA B cells are eliminated by deletion, functional silencing (anergy) and alteration of self-reactive receptors (receptor editing). Paradoxically, although production of pathologic autoantibodies is strictly regulated, a substantial proportion of circulating antibodies in normal sera exhibits self-reactivity. Such antibodies, referred as natural autoantibodies (NAA), often have weak reactivity toward conserved cell components such as DNA, nucleoproteins and phospholipids that are also the common targets seen in autoimmune disease. The function of NAA is presently unknown, as is their relationship to pathologic autoantibodies. Here, we propose two fundamentally different but not mutually exclusive roles of NAA in autoimmunity: 1) they may be an important source of pathologic autoantibodies; 2) they may play a central role in maintaining self-tolerance. To test these hypotheses, we have created a new immunoglobulin knock-in mouse model, where the B cells express a typical NAA. Unlike conventional transgenes, the knock-in gene is able to undergo receptor editing, somatic mutation and isotype switching, all of which are important in development of pathologic antibodies. Using this model, we will define the nature of B cells that produce NAA, and determine whether these B cells will participate in antigen specific responses. Next, by crossing the NAA knock-in mice to an autoimmune-prone background, the relationship between natural and pathologic autoantibodies will be determined, and the molecular mechanisms by which NAA acquire pathogenicity will be explored. Finally, by co-expression of natural autoantibodies and pathologic anti-DNA antibodies in a single animal, we will determine whether NAA can suppress pathologic antibody production and alleviate autoimmune disease; and if so, the mechanisms by which this is achieved. Results from these studies will provide great insight into the etiology of autoimmunity and may lead to new therapeutic strategies for autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI061487-01
Application #
6814821
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$339,750
Indirect Cost
Name
Oregon Health and Science University
Department
Pathology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239