Rheumatoid arthritis (RA) and its animal model collagen-induced arthritis (CIA) are known to be T and B cell dependent diseases. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to develop arthritis while DQ6 and DRB1*0402 provide protection. CIA susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies similar to that in patients. Absence of CIA and low cellular responses in B cell knockout mice suggests that the autoreactive B cells, in addition to producing antibodies may also be involved in presenting auto antigens to T cells. Improvement in ACR response criteria after depletion of B cells in patients further underscores the role of B cells in arthritis. However, the exact role of B cells in antigen presentation and their regulation in susceptible versus resistant strains of transgenic mice remains unclear. B cell function is regulated by B cell receptor, BCR, as well as other B cell specific receptors like BAFF-R. Our hypothesis is that B cells in transgenic mice carrying RA susceptible HLA gene have a defect in regulation which occurs through B cell receptor leading to hyperactivity and increased survival of autoreactive B cells. Females have hyperactive B cells which contribute towards the development of autoantibodies and presentation of antigens to T cells leading to increased incidence in females. Our preliminary data is consistent with this notion. Recent studies have shown that B cell responses are controlled by TLRs. In this study we will address the mechanism by which B cells contribute towards pathogenesis of collagen-induced arthritis in transgenic mice using mice expressing both CIA-susceptible and resistant HLA genes.
In aim1, we will define the requirement of B cells as antigen presenting cells in pathogenesis of CIA.
In aim 2 we will test our hypothesis if hyperactivity of B cell responses and epitope spreading in genetically susceptible mice leads to pathogenic response. Also, since not all transgenic mice positive for RA susceptible allele develop arthritis, potential differences in B cell activation status in those that develop arthritis versus that do not will be determined.
In aim 3, we will determine the control of B cell responses by Toll like receptors, especially, TLR4 in this model. These transgenic mice and experiments proposed here should provide a mechanism of pathogenesis in context of B cells and narrow the focus of B cell-directed therapy.

Public Health Relevance

Rheumatoid arthritis is a disabling disease, affecting women more often than men. B cells produce rheumatoid factor and other autoantibodies. In this study we will use mice that express human arthritis associated genes to delineate the role of B cells in rheumatoid arthritis patients. These humanized mice mimic rheumatoid arthritis in pathology and sex-bias. Arthritic mice produce autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide antibodies that are used for diagnosis of rheumatoid arthritis. We will determine if B cells can present pathogenic antigen and if there is a defect in regulation of B cells in arthritis susceptible mice. The information gained using this unique model may be instructive in developing preventive immunointervention for ongoing arthritis especially in women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075262-04
Application #
8293425
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Peyman, John A
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$259,164
Indirect Cost
$87,646
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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