In surprising findings from the previous funding period of the UChicago ACE we found that systemic lupus erythematous (SLE) patients generated higher-affinity and more potently neutralizing anti-influenza antibodies (manuscript in preparation). We have also demonstrated this tendency in the Mrl-lpr/lpr mouse model of SLE. These findings suggest one of two primary hypotheses that we believe are of central importance to understanding the cause of SLE. First, there is the possibility that people who make higher affinity antibodies in general are also at a higher risk for lupus. All people likely make autoantibody responses from time to time. However, individuals that are prone to make high affinity antibodies during any immune response may make higher affinity and therefore pathological autoantibodies on occasion that with epitope spreading will result in SLE. The second possibility is that autoimmunity may improve antibody responses. Thus higher-affinity and concomitantly autoimmunity are selected together, increasing the risk for SLE. That is the autoimmune repertoire, or other features associated with autoimmunity such as inflammation, enables more effective antibody responses. In this renewal application, we propose to test various hypotheses to reveal the mechanisms by which SLE patients mount more effective humoral immune responses to influenza and other vaccines. We also noted that unlike control subject antibodies that were somewhat autoreactive, those from SLE patients were uniquely reactive to self-antigens without being polyreactive. These findings suggest that in SLE patients, selection against polyreactivity during peripheral immune responses is intact, supporting a model for lupus pathology in which high-affinity autoantibodies are generated in self-antigen specific responses.
In Specific Aim 1 we will perform experiments to explore this hypothesis.
In Specific Aims 2 and 3 we will explore the mechanistic basis for generating high affinity, and conversely, autoimmune-prone responses in SLE patients and controls (Aim 2) or in mouse models of autoimmunity (Aim 3). These experiments will provide insight into why autoimmunity might be maintained in the general population.

Public Health Relevance

We have found that lupus patients make higher affinity antibodies to influenza upon vaccination. This finding suggests that SLE may have resulted from a selective advantage allowing higher affinity antiboy responses to pathogens. Understanding the mechanism by which higher affinity and self-reactive antbodies are produced by patients is important for understanding the underlying causes of SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082724-06
Application #
8732775
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
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