This proposal will test the hypothesis that immunity has a prominent role in the pathogenesis of sarcoidosis, as suggested by abnormalities of the immune function and by the presence of antibodies, including rheumatoid factors and antinuclear antibodies found in this disorder. In addition, sarcoidosis coexists with other systemic inflammatory diseases, and patients frequently show cutaneous anergy and hypergammaglobulinemia. We propose to develop a panel of antibodies/autoantibodies with high sensitivity and specificity to identify patients with sarcoidosis and help to distinguish these patients from controls and individuals with other pulmonary diseases. For this purpose we will construct a T7 phage cDNA library of potential sarcoidosis antigens using mRNA isolated from affected lymph node tissue of patients with sarcoidosis. This cDNA library will be immunoscreened with sera from patients with sarcoidosis containing high titer IgG antibodies and the cloned colonies will be used to construct an antigen microarray that will be hybridized with sera from cases with lung sarcoidosis and controls. Control sera will be obtained from patients with sero-positive rheumatoid arthritis and from patients with a history of tuberculosis. Sequence analyses of informative phage inserts recognized as antigens by sarcoidosis patient sera may identify antigens associated with the etiopathogenesis of sarcoidosis. The autoantibody classifier will be validated with independently obtained collections of sera from cases and controls. In the future, this approach may identify molecular targets useful for the treatment of sarcoidosis.

Public Health Relevance

Aberrant immune responses are a major cause of a vast array of human diseases. Sarcoidosis is an inflammatory disease of unknown etiology sharing similarities with many inflammatory or granulomatous diseases such as Crohn's disease, rheumatoid arthritis, and lupus erythematosus. Sarcoidosis occurs throughout the world with an average incidence of 16.5/100,000 in men and 19/100,000 in women but up to 75/100,000 in African-Americans. Due to its chronicity and to its tendency to affect young individuals, it has high impact on the health and economy in our society. Since the description of this condition more than a century ago, studies have failed to identify specific antigens leading to granulomatous inflammation in sarcoidosis. The proposed studies will identify a panel of antibodies recognizing sarcoidosis granuloma antigens. This will be useful as a tool to diagnose pulmonary sarcoidosis and may identify molecular targets for the treatment of this disease. The main delivery from this project will be a diagnostic instrument useful in a clinical setting for the diagnosis of pulmonary sarcoidosis. Characterization of informative phage may reveal the presence of antigens from bacterial or viral antigens related to the development of pulmonary sarcoidosis. A long term objective of this proposal is the identification of organ-specific antigens which could be targeted by drugs or be the basis for immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL104481-02
Application #
8392229
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Caler, Elisabet V
Project Start
2012-01-01
Project End
2014-06-30
Budget Start
2013-01-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$217,056
Indirect Cost
$74,256
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202