Common variable immunodeficiency (CVID) is a clinical diagnosis given to patients who suffer with unexplained deficiencies of serum immunoglobulins. Most CVID patients present with recurrent sinopulmonary infections. Among our clinic population, the greatest genetic linkage is to the major histocompatibility complex (MHC) on chromosome 6, with more than 80% of our patients inheriting either HLA*B08 or HLA*B44. We recently characterized a separate group of clinic patients who presented with adult-onset recurrent sinopulmonary infections (RESPI) and serum immunoglobulin levels above the threshold for diagnosis with CVID, but with the same distribution of HLA*B08 and HLA*B44 as that seen in CVID. Recognition of RESPI patients among first and second degree relatives of CVID patients, including two identical twins discordant for RESPI and CVID, led us to the hypothesis that RESPI patients are suffering from the effects of the same genetic susceptibility to immune dysfunction that manifests more severely in classic CVID. Careful analysis has shown a variety of abnormalities in either the number or function of a number of different lymphocyte subsets in both RESPI and CVID patients. For example, NK cells have been reported to be depressed in number, but the role of factors that can mediate NK cell function, including the role of KIR and MHC ligands, remains unknown. We propose to use our population of RESPI/CVID patients to map the putative common susceptibility gene for RESPI/CVID within the MHC, to characterize HLA/KIR interactions, and to evaluate the expressed B cell and T cell antigen receptor repertoires in these patients. This comprehensive analysis of the MHC, KIR, BCR and TCR could help define and extend the spectrum of what is already the most common primary immune deficiency under the care of clinical immunologists in the US, as well as to elucidate the mechanism(s) that underlie susceptibility to infection, facilitate diagnosis, and point to new avenues for prevention and treatment.

Public Health Relevance

(provided by applicant): Findings from this proposal will be used to define the relationships between the MHC, KIR, the BCR and TCR repertoires and their functional relevance to the pathogenesis and clinical course of CVID and RESPI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI090902-03
Application #
8320328
Study Section
Special Emphasis Panel (ZAI1-MFH-I (M3))
Program Officer
Rice, Jeffrey S
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$760,281
Indirect Cost
$241,318
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Mroczek, Eva Szymanska; Ippolito, Gregory C; Rogosch, Tobias et al. (2014) Differences in the composition of the human antibody repertoire by B cell subsets in the blood. Front Immunol 5:96
Cha, Soung-Chul; Qin, Hong; Kannan, Shibichakravarthy et al. (2013) Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen. J Immunol 190:4887-98
Foote, Jeremy B; Mahmoud, Tamer I; Vale, Andre M et al. (2012) Long-term maintenance of polysaccharide-specific antibodies by IgM-secreting cells. J Immunol 188:57-67
Mahmoud, Tamer I; Schroeder Jr, Harry W; Kearney, John F (2011) Limiting CDR-H3 diversity abrogates the antibody response to the bacterial polysaccharide ? 1?3 dextran. J Immunol 187:879-86
Endo, L M; Giannobile, J V; Dobbs, A K et al. (2011) Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin. J Investig Allergol Clin Immunol 21:405-9