We demonstrated that patients with common variable immunodeficiency (CVID) and granulomatous and lymphocytic interstitial lung disease (GLILD) are at high risk for the development of B cell lymphomas and early mortality. We also found that a majority of patients with CVID and GLILD (CVID-GLILD) were infected with human herpes virus type 8 (HHV8).
In Aim 1, we will determine the prevalence of HHV8 infection in patients with a larger cohort of patients with CVID and broad spectrum of primary immunodeficiencies. To identify the source of HHV8, we will determine the prevalence of HHV8 infection in family members and household contacts of infected and uninfected patients with CVID and determine the molecular phylogeny of HHV8 in infected cohorts by amplifying the highly polymorphic HHV8 K1 ORF by PCR and performing DNA sequencing of the K1 amplicon.
In Aim 2, we will expand our observations on the role of HHV8 infection in lymphoproliferative disorders, lung and liver disease in patients with CVID by examining lung, liver or lymph node tissue biopsies for evidence of HHV8 infection.
In Aim 3, we will determine if abnormalities in cellular immunity identify patients with CVID at risk for infection with HHV8 and determine if specific promoter polymorphisms in the IL- 6, TNF-1 or IL-10 genes or mutations in the TACI gene predispose patients with CVID to infection with HHV8.
Aim 1 : Ascertain the molecular phylogeny of HHV8 in CVID patients infected with HHV8 and determine if HHV8 is an opportunistic pathogen in a larger cohort of patients with CVID and other primary immunodeficiencies.
Aim 2 : Ascertain the role of HHV8 infection in the etiology of lung disease, liver disease, lymphoproliferative disorders in patients with CVID.
Aim 3 : Determine if promoter polymorphisms of cytokine genes, dysregulated inflammatory cytokine production, and defects in cellular immunity or mutations in the TACI gene predispose patients with CVID to infection with HHV8.

Public Health Relevance

People with impaired immune systems (primary immunodeficiency) have an increased risk of developing and dying from cancer. In this application, we will try to determine the cause of the cancer that occurs in patients with primary immunodeficiency.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122539-04
Application #
8011454
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2008-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2011
Total Cost
$282,926
Indirect Cost
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226