Tumor Necrosis Factor (TNF) and Lymphotoxin-α PolymorphismsAssociated With Common Variable Immunodeficiency: Role in thePathogenesis of Granulomatous Disease

Abstract

Mullighan CG, Fanning GC, Chapel HM, Welsh KIJ Immunol.159199762366241Common variable immunodeficiency is a polygenic disorder of uncertain cause, which is often associated with autoimmune disease. There appear to be several distinct subtypes of common variable immunodeficiency and one subtype includes patients with granulomatous splenomegaly, decreased numbers of circulating CD4 T cells, and lymphadenopathy. This study investigated whether inherited polymorphisms in the MHC class III region (which includes tumor necrosis factor [TNF]-α and lymphotoxin-α) contributed to the development of this subtype of common variable immunodeficiency.Ninety patients with common variable immunodeficiency were studied. Twenty of those 90 patients had granulomas and were felt to belong to a distinct subgroup.Eight HLA class I and class II loci were typed using standard polymerase chain reaction (PCR) methods. Three biallelic TNF-α polymorphisms were genotyped and three lymphotoxin-α polymorphisms were genotyped using allele-specific PCR. Peripheral blood phenotyping was performed using standard flow cytometry techniques.The presence of granulomas correlated strongly with decreased numbers of total T cells, decreased numbers of total B cells, and depletion of naive T cells. This subpopulation of patients with granulomas also had an overrepresentation of the haplotype: A*01−Cw*0701−B*0801−DRB1*0301−DQB1*0201 which contains the TNF-308A polymorphism. In addition, as association between granulomas and the TNF+488A allele was demonstrated.This important study confirms that there is a clinically distinct subset of patients with common variable immunodeficiency and granulomatous disease. This subset appears to have a distinct genetic cause and characteristic derangements of peripheral blood lymphocyte subsets.TNF is essential for the formation of granulomas and this study hypothesized that inherited differences in TNF production might predispose patients to the granulomatous complications of common variable immunodeficiency. In whites, the TNF-308A polymorphism is in linkage disequilibrium with the haplotype cited above, which makes it difficult to prove whether the TNF polymorphism itself is responsible for the granulomatous complications. Despite this limitation, this study makes a compelling case that overproduction of TNF is implicated in the granulomatous complications of common variable immunodeficiency.