TNF AND LYMPHOTOXIN-ALPHA POLYMORPHISMS ASSOCIATED WITH COMMON VARIABLE IMMUNODEFICIENCY - ROLE IN THE PATHOGENESIS OF GRANULOMATOUS-DISEASE

A subgroup of common variable immunodeficiency (CVID) patients have di stinct clinical features, particularly granulomata, splenomegaly, char acteristic blood lymphocyte phenotype, and elevated circulating TNF le vels. To investigate the genetic basis for this phenotype, 150 CVID pa tients and 200 controls were genotyped for six biallelic TNF and lymph otoxin-alpha (LT alpha) polymorphisms and eight class I and II HLA loc i using PCR and sequence specific primers (PCR-SSP) sequence-specific primers. Clinical and immunophenotypic data were collected for 90 pati ents to examine associations with CVID patient subgroups, The presence of granulomata (22% of patients) was strongly associated with splenom egaly, T and B lymphopenia, reduced CD4(+)CD45RA(+) T cells, and CD8()CD57(+) lymphocytosis, confirming the concept of a subgroup of patien ts with distinct clinical and laboratory features. The uncommon TNF +4 88A allele was strongly associated with this subgroup (p = 0.0005). Th e association between ''granulomatous'' CVID and TNF +488A was indepen dent of HLA class I and II associations. We postulate that the presenc e of the TNF +488A allele, or alleles in linkage disequilibrium with i t, contributes to the high levels of TNF and granulomatous complicatio ns characteristic of this subgroup of patients.