Abstract
Tumor necrosis factor-receptor associated periodic syndrome
(TRAPS) is a dominantly inherited auto-inflammatory disorder
caused by mutations in TNFRSF1A, the gene encoding for
tumour necrosis factor receptor superfamily 1A. The
mechanism of inflammation in TRAPS is still unknown. In
particular the involvement of adaptive immunity in autoinflammatory
disorders hasn’t been investigated yet. In this
project we investigated how TNFa/TNRSF1A signalling
network regulates T cell responses. In particular, we focused on
conventional CD4+CD25- (Tconv) and regulatory CD4+CD25+
(Treg) T cell functions in TRAPS patients carrying either high
or low penetrance mutation in TNFRSF1A gene (HP-TRAPS
and LP-TRAPS, respectively). HP-TRAPS showed an upregulation
of several inflammation-related molecular signalling
pathways in Tconv cells. In addition, these patients had a lower
frequency of peripheral Treg cells which also displayed a
defective suppressive phenotype. These alterations were
partially found in LP-TRAPS who also carried a milder
symptomatology thus suggesting suggest a specific link
between the penetrance of the TNFRSF1A mutation and the T
cell phenotype. Taken together, these data envision a novel role
for adaptive immunity in the pathogenesis of TRAPS involving
both CD4+ Tconv and Treg cells raising a novel mechanism of
inflammation in the context of auto-inflammatory disorders
