#tnfa

Cytokines and systemic lupus erythematosus

SLE is an autoimmune rheumatic disease that principally affects women in the childbearing years.1 The prevalence of SLE varies between ethnic groups, being approximately 1:250 among black women, 1:1000 in Chinese women and 1:4300 in white women. SLE affects the joints, skin and blood in over 80% of patients and the kidneys, central nervous system and cardiopulmonary system in 30%–50% of patients. Between 10% and 30% of patients have anticardiolipin antibodies that are associated with arterial and venous thrombosis. The majority of patients demonstrate systemic manifestations, which may include fatigue, malaise, fever, anorexia, nausea and weight loss.

Tregs found in RA-synovial fluid (RA-SF) from patients in equal proportions compared to healthy SF and patient PBMC but are less suppressive in in vitro assays. - inhibition of suppressive capacity increases with increasing doses of RA-SF in culture. - effect replicated with TNFa alone but not other inflammatory cytokines found in RA-SF.

RA-SF Tregs express Foxp3 at similar level as normal Tregs but are less phosphorylated (by pSer/Tyr western) - phosphorylation is inhibited by RA-SF and TNFa.  - by site-directed mutagenesis, Ser418 identified as phosphorylation site required for full Treg activity.

TNFa signalling through NFkB upregulates PP1 phosphatase expression --> increased dephosphorylation of Ser418. - Ser418 is in C-terminal DNA-binding helix domain: phosphorylation may be required for adequate binding (adjacent lysine residues are acetylated). - Ser418 dephophorylation (or mutation to alanine S418A) increases IL-2 production, S418E (phosphoserine mimetic) decreases slightly compared to WT. 

Anti-TNFa therapy (infliximab) in human RA patients restores Foxp3 phosphorylation and suppressive function.

Fig 3

INTERESTING: Draws attention to the role of post-transcriptional modification in modulating Foxp3 function. What event/kinase drives Foxp3 phosphorylation upon activation? Are there other phosphorylation sites which modulate Treg suppression? NOTE: relevance for PI3K inhibition!