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The human immunodeficiency virus type 1 (HIV-1) has evolved to coordinate its replication with the activation state of the host CD4T cell. To this end, it taps into major host cell signaling pathways and their associated transcription factors. Of these, T-cell activation and the transcription factor NF-?B, respectively, have become the best-studied examples. The past several years have revealed compelling evidence that another transcription factor family involved in T-cell activation, the nuclear factor of activated T cells (NFAT), plays an important role in the regulation of HIV-1. Major advances have been made in our understanding of the interaction of HIV-1 with this intriguing transcription factor. The duplicated NF-?B binding sites in the HIV-1 enhancer surprisingly also bind NFAT proteins and appear to be the most important targets for NFAT transactivation of the HIV-1 long terminal repeat. The crystal structure of NFAT1 bound to one of these duplicated sites was solved recently. Interestingly, it showed that NFAT1 binds to this site as a homodimer and occupies the core of the NF-?B site, suggesting mutually exclusive binding and alternate transactivation by these two factors. NFAT also regulates HIV-1 infection indirectly, as it can relieve a block to reverse transcription in quiescent T cells. In turn, HIV-1, and particularly its Tat and Nef gene products, can upregulate NFAT expression and activity. This reciprocal regulation between virus and transcription factor potentially creates a positive feedback loop, which may facilitate the establishment of early HIV-1 infection and, later, the transition from latent to productive infection. The immunosuppressive drug cyclosporin A (CsA) inhibits NFAT activity and thus represents a potential treatment for HIV-1 infection. Recent small-scale clinical trials have yielded optimistic results, suggesting roles for CsA after organ transplantation in HIV-1+ individuals and as adjunct treatment in stable early HIV-1 infection.Genes and Immunity (2004) 5, 158-167. doi:10.1038/sj.gene.6364047 Published online 5 February 2004 [ABSTRACT FROM AUTHOR]

The balance of Th1 (eg, interleukin-2 (IL-2)) and Th2 (eg, IL-4) cytokines produced by CD4 T cells markedly influences the outcome of the adaptive immune response. Although octamer transcription factor proteins increase IL-2 transcription in T cells, their role in IL-4 gene transcription remains controversial We have previously shown and now confirm that the proximal octamer binding site of the human IL-4 promoter, which separates the two most proximal NFAT binding sites, is bound prior to, but not after, activation in vivo. Since these two NFAT sites are essential for optimal IL-4 promoter activity, this suggested that prior engagement by octamer proteins might prevent adjacent NFAT binding and inhibit IL-4 gene transcription. In support of this hypothesis, here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away. Moreover, activity of an IL-4 reporter gene mutated in the proximal octamer binding site is increased compared to the wild-type promoter in human peripheral blood CD4 T cells. In addition, over-expression of either Oct-1 or Oct-2 decreased wild-type IL-4 promoter activity, while increasing IL-2 promoter activity. No decrease in promoter activity was seen when Oct-1 or Oct-2 was over-expressed with the octamermutant IL-4 reporter gene. Thus, octamer proteins are candidates to promote a Th1 rather than Th2 pattern of cytokine gene expression by activated CD4 T cells. [ABSTRACT FROM AUTHOR]

Activation-induced CD154 expression on CD4 T cells is prolonged in systemic lupus erythematosus, but the mechanism(s) for its dysregulation are unknown. The studies reported herein demonstrate that interleukin-15 (IL-15) is capable of prolonging CD154 expression on phytohemagglutinin (PHA)-activated CD4 T cells. As IL-15 signals through signal transducer and activator of transcription 5 (STAT5), predicted STAT5 binding sites in the human CD154 transcriptional promoter were identified, and STAT5 binding to the proximal CD154 promoter in vitro and in vivo following primary CD4 T-cell activation was demonstrated. Moreover, overexpression of wild-type STAT5 in primary human CD4 T cells augmented CD154 transcription, whereas overexpression of a dominant-negative (DN) STAT5 protein inhibited CD154 transcription. Mutation of the most proximal STAT5 binding site in the CD154 promoter resulted in diminished DNA binding and reduced CD154 transcriptional activity. Interestingly, STAT5-specific small interfering RNA inhibited CD154 surface expression at 48 but not 24 h after T-cell activation. Thus, these findings provide some of the first evidence to support a possible mechanistic link to explain how the overexpression of IL-15 observed in lupus patients may be involved in the prolonged expression of CD154 that has also been observed on lupus CD4 T cells. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30-40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro- and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA. [ABSTRACT FROM AUTHOR]

CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-γ-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154.Genes and Immunity (2008) 9, 640–649; doi:10.1038/gene.2008.67; published online 21 August 2008 [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNFα) blockade has recently been found to be ineffective in treating glandular and extraglandular manifestations of adult Sjögren syndrome (SS), including arthralgia and arthritis. We report a girl who developed purpura, polyarthritis, uveitis, and severe dental caries in the first year of life and optic neuritis by age three. SS was diagnosed at 11 years of age, when severe hypokalemic renal tubular acidosis developed during infliximab treatment for arthritis. In contrast to her other disease manifestations, the arthritis responded remarkably well to TNFα blockade, suggesting that TNFα blockers may have a role in the treatment of arthritis with pediatric SS. [ABSTRACT FROM AUTHOR]