Low Levels of NF-κB/p65 Mark Anergic CD4⁺T Cells and Correlate with Disease Severity in Sarcoidosis

Abstract

T lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-B (p50, p65, and p105), IB␣ (inhibitor of NF-B), T-cell receptor (TCR) CD3-chain, tyrosine kinase p56 LCK , and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4 ؉ T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4؉ T cells concurred with decreased levels of p50, p105, CD3, p56 LCK , IB␣, and NF-ATc2. Polyclonal stimulation of NF-B-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-␥]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granuloma formation (15,32). It is associated with anergic responses to skin tests and depressed peripheral T-lymphocyte responses in vitro (16,34). Several studies have examined the mechanisms of peripheral anergy in sarcoidosis. Early reports concluded that the T-cell anergy in sarcoidosis patients was partly due to a decreased production of interleukin 1 (IL-1) by monocytes (28). It was also shown that monocytes contributed to the suppressed lymphocyte responses by releasing increased amounts of prostaglandins (24). More recently, it was demonstrated that expansion of regulatory T cells (Treg cells) and diminished dendritic cell function could be responsible for the peripheral T-cell anergy observed with sarcoidosis. The proposed mechanisms implicated in this suppression included inhibition of IL-2 production and T-cell proliferation by Treg cells and a decreased ability of myeloid dendritic cells to stimulate T lymphocytes (46, 50). Sarcoid patients, however, do not appear to develop significant clinical evidence of immunosuppression, as they are capable of mounting effective immune responses to bacterial, fungal, and viral infections (70). Compartmentalization of these effective responses to the affected organs (i.e., lungs) could also explain the peripheral anergy associated with this disease (30, 31). Although the T-cell anergy associated with sarcoidosis was recognized long ago, the underlying mechanism and implications of this phenomenon for the pathogenesis of sarcoidosis remain unclear.A key event in the induction of CD4 ϩ T-cell responses is the stimulation of the T-cell receptor (TCR)/CD3 complex on the membranes of T cells by major histocompatibility complex class II (MHC-II) mol...

Splenic Niche Cells from Young Heterochronic Parabionts Have Decreased Capability to Amplify T-cell Proliferation in Vitro

“…In a clinical study on patients with sarcoidosis blood CD4 + cells had impaired proliferation and reduced content of RelA and Proliferation in Vitro p50, which are part to NFκB transcription factors, lower expression of p56 Lck -kinase, CD3ξ and a few other proteins, critical for T-cell activation. This can be partly caused by the functional exhaustion of T-cells and induction of the anergylike cell phenotype [33]. Similar results were obtained by Sunstedt and colleagues [34].…”

“…An analysis of expressed NFκB dimers revealed that p50 homodimers characterized as inactive were expressed in anergic T-cells at higher extent higher than p50-p65 heterodimers. Thus it has been established that in anergic T-cells activatory signaling is impaired [33] and decrease in expression of key regulatory proteins plays important role.…”

Solving the Conundrum: Immunogenetics of Sarcoidosis

“…In fact, some overlap with known loci for psoriasis and inflammatory bowel disease (7-9), findings consistent with the finding of multiple aberrations in adaptive immunity in patients with sarcoidosis (10)(11)(12). Others have previously demonstrated the significance of reduced levels of nuclear factor-kB (NF-kB)/P65 to sarcoidosis disease severity (12), as well as dysregulation within IL-12 and IL-23 pathways within cutaneous sarcoidosis specimens, using microarray analysis (13). Reversal of global CD4 1 subset dysfunction is present during spontaneous clinical resolution of pulmonary sarcoidosis.…”

Disturbed Homeostasis and Multiple Signaling Defects in the Peripheral Blood B-Cell Compartment of Patients with Severe Chronic Sarcoidosis

“…All patients had severe chronic sarcoidosis with no evidence of systemic autoimmunity or immunodeficiency diseases and were either on immunosuppressive therapy or not on therapy at the time of blood collection. The clinical features of this distinct subgroup of sarcoidosis patients have been described recently (35). Briefly, most patients were African-American woman with active sarcoidosis, multiple-organ involvement, and worsening disease.…”