Familial Aggregation of High Tumor Necrosis Factor Alpha Levels in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-α) levels. We explored circulating TNF-α levels in SLE families to determine whether high levels of TNF-α were clustered in a heritable pattern. We measured TNF-α in 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF-α trait were assessed. SLE-affected individuals had the highest TNF-α levels, and TNF-α was significantly higher in unaffected first degree relatives than healthy unrelated subjects (P = 0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF-α levels, resulting in a first degree relative recurrence risk of 4.48 (P = 2.9 × 10−5). Interestingly, the median TNF-α value in spouses was similar to that of the first degree relatives. Concordance of the TNF-α trait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-α in SLE pathogenesis, and TNF-α levels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.

Involvement of TLR4 in Oxidized LDL/β2GPI/Anti-β2GPI-Induced Transformation of Macrophages to Foam Cells

“…Shown are the representative results of three separate experiments with similar results. A B mokines promote the formation and development of atherosclerotic plaque as well as intravascular thrombi in patients with autoimmune diseases [35][36][37][38][39][40][41] . Although the involvement of cytokines and chemokines in the pathogenesis of atherosclerosis and autoimmune diseases is widely accepted, little is known about the underlying mechanisms or how these molecules trigger vascular inflammation and interact with autoantibodies.…”

Advances in lupus genetics

“…In African-American SLE patients, it seems that high type I IFN levels are more dependent autoantibodies than in European-American SLE patients, as the correlation between autoantibodies to RNA-binding proteins and high IFN is stronger in African-American SLE cohorts than in European-American SLE cohorts 28, 30 . Familial aggregation has also been observed in IL-10 and tumor necrosis factor alpha (TNF-α) cytokines in SLE families 31, 32 , although in each of these studies there was also correlation between SLE patients and their spouses (unrelated family members), suggesting an environmental contribution to the familial correlation. No spousal correlation was observed with type I IFN levels.…”

Influenza A (H1N1) virus infection triggers severe pulmonary inflammation in lupus-prone mice following viral clearance

“…Although controversial, TNFα plays a role in the pathogenesis of SLE with increased levels of the cytokine circulating in the serum of patients with elevated disease activity [39]. Further, high TNFα levels in SLE patients may be related to heritable factors as unaffected first degree relatives also had significantly higher TNFα levels compared to healthy unrelated control subjects [40]. Interestingly, rheumatoid arthritis patients treated with TNF blockers can develop drug-induced lupus with ANA and anti-dsDNA antibodies, and lupus-prone mice that are TNF deficient develop accelerated autoimmunity [41, 42].…”

“…Increased apoptosis in the spleen and lymph nodes of MRL-Fas lpr without worsening of disease symptoms in the kidney suggests aberrant mechanisms of apoptosis in SLE may be circumvented during IAV infection to improve splenomegaly and lymphadenopathy. As autoimmune patients and numerous lupus-prone mouse models have interference in the expression of apoptotic factors, such as Fas, FasL, TRAIL, TNFα, Bcl2/Bim, and programmed cell death 1, the correction of aberrant apoptotic effector mechanisms in SLE by viral infection may provide insights to the cause and potential therapies in SLE [40, 48-51]. …”