Is α‐actinin a target for pathogenic anti‐DNA antibodies in lupus nephritis?

Objective

Following recent reports that pathogenic murine anti‐DNA antibodies bind to α‐actinin, it was obviously of interest to assess the ability of human pathogenic anti–double‐stranded DNA (anti‐dsDNA) antibodies to bind this antigen. Both human monoclonal anti‐DNA antibodies and antibodies affinity purified from the sera of patients with systemic lupus erythematosus (SLE) were investigated.

Methods

An enzyme‐linked immunosorbent assay was established to measure immunoglobulin binding to α‐actinin. Antibodies binding dsDNA were purified from the sera of SLE patients who either had active renal disease or had never had renal disease. Serum samples were selected at times when the patients' sera exhibited high IgG binding to dsDNA. The binding of supernatants from 3 high‐affinity human anti‐dsDNA IgG hybridomas (RH14, B3, and DIL‐6) and 7 human IgM anti‐DNA hybridomas was also investigated.

Results

A greater proportion of anti‐dsDNA IgG–binding antibodies purified from patients with renal disease bound to α‐actinin than did those purified from the sera of patients without renal disease. The specificity of binding to the 100‐kd α‐actinin molecule was confirmed by Western blotting. The pathogenic human antibodies RH14 and B3 bound strongly to α‐actinin, while nonpathogenic DIL‐6 bound very weakly. RT84, the IgM antibody that binds dsDNA with the highest affinity, exhibited the greatest binding to α‐actinin.

Conclusion

The results of our study support the findings of previous studies using murine anti‐DNA monoclonal antibodies, which suggest that pathogenic anti‐dsDNA antibodies cross‐react with α‐actinin.

     

Is serum uric acid a predictor of long-term renal outcome in lupus nephritis?

Clinical Rheumatology - Recent studies observed an association between increased serum uric acid (SUA) levels and renal damage in lupus. However, the predictive value of UA for the development of...     

Is there a role for anti-CD20 antibodies in CLL?

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Serum level of CXCL 12 in patients with systemic lupus erythematosus: Is it worthy for predilection of lupus nephritis?

Aim of the workTo assess serum level of CXCL12 in systemic lupus erythematosus (SLE) patients and to study its relation to clinical features, disease activity and damage.Patients and methodsForty SLE patients and 40 controls were included. SLE disease activity index (SLEDAI) and the damage index were assessed. Serum CXCL12 level was measured using ELISA and renal biopsy done.ResultsThe mean age of the patients was 34.5 ± 10.4 years, disease duration 5 ± 5.2 years and were 38 females and 2 males (F:M 19:1). Renal biopsy was performed in 16 patients; 6 had inactive and10 active lupus nephritis (LN); 24 without signs suggestive of LN. Serum level of CXCL12 was significantly higher in patients (30.8 ± 16.9 ng/ml) than controls (20.2 ± 15.3 ng/ml) (p = 0.004). CXCL12 in patients with active LN (53.2 ± 25.3 ng/ml) was significantly elevated than those without LN (27 ± 12.5 ng/ml)(p < 0.001); and tended to be higher than those with inactive LN (34.2 ± 8.3 ng/ml)(p = 0.31). Levels were comparable between those with inactive LN and those without LN (p = 0.34). A significant correlation was found between serum CXCL12 and each of platelet count (p = 0.02), ANA titer (p = 0.007) and serum creatinine (p = 0.014). No significant correlations was found between CXCL12 and either SLEDAI (p = 0.59) or the damage index (p = 0.48). Alopecia was inversely associated with CXCL12 (p = 0.02).ConclusionCXCL12 is a potential key-player for SLE development. Adding this test to ANA, serum creatinine, platelet count and renal biopsy findings may enhance their diagnostic capacity for lupus nephritis and can help in early management and prediction of its prognosis.     

Is SAPHO syndrome a target for antibiotic therapy?

The etiology of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome remains unclear. Infectious factors are proposed to be relevant in the etiopathogenesis of the disease. To our knowledge, this is the first reported case of a proposed relationship between Staphylococcus aureus cultured from plantar pustule and SAPHO syndrome, which was successfully treated with co-trimoxazole (CTM) (sulfamethoxazole/trimetoprim). CTM might be the drug of choice for therapy for SAPHO syndrome because of combined antibiotic and immunomodulatory properties. Hypersensitivity testing of the medication in vitro was performed to identify, in the preclinical stage, the hypersensitivity reaction to CTM, which may have been severe.     

Cyclophosphamide-induced gonadal toxicity: a treatment dilemma in patients with lupus nephritis?

For patients with lupus nephritis, a 24-month course of intravenous cyclophosphamide has been advocated as the 'golden' standard of therapy. This regimen is associated with a high risk of persistent amenorrhoea in women or azoospermia in men. The risk of infertility is thus an important issue when discussing treatment options in patients with SLE. In this article I have summarised the information on cyclophosphamide-induced gonadal toxicity. In addition a brief overview is given of the literature on treatment of lupus nephritis. The data indicate that there is no hard evidence to support the superiority of long-term i.v. cyclophosphamide. Therefore, patients with SLE and the wish to have a baby should not be primarily treated with such a regimen.     

Is creatine kinase a target for AMP-activated protein kinase in the heart?

By phosphorylating target proteins, AMP-activated protein kinase (AMPK) inhibits ATP-utilizing proteins and activates ATP-synthesizing proteins, thereby increasing ATP synthesis under conditions such as hypoxia and ischemia. It has been proposed that AMPK also phosphorylates and inhibits creatine kinase (CK), the enzyme which catalyzes the reversible transfer of a phosphoryl group between creatine and ADP. Here, we examine the hypothesis that AMPK inactivates CK activity under three conditions where [AMP] and AMP-dependent AMPK velocity increase: increased workload both in the isolated rat heart and in the living rat, hypoxia in the living rat heart and low-flow ischemia in the isolated red blood cell perfused rat heart. For the experiments varying workload in the isolated rat heart (both ejecting and isovolumic models), we also changed oxidizable substrate available to the isolated heart in order to vary the [AMP]/[ATP]. CK reaction velocity in the intact rat heart was directly measured using (31)P magnetization transfer. The metabolically active AMP and ATP pools were determined from (31)P NMR measurements and we calculate AMP-dependent AMPK velocity from the Michaelis-Menten relationship. We found that under normoxic conditions where [AMP] and AMPK velocity increase, the linear relationship between CK and AMPK velocities is positive, not inverse. Under conditions of low pO(2) (hypoxia and low-flow ischemia), CK velocity fell 2-4-fold while the increase in AMP-activated AMPK activity was modest. This analysis illustrates the complex nature of AMPK regulation in the heart.     

Hypertension and Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide?

Hypertension and ethnicity are important prognostic factors in evolution of lupus nephritis. A cohort of 75 patients with lupus nephritis treated with cyclophosphamide was conducted to investigate the evolution of creatinine levels between Caucasians and Afro-descendants. A multiple linear model was used to evaluate the combined effects of ethnicity and hypertension over delta creatinine controlling confounders. Sample characteristics were: 85% females; mean (+/-SD) age of 33.6 +/- 12.0 years; 77% Caucasians; 40% hypertensive at renal biopsy; 91% WHO class IV; mean basal creatinine: 1.5 +/- 1.3 mg/dL; mean final creatinine: 2.1 +/- 2.5 mg/dL; 40% anaemia; proteinuria: 5.4 +/- 4.8 g/day. Comparing Caucasians and Afro-descendants, it was found: 28.1% versus 72.2% for hypertension (P = 0.002); 31.6% versus 66.7% for anaemia (P = 0.018); 5.9 +/- 5.0 versus 3.8 +/- 4.0. g/day (P = 0.02) for proteinuria. Other comparisons including basal creatinine did not reach statistical significance. Comparing outcomes between Caucasians and Afro-descendants, it was found: 10.5% versus 22.2% for doubling of creatinine (P = 0.24); 0.41 +/- 2.03 versus 1.05 +/- 2.41 for delta creatinine ( P = 0.29); 8.8% versus 22.2% for haemodialysis (P = 0.21) and 3.5% versus 5.6% for death (P = 0.99). Analysing delta creatinine with multiple linear regression showed that hypertension had a significant overall effect (b = 0.80; SE = 0.32; P = 0.015), ethnicity alone was not significant (b = 0.35; SE = 0.29; P = 0.228); however, the effect of hypertension on delta creatinine was more intense among Afro-descendants than among Caucasians (interaction term b = - 0.83; SE = 0.37; P = 0.027). Afro-descendants lupus patients experience worst prognosis of renal function probably due to the effect of hypertension and not ethnicity per se.     

Is TRPV1 a useful target in respiratory diseases?

This review focuses on the transient receptor potential vanilloid 1 (TRPV1). TRPV1 is a non-selective cation channel predominantly expressed in the cell membranes of sensory afferent fibers, which are activated multi-modally. In the mammalian respiratory system, immunohistochemical and electrophysiological studies have revealed heterogeneous localizations of TRPV1 channels in the airways and their presence in pleural afferents. TRPV1 channels in afferents are not only involved with sensory inputs, but also release several neuropeptides upon stimulation. These processes trigger pathophysiological effects (e.g. reflex bronchoconstriction, hypersecretion, cough, etc.) that cause various symptoms of airway diseases. Recent studies have identified several endogenous and exogenous substances that can activate TRPV1 in the lung. Because of its key role in initiating inflammatory processes, TRPV1 receptor antagonists have been proposed as therapeutic candidates. Therefore, a critical update of recent therapeutic results is also given in this review.