Uric Acid Directly Promotes Human T-Cell Activation

BackgroundAbnormally high serum uric acid levels have been associated with several disease conditions including gout and kidney stone disease. More recently, it was shown that uric acid crystals stimulate dendritic cell maturation, activate the NALP3 inflammasome, and enhance antigen-specific immune responses. We hypothesize that uric acid can also stimulate T cells directly and in the absence of antigen presentation.MethodsPurified primary human T cells were incubated with and without uric acid at concentrations of 50, 100, 150, and 200 μg/mL. The expression of T-cell activation markers CD25 and CD70 was assessed by flow cytometry. In other experiments, Jurkat T cells were used and the expression of the costimulatory molecule CD70 was determined at the mRNA level.ResultsUric acid directly activates primary human T cells in the absence of antigen presentation. Furthermore, primary human T cells and Jurkat T cells treated with uric acid overexpress the costimulatory molecule CD70, which plays an important role in T cell-B cell interaction and antibody production.ConclusionsThe finding that uric acid directly promotes T-cell activation in an antigen-independent system is novel and might play a mechanistic role in the inflammatory response observed in gouty arthritis and other immune-mediated diseases.     

Haemolytic anaemia in a multi-ethnic cohort of lupus patients: a clinical and serological perspective

Systemic lupus erythematosus is a chronic autoimmune disease that can be associated with a variety of haematological manifestations. We identified 76 patients with haemolytic anaemia in a cohort of 1251 unrelated female lupus patients enrolled in our studies. The presence of the various American College of Rheumatology clinical criteria for lupus and serological specificities were determined in lupus patients with haemolytic anaemia and compared with a group of race-matched control lupus patients without haemolytic anaemia. Clinical data were obtained from medical records, and serological specificities were determined in our clinical immunology laboratory at OMRF. The presence of haemolytic anaemia in lupus patients was associated with a higher frequency of proteinuria (OR = 2.70, P = 0.000031), urinary cellular casts (OR = 2.83, P = 0.000062), seizures (OR = 2.96, P = 0.00024), pericarditis (OR = 2.21, P = 0.0019), pleuritis (OR = 1.72, P = 0.028) and lymphopenia (OR = 1.79, P = 0.015). These findings were independent of the presence of thrombocytopenia, which was approximately five times more common in lupus patients with haemolytic anaemia. Lupus patients with haemolytic anaemia were about 8 years younger than lupus patients without haemolytic anaemia at the time of disease onset (P = 0.000001). In the absence of thrombocytopenia, lupus patients with haemolytic anaemia were approximately two times more likely to have anti-dsDNA antibodies (P = 0.024). The presence of haemolytic anaemia is associated with a subset of lupus characterized by a younger age of disease onset, and a more severe disease with a higher likelihood of renal involvement, seizures, serositis and other cytopenias.     

Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone mice

We have determined that abnormal DNA methylation in T cells coincides with the development of autoimmunity, using a mouse model that exhibits an age-dependent lupus-like disease (MRL/lpr mice). Splenic CD4(+) T cells were isolated from these mice at 5 and 16 wk of age (before and after autoimmunity is established) and the expression of DNA methyltransferase 1 (Dnmt1) and the methylation-sensitive gene Tnfsf7 (CD70) was measured. Bisulfite DNA sequencing was used to monitor the methylation status of the Tnfsf7 gene. We found that Dnmt1 steady-state mRNA levels were significantly lower in 16-wk-old MRL/lpr mice, which had established autoimmunity, compared to the 5-wk-old MRL/lpr mice. Furthermore, the expression of CD70 was higher in MRL/lpr mice at 16 wk. CD70 was overexpressed in MRL/lpr mice compared to age- and sex-matched MRL(+/+) controls. Bisulfite DNA sequencing of the Tnfsf7 gene in MRL/lpr mice revealed that at 16 wk, CG pairs were hypomethylated compared to 5-wk-old mice, and that Tnfsf7 from MRL/lpr mice was hypomethylated at 16 wk relative to age-matched MRL(+/+) controls. Our data indicate that decreased expression of Dnmt1 and the corresponding T cell DNA hypomethylation correlate with the development of age-dependent autoimmunity in MRL/lpr mice.     

Community pharmacists’ knowledge,behaviors and experiences about adverse drug reaction reporting in Saudi Arabia

Objective

To assess community pharmacists’ knowledge, behaviors and experiences relating to Adverse Drug Reaction (ADR) reporting in Saudi Arabia.

Methods

A cross-sectional study was conducted using a validated self-administered questionnaire. A convenience sample of 147 community pharmacists working in community pharmacies in Riyadh, Saudi Arabia.

Results

The questionnaire was distributed to 147 pharmacists, of whom 104 responded to the survey, a 70.7% response rate. The mean age of participants was 29 years. The majority (n = 101, 98.1%) had graduated with a bachelorette degree and worked in chain pharmacies (n = 68, 66.7%). Only 23 (22.1%) said they were familiar with the ADR reporting process, and only 21 (20.2%) knew that pharmacists can submit ADR reports online. The majority of the participants (n = 90, 86.5%) had never reported ADRs. Reasons for not reporting ADRs most importantly included lack of awareness about the method of reporting (n = 22, 45.9%), misconception that reporting ADRs is the duty of physician and hospital pharmacist (n = 8, 16.6%) and ADRs in community pharmacies are simple and should not be reported (n = 8, 16.6%). The most common approach perceived by community pharmacists for managing patients suffering from ADRs was to refer him/her to a physician (n = 80, 76.9%).

Conclusion

The majority of community pharmacists in Riyadh have poor knowledge of the ADR reporting process. Pharmacovigilance authorities should take necessary steps to urgently design interventional programs in order to increase the knowledge and awareness of pharmacists regarding the ADR reporting process.     

Outcomes of tracheostomy in COVID-19 patients in National Guard Health Affairs,Riyadh, Saudi Arabia

Objectives:To evaluate coronavirus disease 2019 (COVID-19) patient tracheostomy outcomes.Methods:All COVID-19 patients at the National Guard Hospital, Riyadh, Saudi Arabia, were retrospectively recruited. Those who had tracheostomies between April and December 2020 were included.Results:The population was 45 patients, of which 30 (66.7%) were males, 15 (33.3%) were females and the mean age was 66.76±12.74 years. The tracheostomy indications were anticipated prolonged weaning in 40 (88.9%) and failed extubation in 5 (11.1%) of the patients. The mean intubation to tracheostomy duration was 20.62±7.21 days. Mortalities were high, with most attributed to COVID-19. Mortality and a pre-tracheostomy C-reactive protein (CRP) uptrend were significantly related (p=0.039). Mortality and intubation to tracheostomy duration were not significantly related. The mean post-tracheostomy time to death was 10.64±6.9 days. Among the survivors, 20 (44.4%) males and 11 (24.4%) females were weaned off mechanical ventilation; 9 (20%) remained on ventilation during the study. The mean ventilation weaning time was 27.92±20 days.Conclusion:The high mortality rate was attributed to COVID-19. Mortality and a pre-tracheostomy CRP uptrend were significantly related; uptrend patients experienced far more mortalities than downtrend patients. Unlike previous findings, mortality and intubation to tracheostomy duration were not significantly related.     

T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus

CD40 ligand (CD40LG), encoded on the X chromosome, has been reported to be overexpressed on lupus T cells. Herein, we investigated the effect of DNA demethylation on T cell CD40LG expression and the production of IgG by autologous B cells in lupus. We found normal human T cells transfected with CD40LG induced autologous B cell activation and plasma cell differentiation. Both female lupus CD4+ T cells and demethylating agents treated CD4+ T cells overexpressed CD40LG mRNA. Further, lupus T cells from both genders or demethylated CD4+ T cells from healthy women overstimulated autologous B cells, and this could be reversed with anti-CD40LG Ab in only females. We demonstrated that female lupus CD4+ T cells and demethylated CD4+ T cells express high level of CD40LG and overstimulate B cells to produce IgG. This is due to DNA demethylation and thereby reactivation of the inactive X chromosome in female.     

Recurrent haemosiderotic fibrohistiocytic lipomatous lesion of the hand

Haemosiderotic fibrohistiocytic lipomatous lesion (HFLL) is a rare lesion, with uncertain aetiology, occurring almost predominantly in the lower limb. The lesion is known to recur locally in the foot and ankle region. We report a recurrent HFLL affecting the hand in a 55-year-old female, after excision of a soft tissue swelling in the same location 2 years previously. There was no history of trauma and the histological appearances of the original and recurrent lesions were almost identical, favouring a neoplastic nature of HFLL.