Kidney biopsy is essential for the diagnosis and management of lupus nephritis. The risk of bleeding complication, however, is not defined in the systemic lupus erythematosus population. A retrospective cohort study was conducted to determine predictors of major and minor complications among patients with systemic lupus erythematosus undergoing percutaneous ultrasound-guided kidney biopsy. Major complications included bleeding necessitating intervention, hypotension requiring vasopressors or higher level of care or death. Minor complications included moderate or large (≥ 4 cm in largest diameter) perinephric hematoma, gross hematuria or voiding difficulties. All patients were observed for at least 23 h post-procedure. The overall incidence of bleeding was 10.5% (2.7% major, 7.8% minor). Adjusted logistic regression showed that for every 10,000 cells/mm3 decrease in platelet count, risk for major and any complication increased by 27% (odds ratio 1.27; 95% confidence intervals 1.06–1.51; p=0.01) and 8% (odds ratio 1.08; 95% confidence intervals 1.02–1.15; p=0.01), respectively. Patients with a platelet count <150,000 cells/mm3 were 30 times more likely to experience a major complication (p=0.002). Other candidate predictors, including steroid exposure, kidney function, hematocrit and histopathology, were not significant. Kidney biopsies are well tolerated in patients with systemic lupus erythematosus. However, patients with pre-biopsy platelet counts <150,000 cells/mm3 are at markedly increased risk for a major bleeding complication.
Renal lupus; nephritis; systemic lupus erythematosus; kidney biopsy; bleeding complication
The aims of this study were to examine the predictors of time-to-neuropsychiatric (NP) damage and its impact on mortality in 632 systemic lupus erythematosus (SLE) African American, Hispanic and Caucasian LUMINA patients, age ≥ 16 years and disease duration ≤ 5 years at baseline (T0). Time-to-NP damage and its impact on mortality were examined by Cox proportional hazards regressions. One-hundred eighty-five (29.3%) patients developed NP-damage over a mean (SD) disease duration of 5.6 (3.7) years. After adjusting for neuropsychiatric manifestations present, older age [Hazard ratio (HR)=1.02; 95% [Confidence interval (CI) 1.00–1.04)], Caucasian ethnicity (HR=1.87; 95% CI 1.22-2.87), disease activity over the disease course (HR=1.16; 95% CI 1.12–1.21), diabetes (HR=3.47; 95% CI 1.44–8.38) and abnormal illness-related behaviors (HR=1.05; 95% CI 1.02–1.08) were associated with a shorter time to NP-damage. Photosensitivity (HR=0.65; 95% CI 0.44–0.95), anemia (HR=0.56; 95% CI 0.31–0.98), Raynaud’s phenomenon (HR=0.49; 95% CI 0.34–0.72), a medium dose of prednisone (HR=0.56; 95% CI 0.35–0.92) and hydroxychloroquine use (HR=0.58; 95% CI 0.36–0.93) were associated with a longer time. NP-damage did not contribute to mortality. Older age, Caucasian ethnicity, disease activity and abnormal illness-related behaviors are associated with a shorter time-to-NP damage; hydroxychloroquine and a medium dose of prednisone with a longer time.
To examine the role of place of residency in the expression and outcomes of SLE in a multi-ethnic Latin American cohort.
Patients and Methods
SLE patients (<2 years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory, and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses.
122 (8.6%) of 1426 patients were rural residents. Their median age (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and a lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses, and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in both, rural and urban patients.. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06–2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00–3.11).
Rural residency associates with Mestizo ethnicity, lower socioeconomic status, and renal disease occurrence. It also plays a role on disease activity at diagnosis and kidney involvement but not on the other end-points examined.
To determine the factors associated with peripheral vascular damage in systemic lupus erythematosus (SLE) patients and its impact on survival from LUMINA, a longitudinal multiethnic cohort. Peripheral vascular damage was defined by the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). Factors associated with peripheral vascular damage were examined by univariable and multivariable logistic regression models and its impact on survival by a Cox multivariable regression. Thirty-four (5.3%) of 637 patients (90% women, mean [SD] age 36.5 [12.6] (16-87) years developed peripheral vascular damage. Age and the SDI (without peripheral vascular damage) were statistically significant (odds ratio [OR] =1.05, 95% confidence interval [CI] 1.01-1.08; p=0.0107 and OR=1.30, 95% CI 0.09-1.56; p=0.0043, respectively) in multivariable analyses. Azathioprine, warfarin and statins were also statistically significant, glucocorticoid use was borderline statistically significant (OR=1.03, 95% CI 0.10-1.06; p=0.0975). In the survival analysis, peripheral vascular damage was independenly associated with a diminished survival (Hazard Ratio =2.36; 95% CI 1.07-5.19; p=0.0334). In short, age was independently associated with peripheral vascular damage, but so was the presence of damage in others organs (ocular, neuropsychiatric, renal, cardiovascular, pulmonary, musculoskeletal and integument) and some medications (probably reflecting more severe disease). Peripheral vascular damage also negatively affected survival.
Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN) regulated genes because of a continuous production of IFN-α. The cellular and molecular background to this IFN-α production has started to be elucidated during the last years, as well as the consequences for the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDC) activated by immune complexes containing nucleic acids secrete type I IFN in SLE. Type I IFN causes differentiation of monocytes to myeloid-derived dendritic cell (mDC) and activation of auto-reactive T and B cells. A new therapeutic option in patients with SLE is, therefore, inhibition of IFN-α, and recent data from a phase I clinical trial suggests that administration of neutralizing monoclonal antibodies against anti-IFN-α can ameliorate disease activity.
Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder where interplay of environmental and genetic risk factors leads to progressive loss of tolerance to nuclear antigens over time, finally culminating in clinical disease. The heterogeneity of clinical manifestations and the disease’s unpredictable course characterized by flares and remissions are very likely a reflection of heterogeneity at the origin of disease, with a final common pathway leading to loss of tolerance to nuclear antigens. Impaired clearance of immune complexes and apoptotic material and production of autoantibodies have long been recognized as major pathogenic events in this disease. Over the past decade the type I interferon cytokine family has been postulated to play a central role in SLE pathogenesis, by promoting feedback loops progressively disrupting peripheral immune tolerance and driving disease activity. The identification of key molecules involved in the pathogenesis of SLE will not only improve our understanding of this complex disease, but also help to identify novel targets for biological intervention.
autoantibody; autoantigen; B cells; complement; dendritic cells; genetics; immune complex; interferon; pathogenesis; systemic lupus erythematosus; Toll-like receptor
Experimental and animal studies suggested that estrogens play an important role in the development of systemic lupus erythematosus (SLE) through a variety of mechanisms involved in the regulation of the immune system. The objective of this study was to investigate the association between genetic variations in estrogen metabolic pathway genes, including estrogen receptor α (ESR1), estrogen receptor β (ESR2), and aromatase (CYP19A1), and risk of SLE. We performed a genetic study of SLE among 46 medical record-confirmed female SLE cases and 102 female controls participating in an Internet-based case–control study of SLE. Polymorphisms analysed included: ESR1 PvuII, XbaI, and GT repeat; ESR2 RsaI, AluI, and CA repeat; and CYP19A1 RsaI, SfaN1, and TTTA repeat. We found significant association of the ESR1 PvuII (PP vs. pp, odds ratio (OR): 3.1, 95% confidence interval (CI): 1.1–9.3) and XbaI (XX vs. xx, adjusted OR: 3.4, 95% CI: 1.1–10.5) with SLE. Carrying the PPXX genotype conferred the highest risk (PPXX vs. ppxx, OR: 4.6, 95% CI: 1.3–15.9). We also found an association of SLE with the ESR2 CA repeat (SS vs. LL, OR: 2.8, 95% CI: 1.0–8.0). Our results support a role of estrogen in pathogenesis of SLE and suggested that genetic variants in the estrogen receptor genes might influence susceptibility.
aromatase; case–control; estrogen receptor gene; genetic polymorphism; systemic lupus erythematosus
The objective of this study was to determine the feasibility of studying acupuncture in patients with systemic lupus erythematosus (SLE), and to pilot test the safety and explore benefits of a standardized acupuncture protocol designed to reduce pain and fatigue. Twenty-four patients with SLE were randomly assigned to receive 10 sessions of either acupuncture, minimal needling or usual care. Pain, fatigue and SLE disease activity were assessed at baseline and following the last sessions. Safety was assessed at each session. Fifty-two patients were screened to enroll 24 eligible and interested persons. Although transient side effects, such as brief needling pain and lightheadedness, were reported, no serious adverse events were associated with either the acupuncture or minimal needling procedures. Twenty-two participants completed the study, and the majority (85%) of acupuncture and minimal needling participants were able to complete their sessions within the specified time period of 5–6 weeks. 40% of patients who received acupuncture or minimal needling had ≥30% improvement on standard measures of pain, but no usual care patients showed improvement in pain. A ten-session course of acupuncture appears feasible and safe for patients with SLE. Benefits were similar for acupuncture and minimal needling.
acupuncture; pain; randomized controlled trial; systemic lupus erythematosus
Aluminium oxyhydroxide (alum), a nano-crystaline compound forming agglomerates, has been introduced in vaccine for its immunologic adjuvant effect in 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remains incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at site of previous intra-muscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at site of injection or may diffuse and accumulate in distant organs. Animal experiments indicate that biopersistent nanomaterials taken-up by monocytes-lineage cells in tissues, e.g. fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in brain.
Adjuvants, Immunologic; adverse effects; Alum Compounds; adverse effects; Animals; Fasciitis; chemically induced; immunology; pathology; physiopathology; Humans; Myositis; chemically induced; immunology; pathology; physiopathology; Nanostructures; Phagocytes; metabolism; Syndrome
Background and purpose
Systemic lupus erythematosus (SLE) is associated with significant cerebrovascular and neuropsychiatric disease for which multiple pathogeneses have been proposed. Although global cerebral hypoperfusion has been proposed, there are limited data about intracerebral arterial hemodynamics. Transcranial Doppler (TCD) allows portable, high temporal and spatial resolution, noninvasive blood velocity measurements in the middle cerebral arteries, and calculations of standard resistivity (RI) and pulsatility (PI) indices. RI and PI correlate with cerebral hemispheric arteriolar tone, blood flow resistances, and impedances. Accordingly, we hypothesized that there would be significant differences (p<0.05) in RI and PI between SLE patients and healthy, age and gender matched controls.
TCD was used to measure RI and PI bilaterally on 34 stable SLE patients (35±11 years) and 15 control subjects (34±10 years). Patients and controls had similar, normal blood pressures and were examined in the supine position during normal, resting respiration. RI and PI were determined by a blinded, experienced observer.
There were no significant differences in RI and PI bilaterally within each cohort. However, SLE patients had significantly lower average RI and PI values compared with controls: 0.45±0.10 versus 0.52±0.05 (p<0.05); and 0.65±0.19 versus 0.77±0.12, (p<0.05); respectively.
These preliminary data suggest that RI and PI values in the human middle cerebral artery are significantly lower in SLE compared with controls. These indices indicate that middle cerebral arterial resistances and impedances are decreased in SLE. Under normotensive conditions, the results are consistent with hyperperfusion in SLE with increased arteriolar dilation and increased cerebral blood flow.
lupus; middle cerebral artery; pulsatility index; resistivity index; transcranial Doppler
Anti-RNA polymerase III (RNAP III) antibodies are highly specific for scleroderma (SSc) and associated with diffuse SSc and renal crisis. Coexistence of anti-RNAP III and other SSc autoantibodies is rarely documented. We report three cases with coexisting anti-RNAP III and anti-U1RNP. Autoantibodies in 3829 sera from rheumatology clinics were screened by immunoprecipitation. Anti-RNAP III-positive sera were also examined by immunofluorescence and anti-RNAP III ELISA. In total, 35 anti-RNAP III-positive sera were identified by immunoprecipitation, in which three had coexisting anti-U1RNP. All three were anti-RNAP III ELISA positive. Two had anti-RNAP I dominant (vs. RNAP III) reactivity and showed strong nucleolar staining. A case with anti-U1/U2RNP (U2RNP dominant) had systemic lupus erythematosus (SLE)–SSc overlap syndrome; however, the remaining two cases had SLE without signs of SSc. All three cases of anti-RNAP III + U1RNP fulfilled ACR SLE criteria but none in the group with anti-RNAP III alone (p = 0.0002). In contrast, only one case in the former group had sclerodermatous skin changes and Raynaud’s phenomenon, vs. 92% with scleroderma in the latter (p < 0.05). Although anti-RNAP III is highly specific for SSc, cases with coexisting anti-U1RNP are not so uncommon among anti-RNAP III positives (8%, 3/35) and may be SLE without features of SSc.
anti-RNA polymerase III antibodies; anti-U1RNP antibodies; autoantibodies; scleroderma
Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independent of conventional measures of renal function. We examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis.
We measured serum cystatin C, creatinine, TNF-α, IL-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) and other clinical parameters in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models.
Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than controls (1.09[Interquartile range, IQR: 0.85–1.28]mg/L vs. 0.89 [IQR: 0.76–0.99]mg/L; P<0.001 after adjusting for age, race and sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (P=0.04), ESR (P<0.001), CRP (P=0.04), TNF-α (P=0.008) and IL-6 (P=0.01) after adjustment for age, race and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, P= 0.31) and the association remained non-significant after adjustment for age, race, sex and Framingham risk score (P=0.99).
Cystatin C was higher in patients with SLE than control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.
cystatin C; systemic lupus erythematosus; renal function; atherosclerosis; Inflammation
To assess aortic stiffness by transesophageal echocardiography (TEE) and to determine its clinical predictors and relation to age, blood pressure, renal function, and atherosclerosis, 50 patients with systemic lupus erythematosus (SLE), 94% women, with a mean age of 38 ± 12 years and 22 age and gender matched healthy controls underwent clinical and laboratory evaluations and multiplane TEE to assess stiffness, intima-media thickness (IMT), and plaques of the proximal, mid, and distal descending thoracic aorta. At each level and overall aortic stiffness by the pressure-strain elastic modulus was higher in patients than in controls after adjusting for age (overall, 8.25 ± 4.13 versus 6.1 ± 2.5 Pascal units, p = 0.01). Patients had higher aortic stiffness than controls after adjusting both groups to the same mean age, blood pressure, creatinine, and aortic IMT (p = 0.005). Neither IMT nor plaques were predictors of aortic stiffness. Moreover, normotensive patients, those without aortic plaques, and non-smokers had higher stiffness than controls (all p <0.05). Age of SLE diagnosis, non-neurologic damage score, and mean arterial pressure during TEE were the only independent predictors of aortic stiffness (all p ≤0.02). Thus, aortic stiffness may be a primary form of premature functional vasculopathy in SLE.
aortic stiffness; systemic lupus erythematosus; transesophageal echocardiography; atherosclerosis
Antiphospholipid syndrome is characterized by autoantibodies against cardiolipins (aCL), lupus anticoagulant, and independent β2-glycoprotein (β2GPI). Controversy exists as to whether vaccination triggers the development of anti-phospholipid antibodies (aPL) in systemic lupus erythematosus (SLE) patients.
SLE patients (101) and matched controls (101) were enrolled from 2005 to 2009 and received seasonal influenza vaccinations. Sera were tested by ELISA for aCL at baseline, 2, 6, and 12 weeks after vaccination. Vaccine responses were ranked according to an overall anti-influenza antibody response index. Individuals with positive aCL were further tested for β2GPI antibodies.
SLE patients and healthy controls developed new onset aCL post-vaccination (12/101 cases and 7/101 controls, OR 1.81, p=0.34). New onset moderate aCL are slightly enriched in African American SLE patients (5/36 cases; p=0.094). The optical density (OD) measurements for aCL reactivity in patients were significantly higher than baseline at 2 weeks (p<0.05), 6 weeks (p<0.05), and 12 weeks (p<0.05) post vaccination. No new β2GPI antibodies were detected among patients with new aCL reactivity. Vaccine response was not different between patients with and without new onset aCL reactivity (p=0.43).
This study shows transient increases in aCL, but not anti-β2GPI responses, after influenza vaccination.
Influenza; vaccine; antiphospholipid antibodies; systemic lupus erythematosus
The patient’s perspective of how their health affects their function is health-related quality of life (HRQOL). HRQOL is poorer in patients with systemic lupus erythematosus (SLE). Few HRQOL studies in SLE patients have focused on African Americans despite an increased disease burden compared with Caucasians. The African American Gullah population of South Carolina has a homogeneous genetic and environmental background and a high prevalence of multi-patient families with SLE. Demographics, medical history, and Short-Form 36 (SF-36) were measured within a cohort of Gullah SLE cases and related controls. Compared with related controls (n = 37), cases (n = 89) had a lower Physical Component Summary (PCS, 41.8 vs. 52.3, p < 0.01), but not Mental Component Summary (MCS, 55.0 vs. 56.0, p = 0.70). The difference in PCS was no longer significant upon adjustment for working status, disability, and medical conditions. None of the 11 SLE American College of Rheumatology criteria, disease duration, or Systemic Lupus International Collaborating Clinics Damage Index were associated with either PCS or MCS. Cases and controls had similar MCS scores. We hypothesize that this lack of effect of SLE on MCS may be due to disease-coping mechanisms interplaying with cultural factors unique to the Gullah.
quality of life; SLE; systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that has a significantly higher prevalence, morbidity and mortality in African Americans compared with Americans of European descent. The pathogenesis of lupus is unclear but appears to be a result of environmental factors interacting with a genetically susceptible host. Despite the high disease load of SLE in African Americans, there is the perception that lupus is relatively rare in Africa. This prevalence gradient suggests that comparative studies of related cohorts from the two continents may provide insight into the genetic/environmental interactions that result in the development of lupus. To define if a lupus gradient exists, we began a study of autoimmunity prevalence utilizing two unique cohorts. The first is the Gullah population of the Sea Islands of South Carolina, who are unique in their low genetic admixture and their known ancestral heritage. The second is the population of young women served by the West Africa Fistula Foundation in Bo, Sierra Leone. Anthropologic studies indicate a direct ancestral link between the Gullah population and Sierra Leoneans. Since it is impossible to perform an epidemiologic study of lupus in Sierra Leone at this time, we assessed the prevalence of lupus serum autoantibodies, serologic evidence of specific infections and levels of serum 25-OH vitamin D in young women in the two cohorts who have no known relatives with lupus. Our results indicate similar prevalence of serum antinuclear antibodies in the two cohorts, though there was a significantly increased prevalence of antiphospholipid and anti-Sm antibodies in the Sierra Leone cohort. Seropositivity to common viral infections was significantly higher in women from Sierra Leone, while serum 25-OH vitamin D levels were markedly lower in the Gullah population. These data suggest that the prevalence of autoimmunity is similar in the two populations, but that there are significant environmental differences that may impact progression to autoimmune disease. Further studies comparing these two cohorts is likely to provide important insight into the impact of environmental factors on development of lupus.
African American; lupus; prevalence gradient; vitamin D
Women with systemic lupus erythematosus (SLE) have increased risk for coronary heart disease (CHD) which is underestimated by the Framingham risk score (FRS). We hypothesized that new risk scores that include inflammation or vascular age in the risk calculation would better identify women with SLE at risk for CHD, particularly in those with subclinical coronary atherosclerosis. We calculated the FRS and Reynolds risk score (RRS) in 121 women with SLE and 65 age-matched female controls; coronary age-modified risk scores (camFRS, camRRS) were calculated using coronary age derived from the coronary artery calcium (CAC) score. Risk scores were compared in SLE and controls, and in SLE patients with and without CAC. Although CAC was present in 21 SLE patients (17%) and 4 controls (6%) (P=0.033); the FRS, camFRS, RRS, and camRRS, did not differ significantly among SLE and controls (P>0.05), but were all significantly higher in SLE patients with CAC compared to those without (P< 0.001 for all). The cam-FRS (8%, P=0.016) but not cam-RRS (5%, P=0.221) assigned significantly more SLE patients to a category of ≥10% risk than conventional FRS (1%) and RRS (2%). The RRS was of limited use but coronary age may improve CHD risk prediction in SLE.
SLE; cardiovascular risk; atherosclerosis
Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members.
Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method.
In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid Methionine to Arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient’s family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance.
The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)), has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in high risk African-American population.
The antiphospholipid syndrome (APS), as both a primary syndrome and a syndrome in association with systemic lupus erythematosus (SLE), can be a devastating disease. It is unclear what factors (genetic and/or environmental) lead to the generation of antiphospholipid antibodies (aPL). It is equally unclear why only certain individuals with aPL develop clinical events. We hypothesize that innate immune activation plays a critical role at two distinct stages of APS, namely, the initiation phase, in which aPL first appear, and the effector phase, in which aPL precipitate a thrombotic event. According to the model we propose, aPL alone are insufficient to cause thrombosis and a concomitant trigger of innate immunity, e.g. a toll-like receptor (TLR) ligand, must be present for thrombosis to occur. Here, we discuss our findings that mice immunized with β2-glycoprotein I (β2GPI) and lipopolysaccharide (LPS), a TLR ligand, produce high levels of aPL and other SLE-associated autoantibodies, and develop lupus-like glomerulonephritis. We also discuss our data showing that autoantibodies to heat shock protein 60 (HSP60), an ‘endogenous TLR ligand’, promote thrombus generation in a murine model of arterial injury. Thus, both pathogen-derived TLR ligands (e.g. LPS) and endogenous TLR ligands (e.g. HSP60) may contribute to the pathogenesis of APS. This putative dual role of innate immunity provides new insight into the generation of aPL as well as the enigma of why some individuals with aPL develop APS, while others do not.
PMID: 20353968 CAMSID: cams2352
antiphospholipid syndrome; β2-glycoprotein I; heat shock protein 60; innate immunity; lipopolysaccharide; toll-like receptor ligands
Antiphospholipid antibodies (aPL), the majority of which are directed against β2-glycoprotein I (β2GPI), are associated with an increased incidence of venous and arterial thrombosis. The pathogenesis of antiphospholipid/anti-β2GPI-associated thrombosis has not been defined, and is likely multifactorial. However, accumulating evidence suggests an important role for endothelial cell activation with the acquisition of a procoagulant phenotype by the activated endothelial cell. Previous work demonstrated that endothelial activation by antiphospholipid/anti-β2GPI antibodies is β2GPI-dependent. We extended these observations by defining annexin A2 as an endothelial β2GPI binding site. We also observed that annexin A2 plays a critical role in endothelial cell activation induced by anti-β2GPI antibodies, and others have described direct endothelial activation by anti-annexin A2 antibodies in patients with aPL. Similar findings have been reported using human monocytes, which also express annexin A2. Because annexin A2 is not a transmembrane protein, how binding of β2GPI/anti-β2GPI antibodies, or anti-annexin A2 antibodies, to endothelial annexin A2 causes cellular activation is unknown. Recent studies, however, suggest an important role for the Toll-like receptor family, particularly TLR4. In this article, we review the role of these interactions in the activation of endothelial cells by aPL. The influence of these antibodies on the ability of annexin A2 to enhance t-PA-mediated plasminogen activation is also discussed.
annexin; antiphospholipid; β2-glycoprotein I; endothelial; thrombosis
Some T cells react with lipid antigens bound to antigen-presenting molecule CD1d. Numbers and functions of a subset of such lipid-reactive T cells are reduced in patients with systemic lupus erythematosus (SLE) and their relatives, as well as in genetically susceptible and chemically induced animal models of lupus-like disease. We have reported that the germline deletion of CD1d exacerbates lupus, suggesting a protective role of these cells in the development of lupus. The use of a knockout mouse model in this study, however, did not allow examination of the role of these cells at different stages of disease. Here, we describe an approach to deplete CD1d-dependent T cells, which allowed us to investigate the role of these cells at different stages of disease in genetically lupus-prone NZB/NZW F1 (BWF1) mice. Repeated intravenous injections of large numbers of CD1d-transfected cells resulted in ~50–75% reduction in these cells, as defined by the expression of CD4, NK1.1 and CD122, and lack of expression of CD62 ligand. TCR γδ +NK1.1+ cells were also reduced in the recipients of CD1d-transfected cells as compared with control recipients. Such depletion of CD1d-reactive T cells in preclinical BWF1 mice resulted in disease acceleration with a significant increase in proteinuria and mortality. In older BWF1 mice having advanced nephritis, however, such depletion of CD1d-reactive T cells resulted in some disease improvement. Taken together, these data as well as our published studies suggest that CD1d-reactive T cells protect against the development of lupus in animal models. However, these cells appear to be unable to suppress established lupus nephritis in these animals, and might even play a disease aggravating role in late stages of disease.
animal models; antigen-presenting molecule; autoantibody; lupus nephritis
Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.
polymorphism; PTPN22 gene; rheumatoid arthritis; systemic lupus erythematosus
Fatigue and physical deconditioning are common, difficult to treat conditions among patients with systemic lupus erythematosus (SLE). The aim of this pilot study is to evaluate the effectiveness of a home-based exercise program using the Wii Fit system in patients with SLE. Fifteen sedentary African American women with SLE experiencing moderate to severe fatigue participated in a home exercise program using the Wii Fit 3 days a week for 30 minutes each for 10 weeks. A one-group pretest-posttest design was used to evaluate the effectiveness of this program. Primary outcome measure was severity of fatigue. Secondary outcome measures were body weight, waist circumference, fatigue-related symptoms of distress, activity level and physical fitness. At the completion of the 10-week Wii Fit exercise program, participants perceived fatigue severity as measured by the Fatigue Severity Scale to be significantly decreased (P=0.002), body weight and waist circumference were significantly reduced (Ps=0.01). In addition, anxiety level as measured by Hospital Anxiety and Depression Scale, and overall intensity of total pain experience as measured by Short-form of the McGill Pain Questionnaire were also significantly reduced (Ps<0.05). Findings provide preliminary support that the Wii Fit motivates this population to exercise which leads to alleviation of fatigue and reduced body weight, waist circumference, anxiety level, and overall intensity of total pain experience.
systemic lupus; games activities; exercise; fatigue
Atherosclerosis is accelerated in people with systemic lupus erythematosus, and the presence of dysfunctional, pro-inflammatory high-density lipoproteins is a marker of increased risk. We developed a mouse model of multigenic lupus exposed to environmental factors known to accelerate atherosclerosis in humans – high-fat diet with or without injections of the adipokine leptin. BWF1 mice were the lupus-prone model; BALB/c were non-autoimmune controls. High-fat diet increased total serum cholesterol in both strains. In BALB/c mice, non-high-density lipoprotein cholesterol levels increased; they did not develop atherosclerosis. In contrast, BWF1 mice on high-fat diets developed increased quantities of high-density lipoproteins as well as elevated high-density lipoprotein scores, indicating pro-inflammatory high-density lipoproteins; they also developed atherosclerosis. In the lupus-prone strain, addition of leptin increased pro-inflammatory high-density lipoprotein scores and atherosclerosis, and accelerated proteinuria. These data suggest that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background.
atherosclerosis; murine lupus; pro-inflammatory high-density lipoproteins (piHDL)
Patients with systemic lupus erythematosus (SLE) have an impairment in phenotype and function of endothelial progenitor cells (EPCs) which is mediated by interferon α (IFN-α). We assessed whether murine lupus models also exhibit vasculogenesis abnormalities and their potential association with endothelial dysfunction. Phenotype and function of EPCs and type I IFN gene signatures in EPC compartments were assessed in female New Zealand Black/New Zealand White F1 (NZB/W), B6.MRL-Faslpr/J (B6/lpr) and control mice. Thoracic aorta endothelial and smooth muscle function were measured in response to acetylcholine or sodium nitropruside, respectively. NZB/W mice displayed reduced numbers, increased apoptosis and impaired function of EPCs. These abnormalities correlated with significant decreases in endolthelium-dependent vasomotor responses and with increased type I IFN signature in EPC compartments. In contrast, B6/lpr mice showed improvement in endothelium-dependent and endothelium-independent responses, no abnormalities in EPC phenotype or function and downregulation of type I IFN signatures in EPC compartments. These results indicate that NZB/W mice represent a good model to study the mechanisms leading to endothelial dysfunction and abnormal vasculogenesis in lupus. These results further support the hypothesis that type I IFNs may play an important role in premature vascular damage and, potentially, atherosclerosis development in SLE.
endothelial progenitor cells; endothelium; interferon-alpha; systemic lupus erythematosus