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1.  The pathogenesis, diagnosis and treatment of lupus nephritis 
Current opinion in rheumatology  2014;26(5):502-509.
Purpose of review
Renal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). In this review we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis (LN).
Recent findings
Localized long-lived plasma cells have been identified as playing an important role in LN. In addition, the roles of aberrant expression of microRNAs and pro-inflammatory cytokines have been explored. Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none have been yet validated for clinical use. Biomarker panels may turn out to be more accurate than each individual component. Biologic agents for the treatment of LN are being studied, including Belimumab which was recently approved for non-renal SLE. Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of LN.
LN is a potentially devastating complication of SLE. Immune cells, cytokines, and epigenetic factors have all been recently implicated in LN pathogenesis. These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease.
PMCID: PMC4221732  PMID: 25014039
Lupus nephritis; long-lived plasma cells; microRNA; biomarkers
2.  Extracellular RNAs: development as biomarkers of human disease 
Journal of Extracellular Vesicles  2015;4:10.3402/jev.v4.27495.
Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.
PMCID: PMC4553262  PMID: 26320940
ERCC; exRNA; extracellular RNA; biomarkers
3.  Neuropsychiatric Symptoms in Lupus 
Psychiatric annals  2012;42(9):322-328.
PMCID: PMC4302271  PMID: 25620816
4.  Increased Education is Associated with Decreased Compliance in an Urban Multi-Ethnic Lupus Cohort 
To investigate the factors associated with medication compliance in a multi-ethnic population of patients with systemic lupus erythematosus in an urban community.
We surveyed patients in our cohort using the standardized measures of the Compliance-Questionnaire-Rheumatology (CQR), the Beliefs about Medications Questionnaire (BMQ), as well as patient self-reported compliance. Demographic and clinical characteristics of compliant and non-compliant patients underwent bivariate analysis. A multivariate analysis was then performed on variables of interest.
Of the 94 patients who agreed to participate in the survey, 89 fully completed each questionnaire. Overall, 48% of patients were compliant by CQR. In multivariate analyses, higher education level was associated with non-compliance. Spanish-speaking patients and those with an income of greater than $15,000 per year were more likely to be compliant.
In this urban lupus population, several factors may influence medication compliance. Factors associated with non-compliance are not what have been found in other populations. Further studies looking into specific reasons for certain areas of non-compliance as well as addressing these issues will be important in both treatment and outcomes in lupus patients in implementing appropriate interventions.
PMCID: PMC4240278  PMID: 25419480
Systemic lupus erythematosus; Medication compliance; Racial and ethnic minorities
5.  The constant region affects antigen binding of antibodies to DNA by altering secondary structure 
Molecular immunology  2013;56(0):28-37.
We previously demonstrated an important role of the constant region in the pathogenicity of anti-DNA antibodies. To determine the mechanisms by which the constant region affects autoantibody binding, a panel of isotype–switch variants (IgG1, IgG2a, IgG2b) was generated from the murine PL9-11 IgG3 autoantibody. The affinity of the PL9-11 antibody panel for histone was measured by surface plasmon resonance (SPR). Tryptophan fluorescence was used to determine wavelength shifts of the antibody panel upon binding to DNA and histone. Finally, circular dichroism spectroscopy was used to measure changes in secondary structure. SPR analysis revealed significant differences in histone binding affinity between members of the PL9-11 panel. The wavelength shifts of tryptophan fluorescence emission were found to be dependent on the antibody isotype, while circular dichroism analysis determined that changes in antibody secondary structure content differed between isotypes upon antigen binding. Thus, the antigen binding affinity is dependent on the particular constant region expressed. Moreover, the effects of antibody binding to antigen were also constant region dependent. Alteration of secondary structures influenced by constant regions may explain differences in fine specificity of anti-DNA antibodies between antibodies with similar variable regions, as well as cross-reactivity of anti-DNA antibodies with non-DNA antigens.
PMCID: PMC3687031  PMID: 23665381
Systemic lupus erythematosus; anti-DNA antibodies; Antigen-antibody interactions
6.  Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements 
Lupus Science & Medicine  2014;1(1):e000056.
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).
CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
PMCID: PMC4225732  PMID: 25396070
Autoimmune Diseases; Systemic Lupus Erythematosus; Autoantibodies
Journal of autoimmunity  2013;43:44-54.
Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in SLE. However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokines by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.
PMCID: PMC3672366  PMID: 23578591
Systemic lupus erythematosus (SLE); neuropsychiatric lupus; TWEAK; Fn14
10.  Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor 
Arthritis and rheumatism  2013;65(4):1043-1054.
To determine the necessity for any individual BAFF receptor in the development of SLE.
Bcma, Taci, and Br3 null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry, B cell responsiveness to BAFF by in vitro culture, serum BAFF and total IgG and IgG anti-dsDNA levels by ELISA, renal immunopathology by immunofluorescence and histopathology, and clinical disease.
NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice failed to surface-express BCMA, TACI, and BR3, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than the corresponding cells from wild-type (WT), NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison to WT mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored increased spleen B cells, T cells, and plasma cells (PC), whereas serum total IgG and IgG anti-dsDNA levels were similar. Despite their paucity of B cells, NZM.Br3−/− mice harbored increased T cells and WT-like numbers of PC and levels of IgG anti-dsDNA. Serum BAFF levels were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, renal immunopathology and clinical disease in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were at least as severe as in WT mice.
Any single BAFF receptor, including BR3, is dispensable to development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF/BCMA and/or BAFF/TACI interactions contribute to SLE and that profound, life-long reduction in B cells does not guarantee protection from SLE.
PMCID: PMC3618582  PMID: 23334904
11.  Higher Rates and Clustering of Abnormal Lipids, Obesity, and Diabetes in Psoriatic Arthritis Compared with Rheumatoid Arthritis 
Arthritis care & research  2014;66(4):600-607.
We compared the prevalence and the clustering of the Metabolic Syndrome (MetS) components: obese body mass index (BMI ≥ 30 kg/m2), hypertriglyceridemia, low high-density lipids, hypertension and diabetes, in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in the Consortium of Rheumatology Researchers of North America (CORRONA) registry.
We included CORRONA participants with the rheumatologist-confirmed clinical diagnoses of PsA and RA with complete data. We used a modified definition of MetS that did not include insulin resistance, waist circumference or blood pressure measurements. Logistic regression models were adjusted for age, sex and race.
In the overall CORRONA population, the rates of diabetes and obesity were significantly higher in PsA compared with RA. In 294 PsA and 1162 RA participants who had lipids measured, the overall prevalence of MetS in PsA vs. RA was 27% vs. 19%. The odds ratio (OR) of MetS in PsA vs. RA was 1.44 (95% confidence interval (CI) 1.05 to 1.96), p=0.02. The prevalence of hypertriglyceridemia was higher in PsA compared with RA, 38% vs. 28%, OR 1.51 (95% CI 1.15 to 1.98), p=0.003. The prevalence of type II diabetes was also higher in PsA compared with RA (15% vs. 11%), OR 1.56 (95% CI 1.07 to 2.28), p=0.02, in the adjusted model. Similarly, higher rates of hypertriglyceridemia and diabetes were observed in the subgroup of PsA and RA patients with obese BMI.
PsA is associated with the higher rates of obesity, diabetes, and hypertriglyceridemia, compared with RA.
PMCID: PMC3969762  PMID: 24115739
12.  Improving Outcomes in Patients with Lupus and End Stage Renal Disease 
Seminars in dialysis  2013;26(5):590-596.
The development of lupus-related end stage renal disease (ESRD) confers the highest mortality rates among individuals with lupus. Lupus-related ESRD is also associated with higher morbidity and mortality rates compared with non-lupus ESRD.
We review the evidence that persistent lupus activity, hypercoagulability, and continuing immunosuppression may contribute to unfavorable outcomes in dialysis and renal transplantation among lupus patients. Robust epidemiologic studies are needed to develop individualized evidence-based approaches to treating lupus-related ESRD.
In the meantime, managing lupus-related ESRD presents a significant challenge for clinicians and requires a team approach involving nephrologists and rheumatologists. Goals of therapy after developing ESRD should include continuing monitoring of lupus activity, minimizing corticosteroid exposure, and choosing the most appropriate renal replacement therapy based on patient’s risk profile and quality of life considerations.
PMCID: PMC3904221  PMID: 24004337
13.  Dendritic cells: An important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases 
Clinical immunology (Orlando, Fla.)  2012;146(3):197-206.
The presence of dendritic cells, antigen-presenting cells that link innate and adaptive immunity, is necessary to generate and maintain the production of antiphospholipid antibodies in response to exposed intracellular phospholipids on the outer surface of apoptotic cells. In turn, antiphospholipid antibodies enhance dendritic cell-induced inflammatory and proatherogenic responses in a number of conditions that are associated with accelerated atherosclerosis, including diabetes, chronic kidney disease, periodontal infections, and aging. While altering dendritic cells by modifying the ubiquitin-proteasome system enhances antiphospholipid antibody production and leads to development of accelerated atherosclerosis and autoimmune features, inducing tolerance by dendritic cell manipulation leads to decreased atherosclerosis and thrombosis. Therefore, further translational studies are needed to understand the interplay between dendritic cells and antiphospholipid antibodies, and to develop potential new therapies for antiphospholipid syndrome and atherosclerosis. Here we review current experimental and translational studies that have examined the role of dendritic cells in antiphospholipid antibody formation and in antiphospholipid-associated atherosclerosis and thrombosis.
PMCID: PMC3904226  PMID: 23376063
dendritic cells; antiphospholipid antibodies; atherosclerosis; antiphospholipid syndrome
15.  The constant region contributes to the antigenic specificity and renal pathogenicity of murine anti-DNA antibodies 
Journal of autoimmunity  2012;39(4):398-411.
Affinity for DNA and cross-reactivity with renal antigens are associated with enhanced renal pathogenicity of lupus autoantibodies. In addition, certain IgG subclasses are enriched in nephritic kidneys, suggesting that isotype may determine the outcome of antibody binding to renal antigens. To investigate if the isotype of DNA antibodies affects renal pathogenicity by influencing antigen binding, we derived IgM, IgG1, IgG2b and IgG2a forms of the PL9–11 antibody (IgG3 anti-DNA) by in vitro class switching or PCR cloning. The affinity and specificity of PL9–11 antibodies for nuclear and renal antigens were analyzed using ELISA, Western blotting, surface plasmon resonance (SPR), binding to mesangial cells, and glomerular proteome arrays. Renal deposition and pathogenicity were assayed in mice injected with PL9–11 hybridomas. We found that PL9–11 and its isotype-switched variants had differential binding to DNA and chromatin (IgG3 > IgG2a > IgG1 > IgG2b > IgM) by direct and competition ELISA, and SPR. In contrast, in binding to laminin and collagen IV the IgG2a isotype actually had the highest affinity. Differences in affinity of PL9–11 antibodies for renal antigens were mirrored in analysis of specificity for glomeruli, and were associated with significant differences in renal pathogenicity in vivo and survival. Our novel findings indicate that the constant region plays an important role in the nephritogenicity of antibodies to DNA by affecting immunoglobulin affinity and specificity. Increased binding to multiple glomerular and/or nuclear antigens may contribute to the renal pathogenicity of anti-DNA antibodies of the IgG2a and IgG3 isotype. Finally, class switch recombination may be another mechanism by which B cell autoreactivity is generated.
PMCID: PMC3656415  PMID: 22841793
Systemic lupus erythematosus (SLE); Lupus nephritis; Anti-DNA antibodies; Isotype switching
16.  Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis 
Clinical immunology (Orlando, Fla.)  2012;145(2):108-121.
Previously it was shown that the TNF superfamily member TWEAK (TNFSF12) acts through its receptor, Fn14, to promote proinflammatory responses in kidney cells, including the production of MCP-1, RANTES, IP-10 and KC. In addition, the TWEAK/Fn14 pathway promotes mesangial cell proliferation, vascular cell activation, and renal cell death. To study the relevance of the TWEAK/Fn14 pathway in the pathogenesis of antibody-induced nephritis using the mouse model of nephrotoxic serum nephritis (NTN), we induced NTN by passive transfer of rabbit anti-glomerular antibodies into Fn14 knockout (KO) and wild type (WT) mice. Severe proteinuria as well as renal histopathology were induced in WT but not in Fn14 KO mice. Similarly, a pharmacologic approach of anti-TWEAK mAb administration into WT mice in the NTN model significantly ameliorated proteinuria and improved kidney histology. Anti-TWEAK treatment did not affect the generation of mouse anti-rabbit antibodies; however, within the kidney there was a significant decrease in glomerular immunoglobulin deposition, as well as macrophage infiltrates and tubulointerstitial fibrosis. The mechanism of action is most likely due to reductions in downstream targets of TWEAK/Fn14 signaling, including reduced renal expression of MCP-1, VCAM-1, IP-10, RANTES as well as Fn14 itself, and other molecular pathways associated with fibrosis in anti-TWEAK treated mice. Thus, TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the NTN model, apparently mediating a cascade of pathologic events locally in the kidney rather than by impacting the systemic immune response. Disrupting TWEAK/Fn14 interactions may be an innovative kidney-protective approach for the treatment of lupus nephritis and other antibody-induced renal diseases.
PMCID: PMC3483377  PMID: 22982296
Systemic lupus erythematosus (SLE); Nephrotoxic Serum Nephritis; TWEAK; Fn14
17.  Under-treatment of Disease Activity in Lupus Patients with End Stage Renal Failure Is Associated With Increased All-cause Mortality 
The Journal of rheumatology  2011;38(11):2382-2389.
To evaluate whether continuing rheumatology follow-up visits and immunosuppressive therapy after starting renal replacement were associated with increased survival in lupus patients with end stage renal failure.
We identified all lupus patients over 21 years old who started renal replacement therapy between 2005 and 2011 at an urban tertiary care center. Mortality data was obtained using in-hospital records and the Social Security Death Index database.
We identified 80 lupus patients on renal replacement therapy. Twenty two patients (28%) were followed in rheumatology clinics frequently (2 or more visits per year) after starting renal replacement therapy, and 58 patients (72%) were followed infrequently (fewer than 2 visits per year).
Survival rates were significantly higher in transplant patients compared with dialysis patients. However, SLE patients followed frequently after starting dialysis had significantly higher 4-year survival rates compared with patients followed infrequently after starting dialysis, log rank p = 0.03. Furthermore, in the Cox proportional hazards model, treatment with prednisone alone or with no medication was associated with a hazard ratio (HR) of death of 6.1, 95% CI (1.1, 34), p = 0.04, and HR 13, 95% CI (1.5, 106), p = 0.02, respectively, compared with patients treated with a combination of immunosuppressive therapy with or without prednisone, adjusted for age at SLE diagnosis, gender, transplant status and the frequency of rheumatology visits after the development of end stage renal failure.
Active disease in lupus patients on renal replacement therapy may be under-recognized and under-treated, leading to increased mortality.
PMCID: PMC3774792  PMID: 21885495
Lupus Erythematosus; Systemic; Lupus nephritis; Kidney Failure; Chronic; Mortality
18.  Hydroxychloroquine Use is Associated with Lower Odds of Persistently Positive Antiphospholipid Antibodies and/or Lupus Anticoagulant in SLE 
The Journal of rheumatology  2012;40(1):30-33.
Antiphospholipid antibodies (aPL Abs) play an active role in the pathogenesis of the antiphospholipid syndrome (APLS). Primary prevention in APLS may be aimed at decreasing existing elevated aPL Ab levels, or preventing high aPL titers and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown to decrease aPL titers in laboratory studies, and to decrease thrombosis risk in systemic lupus erythematosus (SLE) patients in retrospective studies. We investigated an association between HCQ use and persistent aPL Abs and/or LAC in SLE.
We identified all patients over 21 years old with SLE, from an urban tertiary care center, who had aPL Abs and LAC measured on at least 2 occasions, at least 12 weeks apart. We defined the presence of persistent LAC+ and/or at least one aPL Ab ≥ 40 units (IgA, IgG or IgM) as the main outcome variable.
Among 90 patients included in the study, 17 (19%) had persistent LAC+ and/or at least one aPL Ab ≥ 40 units. HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL Abs ≥ 40 U, OR 0.21 (95% CI 0.05, 0.79) p=0.02, adjusted for age, ethnicity, and gender.
This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL Abs. Data from this study provides a basis for the design of future prospective studies investigating the role of HCQ in primary and secondary prevention of APLS.
PMCID: PMC3768146  PMID: 22859353
Lupus Erythematosus, Systemic; Antiphospholipid Antibodies; Lupus Anticoagulant; Hydroxychloroquine
19.  High Antiphospholipid Antibody Levels are Associated with Statin Use and May Reflect Chronic Endothelial Damage in Non-Autoimmune Thrombosis: cross-sectional study 
Journal of clinical pathology  2012;65(6):551-556.
Persistently elevated antiphospholipid antibodies (aPL Ab) and positive lupus anticoagulant (LAC) are associated with an increased risk of thrombosis. Our objective was to explore whether aPL Ab and/or LAC positivity were associated with the traditional risk factors for thrombosis or with medication use in patients without autoimmune diseases hospitalized with arterial or venous thrombosis.
Cross-sectional study
Montefiore Medical Center, a large urban tertiary care center
Two hundred and seventy patients (93 with deep vein thrombosis (DVT) or pulmonary embolism (PE), and 177 with non-hemorrhagic stroke (CVA)) admitted between January 2006 and December 2010 with a discharge diagnosis of either DVT, PE or CVA, who had LAC and aPL Abs measured within six months from their index admission. We excluded patients with lupus or antiphospholipid syndrome.
Main Outcome Measures
The main dependant variable was aPL Ab ≥ 40 units (aPL Ab+) and/or LAC+. Independent variables: traditional thrombosis risk factors, statin use, aspirin use, and warfarin use.
Thirty one (11%) patients were LAC+ and/or aPL Ab+ (aPL/LAC+). None of the traditional risk factors at the time of DVT/PE/CVA was associated with aPL/LAC+. Current statin use was associated with an OR of 3.2 (95% CI 1.3, 7.9, p = 0.01) of aPL/LAC+, adjusted for age, ethnicity and gender. Aspirin or warfarin use was not associated with aPL Ab levels.
If statin therapy reflects the history of prior hyperlipidemia, high levels of aPL Abs may be a marker for prior endothelial damage caused by hyperlipidemia.
PMCID: PMC3760969  PMID: 22389514
Antiphospholipid antibodies; statins; endothelial damage; thrombosis
20.  Role of TWEAK in Lupus Nephritis: A bench-to-bedside review 
Journal of autoimmunity  2012;39(3):130-142.
There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK – namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis – are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients.
PMCID: PMC3428508  PMID: 22727560
21.  Dispensability of APRIL to development of systemic lupus erythematosus in NZM 2328 mice 
Arthritis and Rheumatism  2012;64(5):1610-1619.
To determine the role for APRIL in the development of SLE.
Wild-type (WT) NZM 2328, NZM.April-/-, NZM.Baff-/-, and NZM.Baff-/-.April-/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by ELISA, for glomerular deposition of IgG and C3 by immunofluorescence, for renal histopathology, and for clinical disease (severe proteinuria).
In comparison to WT mice, NZM.April-/- mice harbored increased spleen B cells, T cells, and plasma cells (PC); increased serum levels of IgG anti-chromatin antibodies; and decreased numbers of bone marrow (BM) PC. In addition, glomerular deposition of IgG and C3 was similar in NZM.April-/- and WT mice; renal histopathology tended to be more severe in NZM.April-/- mice than in WT mice; and development of clinical disease was identical in NZM.April-/- and WT mice. BM (but not spleen) PC and serum IgG anti-chromatin and anti-dsDNA antibody levels were lower in NZM.Baff-/-.April-/- mice than in NZM.Baff-/- mice, whereas renal immunopathology in each cohort was equally mild.
APRIL is dispensable for development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF has no discernable effect on development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PC in hosts doubly-deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without concomitant increase in therapeutic efficacy.
PMCID: PMC3292707  PMID: 22127792
22.  Neutrophil Gelatinase Associated Lipocalin is Instrumental in the Pathogenesis of Antibody-Mediated Nephritis 
Arthritis and Rheumatism  2012;64(5):1620-1631.
The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of Neutrophil Gelatinase Associated Lipocalin (NGAL), an iron-binding protein upregulated in response to kidney injury. However, whether NGAL is instrumental in pathogenesis, induced as part of repair, or irrelevant to damage/repair pathways, is not known.
To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to B6 or 129 mice. To determine if NGAL upregulation is instrumental, we compared the severity of renal damage in NGAL wild-type and knock-out mice following induction of nephrotoxic nephritis.
We found that kidney NGAL expression, as well as urinary NGAL levels, were significantly increased in nephrotoxic nephritis as compared to control injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urinary NGAL excretion. NGAL knock-out mice had attenuated proteinuria and improved renal histopathology as compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induces apoptosis via caspase-3 activation, and upregulates inflammatory gene expression in kidney cells in vitro and when injected in vivo.
We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-GBM disease and lupus nephritis.
PMCID: PMC3325360  PMID: 22083497
23.  Racial Differences in Gait Velocity in an Urban Elderly Cohort 
Background/ Objectives
Gait Velocity (GV) is predictive of hospitalizations and mortality in the elderly. In the US, elderly African Americans have higher rates of physical disability compared to Caucasians. Few studies have investigated if there are racial differences in GV in the elderly.
We performed a cross sectional analysis to investigate racial differences in GV.
Participants were part of the Einstein Aging Study, a longitudinal study of community-residing elderly in the Bronx, NY. They were recruited using Medicare and voter registration records. Records of 213 participants were analyzed.
Demographics, medical history, the Geriatric Depression Scale, the Blessed Information Memory Concentration Test, and the Total Pain Index (TPI) were collected. GV was measured using the GAITrite® mat.
We included 157 Caucasians and 56 African Americans. Caucasians were older (median 79.9y v 75.5y, p<0.01), more educated (median 14y v 12y, p<0.01) and had lower BMIs (mean 26.9±4.3 v 28.9±6.4, p=0.03). African Americans had higher proportions of female participants (80.4% v 59.9%, p<0.01) and diabetes (28.6% v 13.4%, p=0.01). Neither group had significantly higher pain levels. African Americans had a significantly slower GV (mean 90.2±17.9 v 99.1±20.1 cm/sec, p<0.01). This difference persists despite adjusting for multiple covariates. A 7.79 cm /sec slower gait speed in African Americans versus Caucasians was not explained by differences in common factors known to influence gait.
Differences in GV persist between African Americans and Caucasians despite adjusting for many confounders. Increases of just 10cm/sec are associated with reduced mortality. Further studies are needed to evaluate if there are modifiable risk factors that potentially explain this difference and if an intervention could reduce the discrepancy between the groups.
PMCID: PMC3354735  PMID: 22587854
gait velocity; health disparities; elderly; physical function
24.  TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier 
The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells.
In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model.
We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model.
Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.
PMCID: PMC3570290  PMID: 23320797
CCL-2; hCMEC/D3; HMEC; IL-8; MMP-9; Neuroinflammation; TNFSF12; ZO-1
25.  Neuropsychiatric Lupus, the Blood Brain Barrier, and the TWEAK/Fn14 Pathway 
Patients with systemic lupus erythematosus (SLE) can experience acute neurological events such as seizures, cerebrovascular accidents, and delirium, psychiatric conditions including depression, anxiety, and psychosis, as well as memory loss and general cognitive decline. Neuropsychiatric SLE (NPSLE) occurs in between 30 and 40% of SLE patients, can constitute the initial patient presentation, and may occur outside the greater context of an SLE flare. Current efforts to elucidate the mechanistic underpinnings of NPSLE are focused on several different and potentially complementary pathways, including thrombosis, brain autoreactive antibodies, and complement deposition. Furthermore, significant effort is dedicated to understanding the contribution of neuroinflammation induced by TNF, IL-1, IL-6, and IFN-γ. More recent studies have pointed to a possible role for the TNF family ligand TWEAK in the pathogenesis of neuropsychiatric disease in human lupus patients, and in a murine model of this disease. The blood brain barrier (BBB) consists of tight junctions between endothelial cells (ECs) and astrocytic projections which regulate paracellular and transcellular flow into the central nervous system (CNS), respectively. Given the privileged environment of the CNS, an important question is whether and how the integrity of the BBB is compromised in NPSLE, and its potential pathogenic role. Evidence of BBB violation in NPSLE includes changes in the albumin quotient (Qalb) between plasma and cerebrospinal fluid, activation of brain ECs, and magnetic resonance imaging. This review summarizes the evidence implicating BBB damage as an important component in NPSLE development, occurring via damage to barrier integrity by environmental triggers such as infection and stress; cerebrovascular ischemia as result of a generally prothrombotic state; and immune mediated EC activation, mediated by antibodies and/or inflammatory cytokines. Additionally, new evidence supporting the role of TWEAK/Fn14 signaling in compromising the integrity of the BBB in lupus will be presented.
PMCID: PMC3872310  PMID: 24400009
TWEAK; Fn14; blood brain barrier; neuropsychiatric lupus; MRL/lpr

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