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Systemic Lupus Erythematosus: HELP
Articles from Iowa
Based on 22 articles published since 2009

These are the 22 published articles about Lupus Erythematosus, Systemic that originated from Iowa during 2009-2019.
+ Citations + Abstracts
1 Review Nature, functions, and clinical implications of IgG4 autoantibodies in systemic lupus erythematosus and rheumatoid arthritis. 2017

Pan, Qingjun / Lan, Qiaofen / Peng, Yanxia / Cai, Jun / Zheng, Jian / Dickerson, Carol / Xiao, Haiyan / Liu, Hua-Feng. ·Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China. · These authors contributed equally to this article. · Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA. · Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA. ·Discov Med · Pubmed #28472610.

ABSTRACT: Protective autoantibodies in homeostasis, clinical relevance, and therapeutic potential have gained wide attention. Recent studies showed that IgG4 autoantibodies play crucial roles in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In one aspect, IgG4 autoantibodies can bind autoantigens in competition with other classes of immunoglobulins (e.g., IgG1, IgG2a) to form non-inflammatory immune-complexes (ICs), which have a limited ability to induce immune responses because of the low affinity of IgG4 for both Fc receptors and the C1 complement molecule, resulting in reduced inflammatory response in SLE and RA. In another aspect, the CH2 domain of IgG4, post antibody binding with autoantigens, might become a target for rheumatoid factors (RFs) in RA. The resultant bigger ICs containing RF-IgG4-autoantigens were shown to strongly induce immune responses and to cause tissue damage in RA. In addition, the roles of IgG4-IgG1 (IgG4-IgG2 or IgG4-IgG3)-complexes and bispecific IgG4 in SLE and RA are also reviewed. Overall, IgG4 autoantibodies may act as a monitor for the pathogenesis in SLE and RA and even as a treatment for SLE.

2 Review Spotlight on blisibimod and its potential in the treatment of systemic lupus erythematosus: evidence to date. 2017

Lenert, Aleksander / Niewold, Timothy B / Lenert, Petar. ·Division of Rheumatology, University of Kentucky, Kentucky Clinic, Lexington, KY. · Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN. · Division of Immunology, Department of Internal Medicine, The University of Iowa, Iowa City, IA, USA. ·Drug Des Devel Ther · Pubmed #28331294.

ABSTRACT: B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF. Furthermore, blisibimod has a unique structure built on four high-affinity BAFF-binding peptides fused to the IgG1-Fc carrier. It was tested in phase I and II trials in SLE where it showed safety and tolerability. While it failed to reach the primary endpoint in a recent phase II trial, post hoc analysis demonstrated its efficacy in SLE patients with higher disease activity. Based on these results, blisibimod is currently undergoing phase III trials targeting this responder subpopulation of SLE patients. The advantage of blisibimod, compared to its competitors, lies in its higher avidity for BAFF, but a possible drawback may come from its immunogenic potential and the anticipated loss of efficacy over time.

3 Review A systematic review and meta-analysis of cutaneous manifestations in late- versus early-onset systemic lupus erythematosus. 2016

Medlin, Jennifer L / Hansen, Karen E / Fitz, Sara R / Bartels, Christie M. ·University of Wisconsin Hospital and Clinics, Madison, WI. · Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1625 Highland Ave #4132, Madison, WI 53705. · Department of Dermatology, Medical Associates Clinic, Dubuque, IA. ·Semin Arthritis Rheum · Pubmed #26972993.

ABSTRACT: OBJECTIVES: Although systemic lupus erythematosus (SLE) most commonly occurs in reproductive-age women, some are diagnosed after the age of 50. Recognizing that greater than one-third of SLE criteria are cutaneous, we undertook a systematic review and meta-analysis to evaluate differences in cutaneous manifestations in early- and late-onset SLE patients. METHODS: We searched the literature using PubMed, CINAHL, Web of Science, and Cochrane Library. We excluded studies that did not include ACR SLE classification criteria, early-onset controls, that defined late-onset SLE as <50 years of age, or were not written in English. Two authors rated study quality using the Newcastle Ottawa Quality Scale. We used Forest plots to compare odds ratios (95% CI) of cutaneous manifestations by age. Study heterogeneity was assessed using I(2). RESULTS: Overall, 35 studies, representing 11,189 early-onset and 1727 late-onset patients with SLE, met eligibility criteria. The female:male ratio was lower in the late-onset group (5:1 versus 8:1). Most cutaneous manifestations were less prevalent in the late-onset group. In particular, malar rash [OR = 0.43 (0.35, 0.52)], photosensitivity [OR = 0.72 (0.59, 0.88)], and livedo reticularis [OR = 0.33 (0.17, 0.64)] were less common in late-onset patients. In contrast, sicca symptoms were more common [OR = 2.45 (1.91, 3.14)]. The mean Newcastle Ottawa Quality Scale score was 6.3 ± 0.5 (scale: 0-9) with high inter-rater reliability for the score (0.96). CONCLUSIONS: Overall, cutaneous manifestations are less common in late-onset SLE patients, except sicca symptoms. Future studies should investigate etiologies for this phenomenon including roles of immune senescence, environment, gender, and immunogenetics.

4 Review Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations. 2016

Singh, Namrata / Kumar, Bharat / Aluri, Vijay / Lenert, Petar. ·Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. · Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: petar-lenert@uiowa.edu. ·J Allergy Clin Immunol · Pubmed #26953155.

ABSTRACT: B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF-depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed.

5 Review A systematic review of validated methods for identifying systemic lupus erythematosus (SLE) using administrative or claims data. 2013

Moores, Kevin G / Sathe, Nila A. ·Division of Drug Information Service, College of Pharmacy, The University of Iowa, USA. Electronic address: kevin-moores@uiowa.edu. · Vanderbilt Evidence-based Practice Center, Vanderbilt University Medical Center, Suite 600, 2525 West End Avenue, Nashville, TN 37203-1738, USA. Electronic address: nila.sathe@vanderbilt.edu. ·Vaccine · Pubmed #24331075.

ABSTRACT: PURPOSE: To examine the validity of billing, procedural, or diagnosis code, or pharmacy claim-based algorithms used to identify patients with systemic lupus erythematosus (SLE) in administrative and claims databases. METHODS: We searched the MEDLINE database from 1991 to September 2012 using controlled vocabulary and key terms related to SLE. We also searched the reference lists of included studies. Two investigators independently assessed the full text of studies against pre-determined inclusion criteria. The two reviewers independently extracted data regarding participant and algorithm characteristics and assessed a study's methodologic rigor using a pre-defined approach. RESULTS: Twelve studies included validation statistics for the identification of SLE in administrative and claims databases. Seven of these studies used the ICD-9 code of 710.0 in selected populations of patients seen by a rheumatologist or patients who had experienced the complication of SLE-associated nephritis, other kidney disease, or pregnancy. The other studies looked at limited data in general populations. The algorithm in the selected populations had a positive predictive value (PPV) in the range of 70-90% and of the limited data in general populations it was in the range of 50-60%. CONCLUSIONS: Few studies use rigorous methods to validate an algorithm for the identification of SLE in general populations. Algorithms including ICD-9 code of 710.0 in physician billing and hospitalization records have a PPV of approximately 60%. A requirement that the code is obtained from a record based on treatment by a rheumatologist increases the PPV of the algorithm but limits the generalizability in the general population.

6 Review Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. 2010

Lenert, Petar S. ·Department of Internal Medicine, Division of Rheumatology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA. petar-lenert@uiowa.edu ·Mediators Inflamm · Pubmed #20490286.

ABSTRACT: Our immune defense depends on two specialized armed forces. The innate force acts as an alarm mechanism that senses changes in the microenvironment through the recognition of common microbial patterns by Toll-like receptors (TLR) and NOD proteins. It rapidly generates an inflammatory response aimed at neutralizing the intruder at the mucosal checkpoint. The innate arm also communicates this message with more specialized adaptive forces represented by pathogen-specific B cells and T cells. Interestingly, B cells also express some innate sensors, like TLR7 and TLR9, and may respond to bacterial hypomethylated CpG motifs and single-stranded RNA viruses. Intracellular nucleic acid sensing TLRs play an important role in the pathogenesis of Systemic Lupus Erythematosus (SLE). In this review, we describe recent achievements in the development of oligonucleotide-(ODN)-based inhibitors of TLR9 and/or TLR7 signaling. We categorize these novel therapeutics into Classes G, R, and B based on their cellular and molecular targets. Several short ODNs have already shown promise as pathway-specific therapeutics for animal lupus. We envision their future use in human SLE, microbial DNA-dependent sepsis, and in other autoinflammatory diseases.

7 Review Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus. 2010

Lenert, P. ·Department of Internal Medicine, Division of Rheumatology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. petar-lenert@uiowa.edu ·Clin Exp Immunol · Pubmed #20456414.

ABSTRACT: Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-kappaB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.

8 Article Systemic Lupus Erythematosus is a Risk Factor for Complications in Total Joint Arthroplasty. 2018

Gholson, J Joseph / Wilkinson, Brandon G / Brown, Timothy S / Gao, Yubo / Dowdle, S Blake / Callaghan, John J. ·University of Iowa Hospitals and Clinics. ·Iowa Orthop J · Pubmed #30104943.

ABSTRACT: Introduction: Systemic Lupus Erythematosus (SLE) has been associated with increased complications following hip and knee arthroplasty. The Purpose of this study was to determine the extent to which SLE is a risk factor in outcomes following total joint arthroplasty (TJA). Methods: The nationwide inpatient sample was used to identify a cohort of 505,841 patients who had a total hip arthroplasty (THA) or total knee arthroplasty (TKA) between 2009-2011. Of these patients, 2,284 patients (0.45%) had been previously diagnosed with SLE. The impact of SLE on short-term TJA outcomes was determined using multivariate logistic regression. Differences in discharge destination and length of stay were also evaluated. Results: SLE patients were more likely to have an all-cause medical complication, (OR 1.9, p<0.0001) and more likely to have an all-cause surgical complication (OR 1.3, p<0.0001). SLE patients were four times more likely to become septic in the post-operative period (OR 3.8, p<0.0487). SLE patients were more likely to have a genitourinary complication (OR 1.7, p<0.0001) and bleeding complications requiring transfusion (OR 2.1, p<0.0001). Patients with SLE also had an increased length of stay (0.38 days, p<0.0001) and increased probability of discharging to a facility (OR 2.1, p<0.0001). Discussion: Patients with SLE had an increased rate of both medical and surgical all-cause complications. Patients were specifically found to be at higher risk for sepsis, genitourinary complications, and blood transfusions. Future risk adjustment models should include SLE as a contributor to medical and surgical complications in the postoperative period.

9 Article Hydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis. 2018

Kumar, Bharat / Strouse, Jennifer / Swee, Melissa / Lenert, Petar / Suneja, Manish. ·Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. Electronic address: Bharat-Kumar@UIowa.edu. · Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. ·Semin Arthritis Rheum · Pubmed #29519741.

ABSTRACT: INTRODUCTION: Hydralazine is an antihypertensive medication that has been associated with drug-induced lupus erythematosus (DIL) as well as ANCA-associated vasculitis (AAV). Although rare, early diagnosis is critical since drug cessation is the mainstay of therapy. This retrospective study aims to characterize the clinical, laboratory, and histopathologic features of this disease. METHODS: Once approval was obtained from the Institutional Review Board at the University of Iowa, all patients carrying a diagnosis of vasculitis (ICD9 code: 447.6 or ICD10 code: I77.6, I80, L95, M30, or M31) and positive ANCA lab results over the past 15 years were identified. Age, gender, comorbid conditions, medications taken over the prior 6 months, laboratory data, including electrolytes, urine studies and serologies, chest x-rays, CT scans, and pathologic biopsy records were abstracted from the electronic medical record. RESULTS: 323 cases of AAV were identified, of which 12 were exposed to hydralazine, all at the time of diagnosis. The average duration of hydralazine therapy was 22 months and mean cumulative dose was 146g. Patients were typically older (70.3 years old) with slight female preponderance (7 females). Eleven patients presented with dyspnea, fatigue, and unintentional weight loss. Five had polyarthralgias and 8 had lower extremity petechiae. All 12 patients were both ANA and ANCA positive. ANA titers ranged from 1:160 and 1:2560. Ten were of diffuse pattern while 2 were nucleolar. ANCA titers ranged from 1:320 to 1:2560. Eleven had a pANCA pattern while one had cANCA. All 12 patients were positive for histone and 11 were positive for myeloperoxidase antibodies. Eleven also had dsDNA antibodies, and 4 had anti-cardiolipin IgG or IgM antibodies. Nine patients were also hypocomplementemic (mean C3 level: 88.4mg/dL; mean C4 level: 16.5mg/dL). All patients had variable levels of proteinuria (1+ to 3+) and eleven had active urine sediment. Urine protein:creatinine ratios ranged from 0.2 to 1.7. Of the 6 patients who underwent kidney biopsy, all 6 showed pauci-immune crescentic glomerulonephritis. Seven patients had bilateral pulmonary interstitial infiltrates and four had pleural effusions on CT scan. Four had pericardial effusions as demonstrated by echocardiography. CONCLUSIONS: Hydralazine-associated vasculitis is a drug-associated autoimmune syndrome that presents with interstitial lung disease, hypocomplementemia, and pauci-immune glomerulonephritis. Patients have elements of both DIL and DIV, as manifested by high ANA and ANCA titers as well as the presence of histone and MPO antibodies. Further research is needed to understand the etiopathogenesis of this condition.

10 Article Abnormal thymic maturation and lymphoproliferation in MRL-Fas 2017

Ashman, R F / Singh, N / Lenert, P S. ·Division of Immunology, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA, USA. ·Lupus · Pubmed #27837196.


11 Article Alterations in nuclear structure promote lupus autoimmunity in a mouse model. 2016

Singh, Namrata / Johnstone, Duncan B / Martin, Kayla A / Tempera, Italo / Kaplan, Mariana J / Denny, Michael F. ·Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. · Section of Nephrology, Internal Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. · Department of Microbiology/Immunology, Fels Institute for Cancer Research, Temple University, Philadelphia, PA 19140, USA. · Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. · Section of Rheumatology, Temple University School of Medicine, Philadelphia, PA 19140, USA mikedenny@verizon.net. ·Dis Model Mech · Pubmed #27483354.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the development of autoantibodies that recognize components of the cell nucleus. The vast majority of lupus research has focused on either the contributions of immune cell dysfunction or the genetics of the disease. Because granulocytes isolated from human SLE patients had alterations in neutrophil nuclear morphology that resembled the Pelger-Huet anomaly, and had prominent mis-splicing of mRNA encoding the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger-Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes to the development of lupus autoimmunity. The lupus-prone mouse strain New Zealand White (NZW) was crossed with c57Bl/6 mice harboring a heterozygous autosomal dominant mutation in Lbr (B6.Lbr(ic/+)), and the (NZW×B6.Lbr(ic))F1 offspring were evaluated for induction of lupus autoimmunity. Only female (NZW×B6.Lbr(ic))F1 mice developed lupus autoimmunity, which included splenomegaly, kidney damage and autoantibodies. Kidney damage was accompanied by immune complex deposition, and perivascular and tubule infiltration of mononuclear cells. The titers of anti-chromatin antibodies exceeded those of aged female MRL-Fas(lpr) mice, and were predominantly of the IgG2 subclasses. The anti-nuclear antibody staining profile of female (NZW×B6.Lbr(ic))F1 sera was complex, and consisted of an anti-nuclear membrane reactivity that colocalized with the A-type lamina, in combination with a homogeneous pattern that was related to the recognition of histones with covalent modifications that are associated with gene activation. An anti-neutrophil IgM recognizing calreticulin, but not myeloperoxidase (MPO) or proteinase 3 (PR3), was also identified. Thus, alterations in nuclear structure contribute to lupus autoimmunity when expressed in the context of a lupus-prone genetic background, suggesting a mechanism for the development of lupus autoimmunity in genetically predisposed individuals that is induced by the disruption of nuclear architecture.

12 Article Epidemiology of systemic lupus erythematosus and cutaneous lupus erythematosus in a predominantly white population in the United States. 2015

Jarukitsopa, Sudumpai / Hoganson, Deana D / Crowson, Cynthia S / Sokumbi, Olayemi / Davis, Mark D / Michet, Clement J / Matteson, Eric L / Maradit Kremers, Hilal / Chowdhary, Vaidehi R. ·Bumrungrad Hospital, Bangkok, Thailand. · Mercy Arthritis & Osteoporosis Center, Des Moines, Iowa. · Mayo Clinic College of Medicine, Rochester, Minnesota. · Medical College of Wisconsin, Milwaukee. ·Arthritis Care Res (Hoboken) · Pubmed #25369985.

ABSTRACT: OBJECTIVE: Epidemiologic studies comparing the incidence and prevalence of systemic lupus erythematosus (SLE) and isolated cutaneous lupus erythematosus (CLE) are few. Olmsted County, Minnesota provides a unique setting for such a study owing to resources of the Rochester Epidemiology Project. We sought to describe and compare the incidence and prevalence of SLE and CLE from 1993-2005. METHODS: SLE cases were identified from review of medical records and fulfilled the 1982 American College of Rheumatology classification criteria. CLE cases included patients with classic discoid lupus erythematosus, subacute CLE, lupus panniculitis, and bullous lupus erythematosus. Age- and sex-adjusted incidence and prevalence were standardized to the 2000 US white population. RESULTS: The age- and sex-adjusted incidence of SLE (2.9 per 100,000; 95% confidence interval [95% CI] 2.0-3.7) was similar to that of CLE (4.2 per 100,000; 95% CI 3.1-5.2, P = 0.10). However, the incidence of CLE was 3 times higher than SLE in men (2.4 versus 0.8 per 100,000; P = 0.009). The age- and sex-adjusted prevalence of CLE on January 1, 2006 was higher than that of SLE (70.4 versus 30.5 per 100,000; P < 0.001). The prevalences of CLE and SLE in women were similar, but the prevalence of CLE was higher in men than in women (56.9 versus 1.6 per 100,000; P < 0.001). The incidence of CLE rose steadily with age and peaked at 60-69 years. CONCLUSION: The incidences of CLE and SLE are similar, but CLE is more common than SLE in men and in older adults. These findings may reflect differences in genetic or environmental etiology of CLE.

13 Article Left main coronary artery compression by an enlarged pulmonary artery. 2013

Karrowni, Wassef / Sigurdsson, Gardar / Horwitz, Phillip A. ·Division of Cardiovascular Diseases, Department of Internal Medicine at the University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. wassef@hotmail.com ·JACC Cardiovasc Interv · Pubmed #23347871.

ABSTRACT: -- No abstract --

14 Article Rash and loss of vision in a 60-year-old woman with systemic lupus erythematosus. 2012

Sandu, Monica C / Chatterjee, Soumya. ·Division of Immunology (Rheumatology), Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. ·CMAJ · Pubmed #22143237.

ABSTRACT: -- No abstract --

15 Article Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). 2011

Arcipowski, Kelly M / Stunz, Laura L / Graham, John P / Kraus, Zachary J / Vanden Bush, Tony J / Bishop, Gail A. ·Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa 52242, USA. ·J Biol Chem · Pubmed #21262968.

ABSTRACT: Latent membrane protein 1 (LMP1), encoded by Epstein-Barr virus, is required for EBV-mediated B cell transformation and plays a significant role in the development of posttransplant B cell lymphomas. LMP1 has also been implicated in exacerbation of autoimmune diseases such as systemic lupus erythematosus. LMP1 is a constitutively active functional mimic of the tumor necrosis factor receptor superfamily member CD40, utilizing tumor necrosis factor receptor-associated factor (TRAF) adaptor proteins to induce signaling. However, LMP1-mediated B cell activation is amplified and sustained compared with CD40. We have previously shown that LMP1 and CD40 use TRAFs 1, 2, 3, and 5 differently. TRAF6 is important for CD40 signaling, but the role of TRAF6 in LMP1 signaling in B cells is not clear. Although TRAF6 binds directly to CD40, TRAF6 interaction with LMP1 in B cells has not been characterized. Here we tested the hypothesis that TRAF6 is a critical regulator of LMP1 signaling in B cells, either as part of a receptor-associated complex and/or as a cytoplasmic adaptor protein. Using TRAF6-deficient B cells, we determined that TRAF6 was critical for LMP1-mediated B cell activation. Although CD40-mediated TRAF6-dependent signaling does not require the TRAF6 receptor-binding domain, we found that LMP1 signaling required the presence of this domain. Furthermore, TRAF6 was recruited to the LMP1 signaling complex via the TRAF1/2/3/5 binding site within the cytoplasmic domain of LMP1.

16 Article Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice. 2011

Layer, T / Steele, A / Goeken, J A / Fleenor, S / Lenert, P. ·Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. ·Clin Exp Immunol · Pubmed #21235537.

ABSTRACT: Nucleic acid sensors of the Toll-like receptor (TLR) family play a well-established role in the pathogenesis of lupus. This is particularly true for a single-stranded RNA-sensing TLR-7 receptor, as lupus mice lacking TLR-7 show ameliorated disease. Cytosine-guanosine dinucleotide (CpG)-DNA-sensing TLR-9, conversely, has a complex regulatory role in systemic lupus erythematosus (SLE). Much less is known about whether signals through the B cell receptor for antigen (BCR) may affect the ability of B cells to respond to suboptimal TLR-7 agonists and antagonists. We studied this question in prediseased BXSB male and female B cells. We found that male B cells responded more vigorously to numerous TLR-7 ligands and this responsiveness was enhanced further upon co-engagement of the BCR. This synergy was seen primarily with the interleukin (IL)-6 secretion. A number of 32-mer inhibitory oligonucleotides (INH-ODNs) with a nuclease-resistant phosphorothioate backbone were capable of blocking TLR-7, but not BCR-induced B cell activation, with an inhibitory concentration (IC)(50) of approximately 100 nm. Surprisingly, while the presence of a single TGC motif at the 5' end of an ODN did not increase its inhibitory capacity, INH-ODNs containing multiple TGC motifs had greater inhibitory potency. When BCR and TLR-7 were co-engaged, INH-ODNs showed a differential effect on B cell activation. Whereas apoptosis protection and G1-M entry completely escaped suppression, IL-6 secretion remained sensitive to inhibition, although with a 10-fold lower potency. Our results suggest that while TLR-7 antagonists may be considered as lupus therapeutics, simultaneous co-engagement of the TLR-7 and BCR might favour autoreactive B cell survival. This hypothesis needs further experimental validation.

17 Article Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice. 2010

Peters, Anna L / Stunz, Laura L / Meyerholz, David K / Mohan, Chandra / Bishop, Gail A. ·Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA. ·J Immunol · Pubmed #20810985.

ABSTRACT: EBV infection is associated with development of the autoimmune disease systemic lupus erythematosus (SLE), and EBV can reactivate during SLE flares. Latent membrane protein 1 (LMP1) is an EBV-encoded oncogenic mimic of CD40 that can be re-expressed in PBMCs during SLE flares, as >90% of humans are latently EBV-infected. Whether LMP1 signaling exacerbates SLE is unknown. The phenotype of mice expressing a chimeric molecule with the mouse CD40 extracellular domain and the LMP1 intracellular signaling regions (mCD40-LMP1 transgenic [tg]) includes enhanced autoreactivity, yet these mice do not develop fatal autoimmune disease. We hypothesized that LMP1-mediated activation signals cooperate with and/or amplify events that predispose individuals to development of autoimmunity. To determine which aspects of autoimmunity may be exacerbated by LMP1, we bred mCD40-LMP1tg mice to two lupus-prone strains, B6.Sle1 and B6.Sle3, and analyzed autoimmunity parameters. LMP1(+)Sle1(+/+) mice developed enlarged lymphoid organs containing increased frequencies of germinal center, B cells, CD86(+) B cells, and activated and memory T cells compared with non-tg littermates. Anti-histone Abs were elevated in serum of LMP1(+)Sle1(+/+) mice, and they had signs of kidney pathology. LMP1(+)Sle1(+/+) B cells produced increased IL-6 and upregulated CD86 to a higher degree following CD40 stimulation in vitro, suggesting that the in vivo autoimmune exacerbation is B cell intrinsic. In contrast, the LMP1 transgene has no additional effects on autoimmunity on the B6.Sle3 background. These data indicate that LMP1-induced effects can cooperate with distinct subsets of host genes that predispose to autoimmunity and can thus be an exacerbating factor in autoimmune disease via multiple mechanisms.

18 Article B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus. 2010

Goeken, J A / Layer, T / Fleenor, S / Laccheo, M / Lenert, P. ·Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. ·Lupus · Pubmed #20605877.

ABSTRACT: The capacity to make secondary structures significantly affects the ability of Toll-like receptor 9 (TLR9) agonists and antagonists to either induce or block TLR9-dependent activation in B cells. However, it has a minor impact on TLR9-induced activation in interferon alpha (IFNα)-producing dendritic cells. Based on the ability of inhibitory oligodeoxynucleotides to form predictable secondary structures, we have classified TLR9-antagonists into Class R ('restricted', palindromic) and Class B ('broadly reactive', linear) oligodeoxynucleotides. In non-autoreactive B cells, Class R oligodeoxynucleotides are at least 10-fold less potent TLR9-inhibitors. We wanted to determine whether engagement of the B-cell receptor for antigen could overcome this restriction. Here we show that in non-autoreactive mouse B cells, B-cell receptor for antigen engagement increased the potency of Class R oligodeoxynucleotides for TLR9 activation at least 10-fold, making it equal in potency to linear oligodeoxynucleotides. However, this enhanced potency was selective for TLR9-induced B-cell cycling and apoptosis protection while TLR9-induced IL-6, an event that strongly depends on signaling via late endosomes, still required 10 times more Class R oligodeoxynucleotides. Thus, pathway-specific effects of Class R oligodeoxynucleotides for TLR9/B-cell receptor for antigen co-stimulated B cells may have therapeutic advantages over non-selective targeting of B cells, a strategy that may be seen as a potential therapy for human systemic lupus erythematosus.

19 Article B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients. 2009

Hong, Sandy D / Reiff, Andreas / Yang, Hai-Tao / Migone, Thi-Sau / Ward, Christopher D / Marzan, Katherine / Shaham, Bracha / Phei, Wee Choo / Garza, Judith / Bernstein, Bram / Stohl, William. ·Childrens Hospital Los Angeles, Los Angeles, CA 90033, USA. sandy-hong@uiowa.edu ·Arthritis Rheum · Pubmed #19877053.

ABSTRACT: OBJECTIVE: To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS: Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzyme-linked immunosorbent assay and for blood leukocyte full-length BLyS and DeltaBLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls. RESULTS: In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months. CONCLUSION: Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.

20 Article Primary cutaneous nodular amyloidosis: case report and review of the literature. 2009

Schwendiman, Mark N / Beachkofsky, Thomas M / Wisco, Oliver J / Owens, Nicole M / Hodson, Darryl S. ·Des Moines University College of Osteopathic Medicine and Surgery, Iowa, USA. ·Cutis · Pubmed #19746766.

ABSTRACT: Primary cutaneous nodular amyloidosis (PCNA) is a rare form of primary cutaneous amyloidosis. It presents as waxy yellow-red nodules that are located preferentially on the lower extremities, face, scalp, and genitals. Recognition of this condition is of particular importance, as primary systemic amyloidosis can have a similar cutaneous presentation. We report a case of PCNA in a 52-year-old woman with systemic lupus erythematosus (SLE) and Sjögren syndrome (SS). We discuss the need to evaluate for systemic disease and provide a concise review of the literature focusing on clinical presentation, disease associations, and management.

21 Article DNA-like class R inhibitory oligonucleotides (INH-ODNs) preferentially block autoantigen-induced B-cell and dendritic cell activation in vitro and autoantibody production in lupus-prone MRL-Fas(lpr/lpr) mice in vivo. 2009

Lenert, Petar / Yasuda, Kei / Busconi, Liliana / Nelson, Patrice / Fleenor, Courtney / Ratnabalasuriar, Radhika S / Nagy, Peter L / Ashman, Robert F / Rifkin, Ian R / Marshak-Rothstein, Ann. ·Department of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. petar-lenert@uiowa.edu ·Arthritis Res Ther · Pubmed #19476613.

ABSTRACT: INTRODUCTION: B cells have many different roles in systemic lupus erythematosus (SLE), ranging from autoantigen recognition and processing to effector functions (for example, autoantibody and cytokine secretion). Recent studies have shown that intracellular nucleic acid-sensing receptors, Toll-like receptor (TLR) 7 and TLR9, play an important role in the pathogenesis of SLE. Dual engagement of rheumatoid factor-specific AM14 B cells through the B-cell receptor (BCR) and TLR7/9 results in marked proliferation of autoimmune B cells. Thus, strategies to preferentially block innate activation through TLRs in autoimmune B cells may be preferred over non-selective B-cell depletion. METHODS: We have developed a new generation of DNA-like compounds named class R inhibitory oligonucleotides (INH-ODNs). We tested their effectiveness in autoimmune B cells and interferon-alpha-producing dendritic cells in vitro and in lupus-prone MRL-Faslpr/lpr mice in vivo. RESULTS: Class R INH-ODNs have 10- to 30-fold higher inhibitory potency when autoreactive B cells are synergistically activated through the BCR and associated TLR7 or 9 than when stimulation occurs via non-BCR-engaged TLR7/9. Inhibition of TLR9 requires the presence of both CCT and GGG triplets in an INH-ODN, whereas the inhibition of the TLR7 pathway appears to be sequence-independent but dependent on the phosphorothioate backbone. This difference was also observed in the MRL-Faslpr/lpr mice in vivo, where the prototypic class R INH-ODN was more effective in curtailing abnormal autoantibody secretion and prolonging survival. CONCLUSIONS: The increased potency of class R INH-ODNs for autoreactive B cells and dendritic cells may be beneficial for lupus patients by providing pathway-specific inhibition yet allowing them to generate protective immune response when needed.

22 Minor Maintenance of pupillary response in a glaucoma patient with no light perception due to persistence of melanopsin ganglion cells. 2014

Zhou, Yang / Davis, Alexander S / Spitze, Arielle / Lee, Andrew G. ·Baylor College of Medicine, Houston. · The University of Texas Medical Branch, Galveston; The Methodist Hospital, Houston, Tex. · The Methodist Hospital, Houston, Tex. · Baylor College of Medicine, Houston; The University of Texas Medical Branch, Galveston; The Methodist Hospital, Houston, Tex.; Weill Cornell Medical College, New York, N.Y.; The University of Iowa Hospitals and Clinic, Iowa City, Iowa. Electronic address: AGLee@tmhs.org. ·Can J Ophthalmol · Pubmed #24513375.

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