Publications by authors named "Julia Menke"

22 Publications

  • Page 1 of 1

Serum Jo-1 Autoantibody and Isolated Arthritis in the Antisynthetase Syndrome: Review of the Literature and Report of the Experience of AENEAS Collaborative Group.

Clin Rev Allergy Immunol 2017 Feb;52(1):71-80

Interdisciplinary Department of Medicine (DIM), Rheumatology Unit, University of Bari, Bari, Italy.

Anti-Jo-1 is the most frequently detectable antibody in the antisynthetase syndrome (ASSD), an autoimmune disease characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). Recently, we organized an international collaborative group called American and European NEtwork of Antisynthetase Syndrome (AENEAS) for the study of this rare and fascinating disease. The group collected and published one of the largest series of ASSD patients ever described and with one of the longer follow-up ever reported. The number of participating centers is steadily increasing, as well as the available cohort. In the first paper, we showed that arthritis, myositis, and ILD may be frequently the only feature at disease onset, raising problems to reach a correct diagnosis of this syndrome. Nevertheless, we first observed that the ex novo appearance of further manifestations is common during the follow-up, strengthening the importance of a correct diagnosis. In our cohort, the 24 % of the 243 patients up to now collected had isolated arthritis as a presenting feature. These patients represent the most intriguing group in terms of differential diagnosis and clinical time course. Furthermore, data on this aspect are scanty, the reason that lead us to evaluate these aspects in our cohort of patients, reviewing also available literature. In fact, the most relevant aspect is that ASSD is rarely suspected in this setting of patients, in particular in case of poliarticular involvement, positive rheumatoid factor (RF), or anti-cyclic citrullinated peptide antibodies (ACPA) or evidence of joint erosions at plain radiographs. These findings were not rare in our cohort, and they have been also described in other series. Furthermore, manifestations such as Raynaud's phenomenon, mechanic's hands, and fever that may lead to the suspect of ASSD are observed only in a third of cases. If we consider the high rate of clinical picture progression in these patients, we feel that ASSD should be carefully considered in all patients presenting with isolated arthritis, even in those with erosive, RF, and ACPA-positive arthritis.
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http://dx.doi.org/10.1007/s12016-016-8528-9DOI Listing
February 2017

Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome: Results From an International Retrospective Multicenter Study.

Medicine (Baltimore) 2015 Aug;94(32):e1144

From the Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foudation, Pavia, Italy (LC, RC, CM); Servicio de Reumatología, Hospital Universitario La Paz, Madrid, Spain (LN); Epidemiology Unit, Italian Society for Rheumatology, Milano, Italy (CAS); UOC Reumatologia, Azienda Ospedaliero Universitaria S. Anna, University of Ferrara, Ferrara, Italy (M Govoni, RLC, F Furini, VF); Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain (FJLL, JM-B, MH); Rheumatology Unit, University and AO Spedali Civili, Brescia, Italy (F Franceschini, PA, IC); Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (RN, SB); Department of Rheumatology, Hospital Universitario de la Princesa, IIS Princesa, Madrid, Spain (SC); Department of Rheumatology, University Hospital Ramón y Cajal, Madrid, Spain (WASG, JBC); Interdisciplinary Department of Medicine (DIM), Rheumatology Unit, University of Bari, Bari, Italy (FI, M Giannini); Department of Rheumatology, Città Della Salute e della Scienza, Torino, Italy (EF, SP); Rheumatology Unit, Santa Chiara Hospital, Trento, Italy (GP, G Barausse, RB); Division of Rheumatology, Mauriziano Hospital, Turin, Italy (RP, RV, AR); Department of Internal Medicine, Rheumatology and Clinical Immunology, University Hospital Johannes-Gutenberg, Mainz, Germany (AS, JM); Tulane University Lung Center Tulane/UMC Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, LA, USA (LAS); Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain (NO-C); Clinic of Rheumatology, Department of Medical and Biological Sciences (DSMB), Santa Maria della Misericordia Hospital, Udine, Italy (LQ); Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy (E Bartoloni); Department for Rheumatology and Clinical Immunology, St. Josef Krankenhaus, University Clinic, Essen, Germany (C Specker); Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain (TPM, MAG-G); ACURA Rheumatology Center, Bad Kreuznach, Germany (KT); Rheumatology Unit, Department of Internal Medicine, S. Maria Hospital-IRCCS, Reggio Emilia, Italy (G Bajocchi); Rheumatology Unit, Ospedale Guglielmo da Saliceto, Piacenza, Italy (E Bravi); and Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milano, Italy (C Selmi).

Anti Jo-1 antibodies are the main markers of the antisynthetase syndrome (ASSD), an autoimmune disease clinically characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). These manifestations usually co-occur (for practical purpose complete forms) in the same patient, but cases with only 1 or 2 of these findings (for practical purpose incomplete forms) have been described. In incomplete forms, the ex novo occurrence of further manifestations is possible, although with frequencies and timing not still defined. The aim of this international, multicenter, retrospective study was to characterize the clinical time course of anti Jo-1 positive ASSD in a large cohort of patients. Included patients should be anti Jo-1 positive and with at least 1 feature between arthritis, myositis, and ILD. We evaluated the differences between complete and incomplete forms, timing of clinical picture appearance and analyzed factors predicting the appearance of further manifestations in incomplete ASSD. Finally, we collected 225 patients (58 males and 167 females) with a median follow-up of 80 months. At the onset, complete ASSD were 44 and incomplete 181. Patients with incomplete ASSD had frequently only 1 of the classic triad findings (110 cases), in particular, isolated arthritis in 54 cases, isolated myositis in 28 cases, and isolated ILD in 28 cases. At the end of follow-up, complete ASSD were 113, incomplete 112. Only 5 patients had an isolated arthritis, only 5 an isolated myositis, and 15 an isolated ILD. During the follow-up, 108 patients with incomplete forms developed further manifestations. Single main feature onset was the main risk factor for the ex novo appearance of further manifestation. ILD was the prevalent ex novo manifestation (74 cases). In conclusion, ASSD is a condition that should be carefully considered in all patients presenting with arthritis, myositis, and ILD, even when isolated. The ex novo appearance of further manifestations in patients with incomplete forms is common, thus indicating the need for an adequate clinical and instrumental follow-up. Furthermore, the study clearly suggested that in ASSD multidisciplinary approach involving Rheumatology, Neurology, Pneumology, and Internal Medicine specialists is mandatory.
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http://dx.doi.org/10.1097/MD.0000000000001144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616698PMC
August 2015

Correlation between cell free DNA levels and medical evaluation of disease progression in systemic lupus erythematosus patients.

Cell Immunol 2014 Nov-Dec;292(1-2):32-9. Epub 2014 Aug 20.

Department of Sports Medicine, Disease Prevention and Rehabilitation, Johannes Gutenberg-University Mainz, Mainz, Germany. Electronic address:

High levels of cell free DNA (cfDNA) in human blood plasma have been described in patients with autoimmune diseases. The aim of this study was to determine the levels of cfDNA in systemic lupus erythematosus (SLE) patients and to assess fluctuations of cfDNA concentrations compared to the course of disease progression under standard treatment. Therefore, nuclear cfDNA concentrations in plasma were measured in 59 SLE patients and 59 healthy controls. Follow-up blood plasma was collected from 27 of the 59 SLE patients. Patients were characterised by clinical parameters (antinuclear antibodies (ANA), anti-dsDNA-antibodies, C3, C4, and CRP), SLE disease activity index (SLEDAI) and medical therapy. Our results showed that cfDNA concentrations were significantly higher in SLE patients compared to healthy individuals. Levels of cfDNA assessed in serial samples correlated significantly with the medical evaluation of disease activity in SLE patients. Our results could implicate cfDNA as a global marker for disease activity.
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http://dx.doi.org/10.1016/j.cellimm.2014.08.002DOI Listing
February 2015

Colony-stimulating factor-1: a potential biomarker for lupus nephritis.

J Am Soc Nephrol 2015 Feb 10;26(2):379-89. Epub 2014 Jul 10.

Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures.
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http://dx.doi.org/10.1681/ASN.2013121356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310658PMC
February 2015

The effect of ischemia/reperfusion on the kidney graft.

Curr Opin Organ Transplant 2014 Aug;19(4):395-400

aSection of Nephrology, I. Department of Medicine, Johannes-Gutenberg University Mainz, Mainz bDepartment of Nephrology, University Hospital, Technical University Munich, Munich, Germany.

Purpose Of Review: Ischemia/reperfusion injury is an unavoidable companion after kidney transplantation and influences short-term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that eventually result in a distinct inflammatory reaction of the kidney graft.

Recent Findings: Underlying factors include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome.

Summary: It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.
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http://dx.doi.org/10.1097/MOT.0000000000000090DOI Listing
August 2014

The fungal lactone oxacyclododecindione is a potential new therapeutic substance in the treatment of lupus-associated kidney disease.

Kidney Int 2014 Oct 9;86(4):780-9. Epub 2014 Apr 9.

Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Recently oxacyclododecindione (Oxa), a macrocyclic lactone isolated from the imperfect fungus Exserohilum rostratum, has been described as a potent transcription inhibitor of inducible proinflammatory and profibrotic genes in cell culture models. As kidney disease in systemic lupus erythematosus is characterized by aberrant expression of inflammatory mediators and infiltration of immune cells, we investigated the effect of Oxa in MRL-Fas(lpr) mice, a model of systemic lupus erythematosus. These mice develop a spontaneous T-cell and macrophage-dependent autoimmune disease including severe glomerulonephritis that shares features with human lupus. Comparable to the results of in vitro models, we found a reduced expression of the cytokines IFN-γ, IL-6, and TNF-α and the chemokines CCL2, RANTES, and CSF-1 on mRNA and protein level in the kidney of Oxa-treated MRL-Fas(lpr) mice. Accordingly, Oxa treatment reduced the infiltration of immune cells and the frequency of activated proinflammatory T cells in the kidney. Moreover, kidney disease, measured by histopathology, IgG and collagen deposition, and proteinuria, was ameliorated in Oxa-treated MRL-Fas(lpr) mice compared with the control group. Thus, Oxa is a new effective anti-inflammatory compound, which may serve as base structure for the development of new therapeutics for the treatment of chronic inflammatory and/or fibrotic diseases.
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http://dx.doi.org/10.1038/ki.2014.109DOI Listing
October 2014

Haemostasis in chronic kidney disease.

Nephrol Dial Transplant 2014 Jan 16;29(1):29-40. Epub 2013 Oct 16.

Schwerpunkt Nephrologie, I. Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg Universität Mainz, Mainz, Germany.

The coagulation system has gained much interest again as new anticoagulatory substances have been introduced into clinical practice. Especially patients with renal failure are likely candidates for such a therapy as they often experience significant comorbidity including cardiovascular diseases that require anticoagulation. Patients with renal failure on new anticoagulants have experienced excessive bleeding which can be related to a changed pharmacokinetic profile of the compounds. However, the coagulation system itself, even without any interference with coagulation modifying drugs, is already profoundly changed during renal failure. Coagulation disorders with either episodes of severe bleeding or thrombosis represent an important cause for the morbidity and mortality of such patients. The underlying reasons for these coagulation disorders involve the changed interaction of different components of the coagulation system such as the coagulation cascade, the platelets and the vessel wall in the metabolic conditions of renal failure. Recent work provides evidence that new factors such as microparticles (MPs) can influence the coagulation system in patients with renal insufficiency through their potent procoagulatory effects. Interestingly, MPs may also contain microRNAs thus inhibiting the function of platelets, resulting in bleeding episodes. This review comprises the findings on the complex pathophysiology of coagulation disorders including new factors such as MPs and microRNAs in patients with renal insufficiency.
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http://dx.doi.org/10.1093/ndt/gft209DOI Listing
January 2014

Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice.

J Immunol 2012 May 30;188(9):4568-80. Epub 2012 Mar 30.

Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

CSF-1, required for macrophage (Mø) survival, proliferation, and activation, is upregulated in the tubular epithelial cells (TECs) during kidney inflammation. CSF-1 mediates Mø-dependent destruction in lupus-susceptible mice with nephritis and, paradoxically, Mø-dependent renal repair in lupus-resistant mice after transient ischemia/reperfusion injury (I/R). We now report that I/R leads to defective renal repair, nonresolving inflammation, and, in turn, early-onset lupus nephritis in preclinical MRL/MpJ-Faslpr/Fas(lpr) mice (MRL-Fas(lpr) mice). Moreover, defective renal repair is not unique to MRL-Fas(lpr) mice, as flawed healing is a feature of other lupus-susceptible mice (Sle 123) and MRL mice without the Fas(lpr) mutation. Increasing CSF-1 hastens renal healing after I/R in lupus-resistant mice but hinders healing, exacerbates nonresolving inflammation, and triggers more severe early-onset lupus nephritis in MRL-Fas(lpr) mice. Probing further, the time-related balance of M1 "destroyer" Mø shifts toward the M2 "healer" phenotype in lupus-resistant mice after I/R, but M1 Mø continue to dominate in MRL-Fas(lpr) mice. Moreover, hypoxic TECs release mediators, including CSF-1, that are responsible for stimulating the expansion of M1 Mø inherently poised to destroy the kidney in MRL-Fas(lpr) mice. In conclusion, I/R induces CSF-1 in injured TECs that expands aberrant Mø (M1 phenotype), mediating defective renal repair and nonresolving inflammation, and thereby hastens the onset of lupus nephritis.
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http://dx.doi.org/10.4049/jimmunol.1102154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340928PMC
May 2012

Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth.

Cancer Res 2012 Jan 3;72(1):187-200. Epub 2011 Nov 3.

Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Coexpression of the monocytic growth factor colony-stimulating factor (CSF)-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and antiapoptosis during regeneration of renal tubules. Here, we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were coexpressed in RCCs and TECs proximally adjacent to RCCs. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and epidermal growth factor signaling in RCCs. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R, and epidermal growth factor expression in RCCs. Furthermore, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCCs.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-1232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251714PMC
January 2012

Quantitative real-time ARMS-qPCR for mitochondrial DNA enables accurate detection of microchimerism in renal transplant recipients.

Pediatr Transplant 2011 Dec 4;15(8):809-18. Epub 2011 Oct 4.

Department of Pediatrics II, Children's Hospital, University of Duisburg-Essen, Essen, Germany.

The presence of microchimerism in peripheral blood of solid organ transplant recipients has been postulated to be beneficial for allograft acceptance. Kinetics of donor cell trafficking and accumulation in pediatric allograft recipients are largely unknown. In this study, we implemented SNPs of the HVRs I and II of mitochondrial DNA to serve as molecular genetic markers to detect donor-specific cell chimerism after pediatric renal transplantation. Serial dilution of artificial chimeric DNA samples showed a linear correlation coefficient of R > 0.98 and a detection sensitivity of 0.01% with high reproducibility. Longitudinal semiquantitative analysis of donor-specific SNPs was then performed in peripheral blood mononuclear cells samples up to two yr post-transplant. Quantity of donor-specific cell chimerism in peripheral blood was highest in the early post-transplant period reaching values of ~10% after liver-kidney and 2.8% after renal transplantation. From one wk after transplantation, renal transplant patients exhibited an amount of donor-specific mtDNA ranging from 0.01% to 0.1%. We developed a highly accurate, sensitive, and rapid real-time quantitative PCR method using sequence-specific primers and fluorescent hydrolysis probes for the detection of at least 0.01% donor-specific cells in the recipient's peripheral blood after renal transplantation.
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http://dx.doi.org/10.1111/j.1399-3046.2011.01581.xDOI Listing
December 2011

Distinct roles of CSF-1 isoforms in lupus nephritis.

J Am Soc Nephrol 2011 Oct 1;22(10):1821-33. Epub 2011 Sep 1.

Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Colony-stimulating factor-1 (CSF-1), the principal growth factor for macrophages, is increased in the kidney, serum, and urine of patients with lupus nephritis, and eliminating CSF-1 suppresses lupus in MRL-Fas(lpr) mice. CSF-1 has three biologically active isoforms: a membrane-spanning cell surface glycoprotein (csCSF-1), a secreted proteoglycan (spCSF-1), and a secreted glycoprotein (sgCSF-1); the role of each isoform in the circulation and kidney in autoimmune disease is not well understood. Here, we constructed mutant MRL-Fas(lpr) mice that only express csCSF-1 or precursors of the spCSF-1 and sgCSF-1 isoforms. Both csCSF-1 and spCSF-1 shifted monocytes toward proinflammatory, activated populations, enhancing their recruitment into the kidney during lupus nephritis. With advancing lupus nephritis, spCSF-1 was the predominant isoform responsible for increasing circulating CSF-1 and, along with the csCSF-1 isoform, for increasing intrarenal CSF-1. Thus, csCSF-1 appears to initiate and promote the local activation of macrophages within the kidney. Intrarenal expression of csCSF-1 and spCSF-1 increases with advancing nephritis, thereby promoting the intrarenal recruitment of monocytes and expansion of Ly6C(hi) macrophages, which induce apoptosis of the renal parenchyma. Taken together, these data suggest that the three CSF-1 isoforms have distinct biologic properties, suggesting that blocking both circulating and intrarenal CSF-1 may be necessary for therapeutic efficacy.
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http://dx.doi.org/10.1681/ASN.2011010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187183PMC
October 2011

New perspectives on the renal slit diaphragm protein podocin.

Mod Pathol 2011 Aug 15;24(8):1101-10. Epub 2011 Apr 15.

Department of Medicine, Johannes Gutenberg University, Mainz, Germany.

Podocin is a critical component of the glomerular filtration barrier, its mutations causing recessive steroid-resistant nephrotic syndrome. A GenBank analysis of the human podocin (NPHS2) gene resulted in the possible existence of a new splice variant of podocin in the kidney, missing the in-frame of exon 5, encoding the prohibitin homology domain. Using RT-polymerase chain reaction and immunoblotting followed by sequence analysis, we are for the first time able to prove the expression of a novel podocin isoform (isoform 2), exclusively and constitutively expressed in human podocytes. Furthermore, we reveal singular extrarenal podocin expression in human and murine testis. Our data show the Sertoli cells of the seminiferous tubules to be the origin of testicular podocin. Confocal laser microscopy illustrates the co-localization of podocin with filamentous actin within Sertoli cells, suggesting a role of podocin in the blood/testis barrier. These results led to the rationale to examine podocin expression in testes of men with Sertoli cell-only syndrome, a disorder characterized by azoospermia. Interestingly, we observed a complete down-regulation of podocin mRNA in Sertoli cell-only syndrome, indicating a possible role of podocin in the pathogenesis of this germinal aplasia. Men with Sertoli cell-only syndrome show normal renal podocin expression, suggesting an alternate regulation of the testicular promoter. Our findings may change the perception of podocin and give new insights into the ultrastructure of glomerular slit diaphragm and the blood/testis barrier.
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http://dx.doi.org/10.1038/modpathol.2011.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182839PMC
August 2011

Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice.

Kidney Int 2011 Feb 27;79(4):452-63. Epub 2010 Oct 27.

Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Johannes Gutenberg University, Mainz, Germany.

Polymorphisms in the transcription factor Stat4 gene have been implicated as risk factors for systemic lupus erythematosus. Although some polymorphisms have a strong association with autoantibodies and nephritis, their impact on pathophysiology is still unknown. To explore this further we used signal transducers and activators of transcription 4 (Stat4) knockout MRL/MpJ-Fas(lpr)/Fas(lpr) (MRL-Fas(lpr)) mice and found that they did not differ in survival or renal function from Stat4-intact MRL-Fas(lpr) mice. Circulating interleukin (IL)-18 levels, however, were elevated in Stat4-deficient compared to Stat4-intact mice, suggesting that this interleukin might contribute to the progression of lupus nephritis independent of Stat4. In a second approach, Stat4 antisense or missense oligonucleotides or vehicle were given to MRL-Fas(lpr) mice with advanced nephritis. Each of these treatments temporarily ameliorated disease, although IL-18 was increased in each setting. Based on these findings, studies using gene transfer to overexpress IL-18 in MRL-Fas(lpr) and IL-12p40/IL-23 knockout MRL-Fas(lpr) mice reveal a critical role for IL-18 in mediating disease. Thus, the Stat4 and IL-12 (an activator of Stat4)-independent factor, IL-18, can drive autoimmune lupus nephritis in MRL-Fas(lpr) mice. Temporarily blocking Stat4 during advanced nephritis ameliorates disease, suggesting a time-dependent compensatory proinflammatory mechanism.
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http://dx.doi.org/10.1038/ki.2010.438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197226PMC
February 2011

Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus.

J Rheumatol 2010 Jan 1;37(1):60-70. Epub 2009 Dec 1.

Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Johannes Gutenberg-University, Mainz, Germany.

Objective: To investigate the pathophysiological effect of interleukin 6 (IL-6) on lupus nephritis in MRL-Fas(lpr) mice.

Methods: We generated IL-6-deficient MRL-Fas(lpr) mice using a backcross/intercross breeding scheme. Renal pathology was evaluated using immunohistochemistry detection for macrophages, lymphocytes, vascular cell adhesion molecule-1 (VCAM-1), and TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick end-labeling) for apoptotic cells, and renal IgG and C3 deposition by immunofluorescence staining. Expression of inflammatory markers in the spleen was analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Serum cytokine concentrations were detected by FACS analysis.

Results: IL-6 deficiency was highly effective in prolonging survival and ameliorating the clinical, immunological, and histological indicators of murine systemic lupus erythematosus. During the study period of 6 months, MRL-Fas(lpr) IL-6 -/- mice showed delayed onset of proteinuria and hematuria compared to IL-6-intact control mice. Survival rate was 100% in IL-6-deficient MRL-Fas(lpr) mice and 25% in the control group at 6 months of age. The absence of IL-6 resulted in significant reduction of infiltrating macrophages in the kidney (p < 0.05), a decrease in renal IgG and C3 deposition, and a reduction of CD4+ and CD8+ lymphocytes. The parenchymal adhesion molecule VCAM-1 was found to be downregulated in kidneys of MRL-Fas(lpr) IL-6 -/- compared to IL-6-intact mice. We found elevated serum levels of IL-10 and interferon-gamma in IL-6-deficient mice, while splenic mRNA showed an overall downregulation of immunoregulatory genes.

Conclusion: IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.
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http://dx.doi.org/10.3899/jrheum.090194DOI Listing
January 2010

Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis.

J Am Soc Nephrol 2009 Dec 19;20(12):2581-92. Epub 2009 Nov 19.

Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas(lpr)) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas(lpr) mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas(lpr) mice. Using mutant MRL-Fas(lpr) strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC(low)CD11b(+)), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC(low)CD11b(+)Ly6C(high)) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b(+)CSF-1R(+) or CD68(+)) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.
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http://dx.doi.org/10.1681/ASN.2009050499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794229PMC
December 2009

CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice.

J Clin Invest 2009 Aug 1;119(8):2330-42. Epub 2009 Jul 1.

Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-1R-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b+ cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.
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http://dx.doi.org/10.1172/JCI39087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719924PMC
August 2009

Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice.

J Immunol 2008 Nov;181(10):7367-79

Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Sunlight (UVB) triggers cutaneous lupus erythematosus (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø)-mediated mechanism in MRL-Fas(lpr) mice. By constructing mutant MRL-Fas(lpr) strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex vivo gene transfer to deliver CSF-1 intradermally, we determined that CSF-1 induces CLE in lupus-susceptible MRL-Fas(lpr) mice, but not in lupus-resistant BALB/c mice. UVB incites an increase in Møs, apoptosis in the skin, and CLE in MRL-Fas(lpr), but not in CSF-1-deficient MRL-Fas(lpr) mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Møs that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Fas(lpr) but not lupus-resistant BALB/c mice. Taken together, CSF-1 is envisioned as the match and lupus susceptibility as the tinder leading to CLE.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607048PMC
http://dx.doi.org/10.4049/jimmunol.181.10.7367DOI Listing
November 2008

Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice.

J Immunol 2008 Aug;181(4):2513-21

Laboratory of Molecular Autoimmune Disease, Renal Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

MRL/MpJ-Fas(lpr) (MRL-Fas(lpr)) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Fas(lpr) mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (-/-) and PD-L1 intact (wild type, WT) MRL-Fas(lpr) mice. Unexpectedly, PD-L1(-/-);MRL-Fas(lpr) mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8(+) > CD4(+)), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1(-/-);MRL-Fas(lpr) mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1(-/-);MRL(+/+) mice lacking the Fas(lpr) mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1(-/-);MRL(+/+) bone marrow cells induced myocarditis and pneumonitis in WT;MRL(+/+) mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL(+/+) mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587295PMC
http://dx.doi.org/10.4049/jimmunol.181.4.2513DOI Listing
August 2008

CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.

J Am Soc Nephrol 2008 Jun 12;19(6):1177-89. Epub 2008 Mar 12.

Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA, USA.

Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2-/- and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10-/- MRL-Fas(lpr) mice, and CXCL10-/- C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3-/- , CXCL9-/- , and CXCL10-/- B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3-/- and CXCL9-/- mice but not in CXCL10-/- mice. With nephrotoxic serum nephritis, CXCR3-/- and CXCL9-/- mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9
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http://dx.doi.org/10.1681/ASN.2007111179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396941PMC
June 2008

Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: distinct roles.

J Immunol 2007 Dec;179(11):7466-77

Laboratory of Molecular Autoimmune Disease, Renal Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

The programmed death 1/programmed death 1 ligand (PD-L) pathway is instrumental in peripheral tolerance. Blocking this pathway exacerbates experimental autoimmune diseases, but its role in autoimmune kidney disease has not been explored. Therefore, we tested the hypothesis that the programmed death 1 ligands (PD-L1 and PD-L2), provide a protective barrier during T cell- and macrophage (Mphi)-dependent autoimmune kidney disease. For this purpose, we compared nephrotoxic serum nephritis (NSN) in mice lacking PD-L1 (PD-L1(-/-)), PD-L2 (PD-L2(-/-)), or both (PD-L1/L2(-/-)) to wild-type (WT) C57BL/6 mice. Kidney pathology, loss of renal function, and intrarenal leukocyte infiltrates were increased in each PD-L(-/-) strain as compared with WT mice. Although the magnitude of renal pathology was similar in PD-L1(-/-) and PD-L2(-/-) mice, our findings suggest that kidney disease in each strain is regulated by distinct mechanisms. Specifically, we detected increased CD68(+) cells along with elevated circulating IgG and IgG deposits in glomeruli in PD-L2(-/-) mice, but not PD-L1(-/-) mice. In contrast, we detected a rise in activated CD8(+) T cells in PD-L1(-/-) mice, but not PD-L2(-/-) mice. Furthermore, since PD-L1 is expressed by parenchymal and hemopoietic cells in WT kidneys, we explored the differential impact of PD-L1 expression on these cell types by inducing NSN in bone marrow chimeric mice. Our results indicate that PD-L1 expression on hemopoietic cells, and not parenchymal cells, is primarily responsible for limiting leukocyte infiltration during NSN. Taken together, our findings indicate that PD-L1 and PD-L2 provide distinct negative regulatory checkpoints poised to suppress autoimmune renal disease.
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http://dx.doi.org/10.4049/jimmunol.179.11.7466DOI Listing
December 2007

Interferon-beta: a therapeutic for autoimmune lupus in MRL-Faslpr mice.

J Am Soc Nephrol 2005 Nov 12;16(11):3264-72. Epub 2005 Oct 12.

First Department of Medicine, Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, Mainz 55131, Germany.

Type I interferons are associated with lupus. Genes that are regulated by IFN-alpha are upregulated in pediatric lupus patients. Gene deletion of the IFN-alpha/beta receptor in experimental lupus-like NZB mice results in reduced disease activity. Conversely, IFN-beta is a well-established treatment in multiple sclerosis, another autoimmune disease. For determining whether IFN-beta treatment is harmful or beneficial in lupus, MRL-Fas(lpr) mice were injected with this type I IFN. Treatment was initiated in MRL-Fas(lpr) mice with mild and advanced disease. IFN-beta was highly effective in prolonging survival and ameliorating the clinical (renal function, proteinuria, splenomegaly, and skin lesions), serologic (autoantibodies and cytokines), and histologic parameters of the lupus-like disease in mice that had mild and advanced disease. Several underlying mechanisms of IFN-beta therapy involving cellular (decreased T cell proliferation and infiltration of leukocytes into the kidney) and humoral (decrease in IgG3 isotypes) immune responses and a reduction in nephrogenic cytokines were identified. In conclusion, IFN-beta treatment of lupus nephritis in MRL-Fas(lpr) mice is remarkably beneficial and suggests that IFN-beta may be an appealing therapeutic candidate for subtypes of human lupus.
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http://dx.doi.org/10.1681/ASN.2004111014DOI Listing
November 2005

Correlation of renal tubular epithelial cell-derived interleukin-18 up-regulation with disease activity in MRL-Faslpr mice with autoimmune lupus nephritis.

Arthritis Rheum 2002 Nov;46(11):3083-95

Johannes Gutenberg-University of Mainz, Mainz, Germany.

Objective: MRL-Fas(lpr) mice spontaneously develop an autoimmune disease that mimics systemic lupus erythematosus in humans. Infiltrating T cells expressing interferon-gamma (IFNgamma) are responsible for the autoimmune kidney destruction in MRL-Fas(lpr) mice, and interleukin-18 (IL-18) released by mononuclear phagocytes stimulates T cells to produce the IFNgamma. Since MRL-Fas(lpr) T cells are characterized by an overexpression of the IL-18 receptor accessory chain, we sought to determine the impact of IL-18 on the progression of lupus nephritis in MRL-Fas(lpr) mice.

Methods: IL-18 expression in sera and kidney tissues from MRL-Fas(lpr) mice was determined by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blotting. IL-18 production by primary cultured tubular epithelial cells (TECs) from MRL-Fas(lpr) and BALB/c mice were examined by RT-PCR, ELISA, and Western blotting. The interactions of TEC-derived IL-18 and MRL-Fas(lpr) T cells were studied in coculture assays. IL-18-related effects on TEC viability and adhesion molecule expression were determined by fluorescence-activated cell sorting and cell proliferation assays.

Results: Up-regulation of mature IL-18 was restricted to nephritic MRL-Fas(lpr) kidneys and increased in parallel with the severity of lupus nephritis. IL-18 expression was not confined to infiltrating monocytes but was primarily detected in TECs. Similarly, interleukin-1beta-converting enzyme expression, which is required for the processing of precursor IL-18, was localized in TECs. De novo synthesis of IL-18 by MRL-Fas(lpr) TECs was confirmed by RT-PCR and Western blotting. Functional assays revealed that activated TECs induced IFNgamma production in MRL-Fas(lpr) T cells through IL-18. IL-18, in turn, increased apoptotic TEC death and up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1.

Conclusion: Taken together, our findings suggest that IL-18-producing TECs may directly be involved in the pathogenesis of lupus nephritis.
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http://dx.doi.org/10.1002/art.10563DOI Listing
November 2002