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author:("Hahn, bera H.")
1.  Impact of the Medicare Short Stay Transfer Policy on Patients undergoing Major Orthopedic Surgery 
Health Services Research  2007;42(1 Pt 1):25-44.
Objective
To examine the impact of the Short Stay Transfer Policy (SSTP) on practice patterns.
Data Sources
This study uses data from the Centers for Medicare and Medicaid Services Medicare Provider Analysis and Review (MEDPAR) file, Home Health Standard Analytical File, 1999 Provider of Service file, and data from the 2000 United States Census.
Study Design
An interrupted time-series analysis was used to examine the length of stay (LOS) and probability of “early” discharge to post acute care (PAC).
Data Collection
Separate 100percent samples of all fee-for-service Medicare recipients undergoing either elective joint replacement (JR) surgery or surgical management of hip fracture (FX) between January 1, 1996 and December 31, 2000 were selected.
Principal Findings
Prior to implementation of the SSTP. LOS had been falling by 0.37 and 0.30 days per year for JR and FX patients respectively. After implementation of the SSTP, there was an immediate increase in LOS by 0.20 and 0.17 days, respectively. Thereafter, LOS remained flat. The proportion of patients discharged “early” to PAC had been rising by 4.4 and 2.6 percentage points per year for JR and FX patients respectively, to a peak of 28.8percent and 20.4percent early PAC utilization in September 1998. Immediately after implementation of the SSTP, there was a 4.3 and 3.0 percentage point drop in utilization of “early” PAC. Thereafter utilization of early PAC increased at a much slower rate (for JR) or remained flat (for FX). There was significant regional variation in the magnitude of response to the policy.
Conclusion
Implementation of the SSTP reduced the financial incentive to discharge patients early to PAC. This was accomplished primarily through longer LOS without meaningful change in PAC utilization. With the recent expansion of the SSTP to 29 DRGs (representing 34percent of all discharges), these findings have important implications regarding patient care.
doi:10.1111/j.1475-6773.2006.00606.x
PMCID: PMC1955238  PMID: 17355580
Medicare; Short Stay Transfer Policy; hip fracture; joint replacement; length of stay; post-acute care
2.  Cellular and Molecular Mechanisms of Regulation of Autoantibody Production in Lupus 
The hyperactive interaction between helper T cells and autoimmune B cells in individuals predisposed to systemic lupus erythematosus (SLE) can be interrupted by induction of regulatory and suppressor T cells. Using two strategies—high dose tolerance to an immunoglobulin-derived peptide, and minigene vaccination with DNA encoding T cell epitopes presented by MHC class I molecules—our group has induced at least three types of regulatory/suppressive T cells. They include CD8+ T cells that suppress helper T cells by cytokine secretion, CD8+ T suppressors that kill B cells making anti-DNA antibodies, and peptide-binding CD4+CD25+ regulatory T cells that suppress B cells by direct cell contact. Each of these lymphocyte subsets suppresses anti-DNA antibody production and delays the onset of nephritis in BWF1 lupus-prone mice. Patients with SLE have amino acid sequences similar to those from murine anti-DNA antibodies used in these studies, and at similar locations in the VH regions of anti-DNA immunoglobulins. Therefore, strategies described here might ultimately be useful in therapy of the human disease.
doi:10.1196/annals.1361.085
PMCID: PMC2291525  PMID: 16126985
systemic lupus erythematosus; CD8+ T cells; regulatory T cells; suppressor T cells
3.  Differences between CD8+ T cells in lupus-prone (NZB × NZW) F1 mice and healthy (BALB/c × NZW) F1 mice may influence autoimmunity in the lupus model 
European journal of immunology  2004;34(9):2489-2499.
Immunization with portions of a murine antibody to DNA induced Ig peptide-reactive peripheral CD8+ inhibitory T (Ti) cells in non-autoimmune (BALB/c × NZW) F1 (CWF1) mice. Those Ti suppressed in vitro production of IgG anti-DNA by lymphocytes from MHC-matched, lupus-prone (NZB × NZW) F1 (BWF1) mice, primarily via secretion of transforming growth factor-β (TGF-β). However, splenic CD8+ cells from immunized BWF1 mice failed to suppress anti-DNA. Therefore, BWF1 mice were studied for defects in peripheral CD8+ T cells. The potential to suppress autoimmunity mediated by activated CD4+ helper T and B cells in BWF1 mice was assessed. As BWF1 mice aged, peripheral CD8+ T cells expanded little; fewer than 10% displayed surface markers of activation and memory. In contrast, quantities of splenic CD4+ T and B cells increased; high proportions displayed activation/memory markers. In old compared to young BWF1 mice, splenic cell secretion of two cytokines required for generation of CD8+ T effectors, IL-2 and TGF-β, was decreased. Immunizing BWF1 mice activated peptide-reactive CD8+ T cells, but their number was decreased compared to young BWF1 or old normal mice. While peptide-reactive splenic CD8+ T cells from immunized BWF1 mice did not survive in short-term cultures, similar CD8+ T cell lines from immunized CWF1 mice expanded and on transfer into BWF1 mice delayed autoimmunity and prolonged survival. Therefore, CD8+ T cells in old BWF1 mice are impaired in expansion, acquisition of memory, secretion of cytokine, and suppression of autoimmunity. Understanding these defects might identify targets for therapy in systemic lupus erythematosus.
doi:10.1002/eji.200424978
PMCID: PMC2291530  PMID: 15307181
Inhibitory CD8+ T cells; Lupus
4.  Blockade of Programmed Death-1 (PD-1) in young (New Zealand Black × New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease 
PD-1 usually acts as a negative signal for T cell activation, and its expression on CD8+Foxp3+ T cells is required for their suppressive capacity. Here we show that PD-1 signalling is required for the maintenance of functional regulatory CD4+CD25+Foxp3+T cells (CD4+Treg) that can control autoimmunity in (New Zealand Black × New Zealand White) F1 (BWF1) lupus mice. PD-1 signalling induced resistance to apoptosis and prolonged the survival of CD4+Treg. In vivo, the blockade of PD-1 with a neutralizing antibody (Ab) reduced PD-1 expression on CD4+Treg (PD1loCD4+Treg). PD1loCD4+Treg had an increased ability to promote B cell apoptosis and to suppress CD4+ helper T cells (Th) as compared to CD4+Treg with elevated PD-1 expression (PD1hiCD4+Treg). When PD-1 expression on CD4+Treg was blocked in vitro, PD1loCD4+Treg suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4+Treg depended on PD-1 expression, and that a fine tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.
doi:10.4049/jimmunol.1202382
PMCID: PMC3700538  PMID: 23636058
5.  The role of the immune system in atherosclerosis: molecules, mechanisms and implications for management of cardiovascular risk and disease in patients with rheumatic diseases 
Nature reviews. Rheumatology  2012;8(4):214-223.
Rapid-onset cardiovascular disease is a major concern for many patients suffering from SLE. Cardiovascular events are more frequent and occur much earlier in SLE patients compared to healthy controls. Traditional risk factors such as altered lipid levels, older age and smoking do not fully explain the increased risk of cardiovascular disease, strongly suggesting that autoimmunity contributes to accelerated atherosclerosis. Altered immune system function is recognized as the primary contributor to both the initiation and progression of atherosclerosis. Multiple manifestations of autoimmunity, including autoantibodies, altered cytokine levels and innate immunity response, adipokines, dysfunctional lipids, and oxidative stress appear to contribute to atherosclerotic risk. In addition, multiple SLE therapeutics appear to affect the development and progression of atherosclerosis both positively and negatively. SLE-specific biomarkers for identifying patients at risk of developing accelerated atherosclerosis are starting to be identified by multiple groups, and a comprehensive, clinically testable biomarker panel could be invaluable for identifying and treating these patients.
doi:10.1038/nrrheum.2012.14
PMCID: PMC3765069  PMID: 22331061
6.  Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention 
Patients with systemic lupus erythematosus have a significantly increased risk of cardiovascular events due to atherosclerosis. Traditional cardiac risk factors cannot fully explain this increased risk. Recent evidence strongly suggests that atherosclerotic plaque is largely driven by inflammation and an active immunological response, in contrast to the long-held belief that plaque is a passive accumulation of lipids in the arterial wall. Current approaches to the prevention of atherosclerosis in systemic lupus erythematosus involve targeting modifiable cardiac risk factors. Future preventive strategies may include therapies that counteract the immunologic responses that lead to plaque formation.
doi:10.1586/eci.10.98
PMCID: PMC3718673  PMID: 21426260
apoA-1; atherosclerosis; HMG-CoA reductase inhibitors; homocysteine; oxidized LDL; proinflammatory HDL; statins; systemic lupus erythematosus
7.  Genes, Tolerance and Systemic Autoimmunity 
Autoimmunity Reviews  2011;11(9):664-669.
The characterization of functional CD8+ inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8+ T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8+ Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8+ Ti.
doi:10.1016/j.autrev.2011.11.017
PMCID: PMC3306516  PMID: 22155015
Autoimmunity; Systemic Lupus Erythematosus; CD8+ Treg; Genes and Tolerance
9.  Tolerance induced by anti-DNA Ig peptide in (NZB × NZW)F1 lupus mice impinges on the resistance of effector T cells to suppression by regulatory T cells 
Clinical Immunology (Orlando, Fla.)  2011;142(3):291-295.
We have previously shown that immune tolerance induced by the anti-DNA Ig peptide pCons in (NZB × NZW)F1 (NZB/W) lupus mice prolonged survival of treated animals and delayed the appearance of autoantibodies and glomerulonephritis. Part of the protection conferred by pCons could be ascribed to the induction of regulatory T cells (TReg) that suppressed the production of anti-DNA antibodies in a p38 MAPK-dependent fashion. Here we show that another effect of pCons in the induction of immune tolerance in NZB/W lupus mice is the facilitation of effector T cell suppression by TReg. These new findings indicate that pCons exerts protective effects in NZB/W lupus mice by differentially modulating the activity of different T cell subsets, implying new considerations in the design of TReg–based approaches to modulate T cell autoreactivity in SLE.
doi:10.1016/j.clim.2011.11.004
PMCID: PMC3288892  PMID: 22137928
Systemic lupus erythematosus; immune tolerance; anti-DNA antibodies; regulatory T cells; effector T cells; tolerogenic peptide
10.  Dysfunctional, pro-inflammatory HDL directly upregulate monocyte PDGFRβ, chemotaxis and TNFα production 
Clinical immunology (Orlando, Fla.)  2010;137(1):147-156.
Accelerated atherosclerosis is a major co-morbid condition in autoimmune diseases. Monocytes are the main immune cell involved in atherosclerosis initiation. We hypothesized that dysfunctional, pro-inflammatory HDL (piHDL), which occur in approximately half of SLE patients, might directly influence monocyte gene expression and function. SLE subjects were stratified into three groups: 1) carotid artery plaque+piHDL+ 2) plaque-piHDL+ and 3) plaque-piHDL- (n=18/group). PDGFRβ was upregulated in primary monocytes from plaque+piHDL+ patients and in THP-1 cells acutely treated in vitro with piHDL compared to normal HDL. THP-1 chemotaxis was enhanced after treatment with piHDL versus normal HDL. Abnormal migration was restored to normal levels by treatment with imatinib or an apoJ-mimetic peptide. Increased piHDL-mediated TNFα protein levels were reduced with both inhibitors. Dysfunctional piHDL directly influences expression of a small number of transcripts and proteins, and piHDL inhibition through reducing piHDL oxidation or blocking PDGFRβ kinase activity restored normal monocyte chemotaxis.
doi:10.1016/j.clim.2010.06.014
PMCID: PMC2941543  PMID: 20637704
high-density lipoproteins; monocyte; PDGFRβ; atherosclerosis; systemic lupus erythematosus
11.  CD8+ Tregs in Lupus, Autoimmunity, and Beyond 
Autoimmunity reviews  2010;9(8):560-568.
While CD4+CD25high regulatory T cells (Tregs) have garnered much attention for their role in the maintenance of immune homeostasis, recent findings have shown that subsets of CD8+ T cells (CD8+ Tregs) display immunoregulatory functions as well. Both CD4+ Tregs and CD8+ Tregs appear impaired in number and/or function in several autoimmune diseases and in experimental animal models of autoimmunity, suggesting the possibility of immunotherapeutic targeting of these cells for improved management of autoimmune conditions. Our group has developed a strategy to induce CD8+ Tregs in autoimmune mice through the use of a tolerogenic self-peptide, and new information has been gained on the phenotype, function and role of induced CD8+ Tregs in autoimmunity. Here we present an overview of the role and mechanisms of action of CD8+ Tregs in autoimmunity, with a special focus on lupus. We also discuss the potential role of CD8+ Tregs in other diseases, including chronic infection and cancer.
doi:10.1016/j.autrev.2010.03.006
PMCID: PMC2879466  PMID: 20385256
Autoimmunity; Systemic Lupus Erythematosus; CD8+Tregs; Immune tolerance/ Suppression
12.  PD-1, gender, and autoimmunity 
Autoimmunity reviews  2010;9(8):583-587.
Programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are responsible for inhibitory T cell signaling that helps mediate the mechanisms of tolerance and immune homeostasis. The PD-1:PD-L signaling pathway has been shown to play an important role in a variety of diseases, including autoimmune conditions, chronic infection, and cancer. Recently, investigators have explored the role of sex hormones in modulating the pathway in autoimmune conditions. Exploring the effects of sex hormones on the PD-1:PD-L pathway could shed light on the gender biased nature of many autoimmune conditions as well as aide in the development of therapeutics targeting the immune system.
doi:10.1016/j.autrev.2010.04.003
PMCID: PMC2884990  PMID: 20433954
PD-1; Gender; Sex hormones; Autoimmunity; Systemic lupus erythematosus; Immune system
13.  Cutting Edge: Regulatory T Cells Directly Suppress B Cells in Systemic Lupus Erythematosus1 
In systemic lupus erythematosus (SLE), adaptive CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress Th cells that help autoantibody (autoAb)-producing B cells. It is not known whether naturally occurring Tregs can directly suppress B cells in SLE without an intermediate suppression of Th cells. This aspect is important for its implications in the natural course of SLE, because most if not all of the clinical and pathologic effects in SLE are associated with a dysregulated production of autoAbs. In this study, we show that natural Tregs can inhibit B cell activity in vitro and in vivo in SLE through cell contact-mediated mechanisms that directly suppress autoAb-producing B cells, including those B cells that increase numerically during active disease. These results indicate that one way by which natural Tregs attempt to limit humoral autoimmunity in SLE is by directly targeting autoreactive B cells.
doi:10.4049/jimmunol.0901163
PMCID: PMC2730469  PMID: 19570829
14.  Modulation of p38 MAP kinase activity in regulatory T cells after tolerance with anti-DNA Ig peptide in (NZB × NZW)F1 lupus mice 
Treatment of (NZB × NZW)F1 (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pCons prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) that suppressed autoantibody responses. Since the effects of pCons appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the mitogen-activated protein kinase p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naïve NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.
doi:10.4049/jimmunol.0804214
PMCID: PMC2758643  PMID: 19494264
15.  Induction of immune tolerance by activation of CD8+ T suppressor/regulatory cells in lupus-prone mice 
Human immunology  2008;69(11):790-796.
Multiple CD8+ suppressive T cell (Ts) subtypes are now recognized as essential regulators of the immune system that prevent autoimmunity through secretion of multiple cytokines and the subsequent inhibition of effector lymphocyte function. CD8+ Ts are an exciting area of study because of the possible therapeutic implications of inducing suppressive cells that are able to subdue or anergize autoimmune manifestations. Current research in systemic lupus erythematosus (SLE), a disease in which most effective therapies are widely immunosuppressive, is often focused on novel and highly targeted ways in which to treat this multiorgan disease. CD8+ Ts have been shown to be impaired in human and murine SLE. Our group and others have utilized tolerogenic peptides to induce and study CD8+ Ts in order to understand their function as well as investigate a possible new SLE therapy. This review will discuss the similarities and differences in CD8+ Ts subsets, the concept of tolerance as a therapy, and the current understanding of CD8+ Ts in mouse SLE models.
doi:10.1016/j.humimm.2008.08.284
PMCID: PMC2621070  PMID: 18817829
lupus; CD8; suppressor; regulatory; tolerance
16.  Cutaneous vasculitis in breast cancer treated with chemotherapy 
A patient from the University of California Los Angeles Medical Center who developed cutaneous vasculitis during the course of treatment for metastatic breast cancer is presented (status: post-lumpectomy and radiation therapy). Since the onset of vasculitis occurred during the course of therapy for the neoplasm, it was difficult to differentiate between drug-induced vasculitis and paraneoplastic vasculitis. The patient had been exposed to medications including gabapentin, methimazole, trastuzumab, fulvestrant, and letrozole - which could cause endothelial cell toxicity. Drug-induced small vessel vasculitis usually attacks the skin or subcutaneous parts of the skin. In cancer therapy, there have been case reports that hormonal drugs such as estrogen receptor antagonists, aromatase inhibitors, and epidermal growth factor receptor (EGFR) inhibitors can induce cutaneous vasculitis. On the other hand, paraneoplastic syndromes manifested as cutaneous vasculitis have been documented, possibly mediated by unknown immunological mechanisms associated with the tumor such as formation of immune complexes, direct antibody-mediated effects on endothelial cells, or direct effects of tumor cells on the vascular wall. Some patients with drug-induced cutaneous vasculitis have antineutrophil cytoplasm antibodies (ANCA) directed to one or more neutrophil cytoplasm antigens - the most common being granule protein myeloperoxidase (MPO), human leukocyte elastase (HLE), cathepsin G and lactoferrin. Some patients also have antibodies against histones and antiphospholipid. Serologic testing and measurements suggest an influence of therapy on vasculitis, yet the lack of sensitivity and specificity for a biomarker in endothelial injury indicate the need to search and evaluate new markers for improved predictive value of the tests, and to provide guidance in therapy.
doi:10.1016/j.clim.2008.07.001
PMCID: PMC2579274  PMID: 18640073
18.  Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis 
In this review, the authors discuss the formation and structure of high-density lipoproteins (HDLs) and how those particles are altered in inflammatory or stress states to lose their capacity for reverse cholesterol transport and for antioxidant activity. In addition, abnormal HDLs can become proinflammatory (piHDLs) and actually contribute to oxidative damage. The assay by which piHDLs are identified involves studying the ability of test HDLs to prevent oxidation of low-density lipoproteins. Finally, the authors discuss the potential role of piHDLs (found in some 45% of patients with systemic lupus erythematosus and 20% of patients with rheumatoid arthritis) in the accelerated atherosclerosis associated with some chronic rheumatic diseases.
doi:10.1186/ar2471
PMCID: PMC2575639  PMID: 18828865
19.  Identification and Characterization of a Peptide Mimetic That May Detect a Species of Disease-Associated Anticardiolipin Antibodies in Patients With the Antiphospholipid Syndrome 
Arthritis and rheumatism  2003;48(3):737-745.
Objective
To test the feasibility of applying a mimetic (specific for a patient-derived prothrombotic anticardiolipin antibody [aCL]) to study the homologous, disease-associated aCL in patients with antiphospholipid syndrome (APS).
Methods
We used the CL15 monoclonal aCL to screen 17 phage-display peptide libraries. Peptides (corresponding to recurrent peptide sequences) and their derivatives were synthesized and analyzed for binding to CL15 and for their abilities to inhibit CL15 from binding to cardiolipin. A peptide was chosen and used to study CL15-like IgG aCL in plasma samples from patients with APS, patients with systemic lupus erythematosus (SLE) but without APS, and normal healthy donors.
Results
Library screening with CL15 yielded 4 recurrent peptide sequences. Analyses of peptides showed that peptide CL154C reacted with antibody CL15 and inhibited binding of CL15 to cardiolipin, indicating that peptide CL154C may be a peptide mimetic for the CL15 aCL. Initial studies with plasma samples revealed that CL154C-reactive IgG was present (positivity defined as the mean + 3 SD optical density of the 25 normal controls) in 15 of 21 APS patients and 1 of 12 SLE patients.
Conclusion
These findings suggest that it is feasible to develop a specific enzyme-linked immunosorbent assay for each immunologically and functionally distinct disease-associated aCL. Additional testing of CL154C with a larger number of APS patients and SLE patients, as well as identification of peptide mimetics for each distinct aCL, will reveal the diagnostic potential of CL154C and other mimetics in identifying patients with aCL who are at risk of developing life-threatening thrombosis.
doi:10.1002/art.10836
PMCID: PMC2206208  PMID: 12632428
20.  Antibodies Against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome that Interfere With the FXa Inactivation by Antithrombin 
Antiphospholipid Ab (aPL) have been shown to promote thrombosis and fetal loss in the antiphospholipid syndrome (APS). Previously, we found IgG anti-thrombin Ab in some APS patients that could interfere with inactivation of thrombin by antithrombin (AT). Considering that activated coagulation factor X (FXa) is homologous to thrombin in the catalytic domains and is also regulated primarily by AT, we hypothesized that some thrombin-reactive Ab may bind to FXa and interfere with AT inactivation of FXa. To test these hypotheses, we studied reactivity of 8 patient-derived monoclonal IgG aPL with FXa and the presence of IgG anti-FXa Ab in APS patients, and investigated the effects of FXa-reactive mAb on AT inactivation of FXa. The results revealed that 6/6 thrombin-reactive IgG mAb bound to FXa, and that the levels of plasma IgG anti-FXa Ab in 38 APS patients were significantly higher than those in 30 normal controls (p < 0.001). When the mean plus 3 standard deviations of the 30 normal controls was used as the cutoff, 5/38 APS patients (13.2%) had IgG anti-FXa Ab. Importantly, 3/6 FXa-reactive mAb significantly inhibited AT inactivation of FXa. Combined, these results indicate that anti-FXa Ab may contribute to thrombosis by interfering with the anticoagulant function of AT on FXa in some APS patients.
PMCID: PMC1950736  PMID: 17114499
human; autoimmunity; antibodies
21.  A thrombin-crossreactive anti-cardiolipin antibody binds to activated protein C and inhibits the anticoagulant function of activated protein C 
Arthritis and rheumatism  2003;48(6):1622-1630.
Objective
To test the hypotheses that some thrombin-reactive anti-cardiolipin antibodies (aCL) may bind to protein C (PC) and/or activated PC (APC), and that some of the PC- and APC-reactive aCL may inhibit PC activation and/or the function of APC.
Methods
We studied the reactivity of patient-derived monoclonal aCL with PC and APC. Of the reactive antibodies, we examined their effects on PC activation and the activity of APC in plasma coagulation.
Results
Five of five patient-derived thrombin-reactive monoclonal aCL bind to PC and APC. In addition, one patient-derived monoclonal anti-prothrombin antibody (aPT) that displays aCL activity and reacts with thrombin also binds to PC and APC. Of these 6 PC- and APC-reactive aCL/aPT, all failed to inhibit PC activation, but one (CL15) shortened the plasma coagulation time in the presence of exogenous APC and thus inhibited the anticoagulant function of APC.
Conclusion
Most of the thrombin-reactive aCL in APS patients may bind to PC and APC. Of the APC-reactive aCL, some (like CL15) may inhibit the anticoagulant function of APC and thus are likely to be prothrombotic in the host.
doi:10.1002/art.10983
PMCID: PMC1978198  PMID: 12794830
22.  Some antiphospholipid antibodies recognize conformational epitopes shared by β2GPI and the homologous catalytic domains of several serine proteases 
Arthritis and rheumatism  2007;56(5):1638-1647.
Objective
To test the hypothesis that some antiphospholipid antibodies (aPL) in patients with the Antiphospholipid Syndrome (APS) recognize a conformational epitope shared by β2 glycoprotein I (β2GPI, the major autoantigen for the antiphospholipid antibodies) and the homologous catalytic domains of several serine proteases (such as thrombin, activated protein C and plasmin) in hemostasis.
Methods
We generated four new IgG monoclonal aPL (including two screened against β2GPI, one against thrombin and one against protein C) from two APS patients. The monoclonal antibodies (mAb) were analyzed for binding to β2GPI, thrombin, activated protein C (APC) and plasmin, and for anti-cardiolipin antibody (aCL) activity. To demonstrate a shared epitope between β2GPI and a serine protease, one mAb was studied by cross-inhibition.
Results
Both IgG anti-β2GPI mAb bound to thrombin, APC and plasmin. On the other hand, one anti-thrombin mAb and one anti-protein C mAb also bound to β2GPI. Moreover, the binding of one crossreactive mAb to β2GPI was inhibited by α-thrombin (that contains only the catalytic domain of thrombin). All four mAb displayed aCL activity.
Conclusion
Taken together with the findings that some aCL bind to several serine proteases that participate in hemostasis and share homologous catalytic domains, these data demonstrate that some aCL in APS patients recognize one or more conformational epitopes shared by β2GPI and the catalytic domains of disease-relevant serine proteases.
doi:10.1002/art.22522
PMCID: PMC1950582  PMID: 17469158
23.  PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus 
Journal of Clinical Investigation  1999;103(8):1135-1140.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41–q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41–q42 region linked to SLE.
PMCID: PMC408279  PMID: 10207165
24.  Fine Mapping of Xq28: Both MECP2 and IRAK1 Contribute to Risk for Systemic Lupus Erythematosus in Multiple Ancestral Groups 
Annals of the rheumatic diseases  2012;72(3):437-444.
Objectives
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
Methods
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Results
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
Conclusion
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
doi:10.1136/annrheumdis-2012-201851
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
25.  MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus 
PLoS Genetics  2013;9(2):e1003336.
We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Author Summary
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease contributed to by excessive innate immune activation involving toll-like receptors (TLRs, particularly TLR7/8/9) and type I interferon (IFN) signaling pathways. TLR7 responds against RNA–containing nuclear antigens and activates IFN-α pathway, playing a pivotal role in the development of SLE. While a genomic duplication of Tlr7 promotes lupus-like disease in the Y-linked autoimmune accelerator (Yaa) murine model, the lack of common copy number variations at TLR7 in humans led us to identify a functional single nucleotide polymorphism (SNP), rs3853839 at 3′ UTR of the TLR7 gene, associated with SLE susceptibility in Eastern Asians. In this study, we fine-mapped the TLR7-TLR8 region and confirmed rs3853839 exhibiting the strongest association with SLE in European Americans, African Americans, and Amerindian/Hispanics. Individuals carrying the risk G allele of rs3853839 exhibited increased TLR7 expression at the both mRNA and protein level and decreased transcript degradation. MicroRNA-3148 (miR-3148) downregulated the expression of non-risk allele (C) containing transcripts preferentially, suggesting a likely mechanism for increased TLR7 levels in risk-allele carriers. This trans-ancestral mapping provides evidence for the global association with SLE risk at rs3853839, which resides in a microRNA–gene regulatory site affecting TLR7 expression.
doi:10.1371/journal.pgen.1003336
PMCID: PMC3585142  PMID: 23468661

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