Defective Apoptosis of Peripheral Blood Lymphocytes in Hyper-IgD and Periodic Fever Syndrome
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1 Blood First Edition Paper, prepublished online November 30, 2006; DOI /blood Defective Apoptosis of Peripheral Blood Lymphocytes in Hyper-IgD and Periodic Fever Syndrome Evelien J. Bodar 1, Jeroen C.H. van der Hilst 1, Waander van Heerde 2, Jos W.M. van der Meer 1, Joost P.H. Drenth 3 and Anna Simon 1 From the Department of General Internal Medicine 1, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Haematology 2, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Gastroenterology and Hepatology 3, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Short title: Defective Apoptosis in HIDS Supported by a program grant from the Netherlands Organization for Health Research and Development (ZonMW, nr ) and a NWO-VIDI grant (J.P.H.D.). Corresponding Author: Evelien.J. Bodar, Department of General Internal Medicine 463, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, tel: , fax: ; e.bodar@aig.umcn.nl Key words : HIDS, apoptosis, periodic fever Author responsibility: E.J.B., J.P.H.D., W.H. and A.S. designed research, E.J.B. and J.C.H.H. performed research, E.J.B., W.H. and A.S. analyzed data, E.J.B., J.W.M.M, A.S. and W.H. wrote the paper and all authors checked the final version of the manuscript. Presented in abstract form at The Fourth International Congress on Systemic Autoinflammatory Diseases, Bethesda, Maryland, November 8, 2005 Reprints: Evelien.J. Bodar, Department of General Internal Medicine 463, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; e.bodar@aig.umcn.nl Copyright 2006 American Society of Hematology 1
2 Abstract Hereditary periodic fever syndromes are characterized by incapacitating attacks of fever and generalized inflammation. While the mutated genes for the major syndromes in this group are known, the pathogenesis remains unclear. Aim of this study was to investigate apoptosis in periodic fever patients as a possible pathogenic factor. We measured anisomycin-induced apoptosis with annexin-v flowcytometry and caspase 3/7 activity in peripheral blood lymphocytes from symptom-free patients with HIDS (n=10), TRAPS (n=7) and FMF (n=2). HIDS lymphocytes showed a decreased percentage of apoptosis during remission compared to controls by both methods (17.8 vs 55.4%), whereas no difference was observed in TRAPS or FMF lymphocytes. This defective apoptosis of lymphocytes may be a central pathogenic mechanism in HIDS since dysfunction of one of the inhibitory mechanisms to curtail the immunological response could cause an unbridled generalized inflammation after a trivial stimulus. 2
3 Introduction Hereditary periodic fever syndromes, also known as auto-inflammatory disorders, are characterized by incapacitating attacks of fever and generalized inflammation. Patients present with a long history of recurrent episodes with spiking fever, abdominal discomfort, diarrhea, vomiting, chest pain or arthralgia. The most prevalent examples of this group of syndromes are Familial Mediterranean Fever (FMF), TNF-receptor associated periodic syndrome (TRAPS) and hyper-igd and periodic fever syndrome (HIDS) 1. Although the genetic defects are known, the mechanisms by which these cause inflammatory attacks are largely unclear 1;2. Factors known to precipitate an attack are infection, trauma, vaccination and both physical and psychological stress. It is hypothesized that the normal immunological response to relatively trivial insults is not stopped in time, but, instead, leads on to an overwhelming and generalized inflammatory attack. This may be caused by a lack of inhibitory signals to down-regulate the inflammation, or an inability to respond to such signals. Apoptosis plays an important role in down-regulation of the inflammatory response, e.g., by reducing the lifespan of activated lymphocytes. We hypothesized that a defect in apoptosis regulation is the cause of the exaggerated inflammatory response in periodic fever patients. This was investigated in peripheral blood lymphocytes of patients with periodic fever syndromes. Study design Ten patients with HIDS (2 female, age range years), seven patients with TRAPS (6 female, age range years) and two patients with FMF (both male, age 24 and 36 years) were included in this study. All patients showed the relevant pathogenic mutations (Table 1). Nineteen healthy unrelated persons served as controls (13 females, age range years). The study was approved by the local ethical committee and written informed consent was obtained from all participants. Peripheral venous blood from patients in a symptom-free interval and from controls was collected simultaneously and processed in pairs. Peripheral blood mononuclear cells (PBMCs) were isolated using a Ficoll gradient separation (Ficoll-Paque Plus, Amersham Biosciences, UK). Cells were resuspended at a concentration of 5,0 x 10 6 /ml in RPMI 1640 medium (Dutch modification, Invitrogen Corporation, 3
4 UK) and incubated at 37ºC. The protease inhibitor anisomycin (Sigma-Aldrich Chemicals Corporation, USA) was added in a concentration of 20 µg/ml to induce apoptosis. At different times (0, 2, 5, 24 hours) the reaction was stopped. At 0, 5, and 24 hours cells were stained with annexin-v- FITC and PI (Apoptest-FITC, VPS Diagnostics, the Netherlands) and analyzed by flow cytometry (Coulter XL, Beckman Coulter Inc., USA) The Lymphocyte population was selected based on forward and side scatter and staining with labeled antibodies to CD14, CD3 and CD19 3. At 2 hours cells were permeabilized and the profluorescent caspase-3/7 substrate was added (Apo-One Homogenous Caspase-3/7 Assay, Promega, USA). Fluorescence was measured using a fluorometer (POLARstar Galaxy, BMG labtech, Germany) at excitation 485 nm and emission 520 nm. Results shown are corrected for background emission. Results were analyzed using the unpaired t-test by GraphPad Prism, version 4.00 (GraphPad Software, Inc.). Results and discussion After 24 hours of incubation with anisomycin, lymphocytes from 10 HIDS patients show a significantly smaller percentage of apoptosis than healthy controls using annexin-v staining (17.8% vs 55.4%, p<0.0001; Figure 1B and E). This difference was not observed in unstimulated cells (Figure 1A). There were no differences in the percentages of apoptosis in lymphocytes from patients with TRAPS (n=7) and FMF (n=2) compared to those of healthy donors, whether stimulated with anisomycin or unstimulated (Figure 1C and 1D). At all times, PI binding of cells was less than 0.5% indicating that the amount of necrotic or late apoptotic cells was negligible. A caspase-3/7 activity essay confirmed the difference in apoptosis found with annexin-v staining in HIDS patients compared to controls (9060 vs 15971, p=0.026; Figure 1F). Decreased apoptosis in stimulated lymphocytes in HIDS may well be central to the pathogenesis of the inflammatory attacks: dysfunction of one of the inhibitory mechanisms to curtail the immunological response can explain the unbridled generalized inflammation seen after a trivial stimulus. The causative mutations in HIDS are located in the gene encoding mevalonate kinase (MVK), an enzyme in the isoprenoid metabolism, the end-products of which include cholesterol, protein 4
5 isoprenylation (included the prenylated Ras/Rho proteins), dolichol and ubiquinone 1. The exact pathogenesis of HIDS is unclear. However, several of the isoprenoid end-products have been linked with apoptosis 4. A link between the isoprenoid pathway and apoptosis was also suggested by Nagashima et al., who showed that inhibition of this pathway by statins induced apoptosis in rheumatoid arthritis synoviocytes 5. This might offer an explanation for the beneficial effect of statins seen in HIDS patients 6. Other periodic fever syndromes are caused by mutations in molecules that contain a death domain, death-effector domain and/or CARD, involved in the protein-protein interactions required for apoptosis or signalling through NFκB. These include the TNF-receptor type 1 (TNFRSF1A) in TRAPS, pyrin in FMF, cryopyrin in cryopyrin-associated periodic syndrome (CAPS) and NOD2/CARD15 in Blau syndrome. A central role for an apoptosis defect in these syndromes has therefore been hypothesized and such a defect has been found in vitro, i.e. decreased apoptosis of macrophages from pyrin-mutant mice 7. However, available data on apoptosis measured in patient cells is limited to. Two studies in Turkish FMF patients show normal apoptosis of peripheral blood leukocytes in symptom-free patients but increased apoptosis of neutrophils and monocytes during inflammatory attacks 8 or elevated serum soluble FAS concentrations 9. A third study showed decreased TNF induced neutrophil apoptosis in TRAPS patients 10. We included 2 symptom-free FMF patients, who showed no defect in lymphocyte apoptosis. Neither did we find an apoptosis defect in 7 TRAPS patients. Preliminary studies from our laboratory suggest that the apoptotic potential of lymphocytes in TRAPS is not affected by an attack (data not shown). Conceptually it would be interesting to measure apoptosis in HIDS patients during inflammatory attacks. However the profound lymphopenia early during attacks so far has hampered these measurements. At recovery from an attack, we measured restored apoptotic activity in two patients (59.8% early apoptosis after 24 hours stimulation with anisomycin) compared to controls. This might mean that apoptotic pathways are activated at that stage to end the attack. An explanation for the difference between HIDS and the other syndromes found in our study may be the cell type studied. Reasoning from the clinical phenotype, we chose to investigate apoptosis of lymphocytes in HIDS. Lymphadenopathy, lymphocytic infiltrates in skin biopsies and many B lymphocytes containing IgD in the cytoplasm in bone marrow can be observed in HIDS 11;12, 5
6 and this may be related to the lymphocyte apoptosis defect. In the other periodic fever syndromes, different cell types are more prominent and point to cell-specific defects. FMF is characterized by infiltrates that are almost exclusively composed of neutrophils, while the urticarial response in certain cryopyrin-associated periodic syndromes could point to a role of mast cells. This hypothesis of cell type specificity is supported by the above-mentioned study by D Osualdo et al., showing abnormal neutrophil apoptosis in 8 TRAPS patients. In this paper one patient with HIDS was measured and found to have normal neutrophil apoptosis 10. In conclusion, we have shown decreased apoptosis of circulating lymphocytes ex vivo in fever-free HIDS patients after stimulation with anisomycin. This lymphocytic defect was not seen in TRAPS or FMF. Decreased apoptosis may be central to the pathogenesis of HIDS. 6
7 Reference List 1. Drenth JP, van der Meer JW. Hereditary periodic fever. N.Engl.J.Med. 2001;345: Touitou I, Notarnicola C, Grandemange S. Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies? Am.J.Pharmacogenomics. 2004;4: van Heerde WL, Robert-Offerman S, Dumont E et al. Markers of apoptosis in cardiovascular tissues: focus on Annexin V. Cardiovasc.Res. 2000;45: Edwards PA, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu.Rev.Biochem. 1999;68: Nagashima T, Okazaki H, Yudoh K, Matsuno H, Minota S. Apoptosis of rheumatoid synovial cells by statins through the blocking of protein geranylgeranylation: a potential therapeutic approach to rheumatoid arthritis. Arthritis Rheum. 2006;54: Simon A, Drewe E, van der Meer JW et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin.Pharmacol.Ther. 2004;75: Chae JJ, Komarow HD, Cheng J et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol.Cell. 2003;11: Ozen S, Uckan D, Baskin E et al. Increased neutrophil apoptosis during attacks of familial Mediterranean fever. Clin.Exp.Rheumatol. 2001;19:S68-S Kiraz S, Ertenli I, Ozturk MA et al. Increased soluble FAS suggests delayed apoptosis in familial Mediterranean fever complicated with amyloidosis. J.Rheumatol. 2003;30: D'Osualdo A, Ferlito F, Prigione I et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum. 2006;54: Boom BW, Daha MR, Vermeer BJ, van der Meer JW. IgD immune complex vasculitis in a patient with hyperimmunoglobulinemia D and periodic fever. Arch.Dermatol. 1990;126: van der Meer JWM, Vossen JM, Radl J et al. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet. 1984;1:
8 Table 1. Genotype of study participants. Syndrome Protein - Gene HIDS Mevalonate kinase - MVK TRAPS FMF Pyrin - MEFV Mutations No. of patients V377I/V377I 1 V377I/I268T 1 V377I/H20P 1 V377I/del 1 P167L/I268T 2 V377I/417insC 4 C43Y 1 Y38C 2 C29F 2 TNFreceptor type 1 - TNFRSF1A C70Y 2 M694V/M694V 2 Figure 1. Lymphocyte apoptosis in periodic fever patients. Apoptosis of lymphocytes is expressed as percentage of annexin-v positive lymphocytes (PI negative); white bars represent controls, black bars patients. (A) HIDS patients vs. controls without anisomycin stimulation; neither group shows apoptosis. (B) Incubation of lymphocytes with anisomycin results in a significant increase of apoptosis after 24 hours when compared with unstimulated lymphocytes in both controls (p<0.0001) and patients (p=0.005), but the increase in HIDS lymphocytes is significantly less than in controls (p=0.0002). Lymphocytes from patients with (C) TRAPS or (D) FMF show as much apoptosis as controls. (* p=0.005; ** p<0.001). (E) Healthy control (white) versus HIDS patient (black) after 24 hours exposure to anisomycin. Representative result from 10 experiments. (F) Apoptosis of lymphocytes of HIDS patients expressed as caspase-3/7 activity after 2 hours anisomycin stimulation. Patients show decreased caspase-3/7 activity compared to controls. 8
9 Figure 1. number of cells counted annexin staining 9
10 Prepublished online November 30, 2006; doi: /blood Defective apoptosis of peripheral blood lymphocytes in hyper-igd and periodic fever syndrome Evelien J. Bodar, Jeroen C.H. van der Hilst, Waander van Heerde, Jos W.M. van der Meer, Joost P.H. Drenth and Anna Simon Information about reproducing this article in parts or in its entirety may be found online at: Information about ordering reprints may be found online at: Information about subscriptions and ASH membership may be found online at: Advance online articles have been peer reviewed and accepted for publication but have not yet appeared in the paper journal (edited, typeset versions may be posted when available prior to final publication). Advance online articles are citable and establish publication priority; they are indexed by PubMed from initial publication. Citations to Advance online articles must include digital object identifier (DOIs) and date of initial publication. Blood (print ISSN , online ISSN ), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Copyright 2011 by The American Society of Hematology; all rights reserved.
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