- Email: [email protected]
Is osteoporosis linked to vaccinations and Gulf War Syndrome?
Medical Hypotheses (2004) 62, 670–673
http://intl.elsevierhealth.com/journals/mehy
Is osteoporosis linked to vaccinations and Gulf War Syndrome?q Donald R. Staines* Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Queensland, Australia Received 20 January 2004; accepted 21 January 2004
Summary Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigations and lack of a biologically plausible aetiology. Assertions have been made that GWS may be the result of vaccinations given to serving military personnel in the Persian Gulf and may be associated with osteoporosis. Calcitonin gene related protein (CGRP) is a vasoactive neuropeptide that is synthesised in conjunction with calcitonin gene expression. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. This paper describes a biologically plausible mechanism for the development of osteoporosis in the context of GWS based on loss of immunological tolerance to the vasoactive neuropeptide CGRP or its receptors following a variety of antigenic events. c 2004 Elsevier Ltd. All rights reserved.
Introduction Gulf War Syndrome (GWS), a disabling fatigue-associated state acquired in armed services personnel during the Persian Gulf War, is a disorder of unknown aetiology and no proven biologically plausible mechanism [1]. GWS has been associated with multiple chemical sensitivity (MCS) and a range of neu-
q The author declares no grants or financial conflict of interest are relevant in the development of this paper. Abstracts from PubMed, National Library of Medicine, were used in the development of this paper. * Tel.: +61-7-55097202; mobile: +61-414-278-031; fax: +61-75561-1851. E-mail address: [email protected] (D.R. Staines).
ropsychiatric, somatic and behavioural disorders in addition to fatigue [2]. GWS has been possibly attributed to stress, vaccinations and their adjuvants, exposure to neurotoxic substances, and biological warfare agents [3]. Some presenting features of GWS are consistent with a neurological illness [4]. Diverse neurological symptoms have been reported [5]. Vaccinations are suggested to have contributed to osteoporosis in Gulf War veterans, as part of the syndrome constellation of GWS. An autoimmune process has been suggested however no published reports detailing an hypothesised mechanism are currently available. A biologically plausible link exists between the vasoactive neuropeptide, calcitonin gene related protein (CGRP), and osteoporosis. GWS may also be linked to chronic fatigue syndrome (CFS) through similar autoimmune mechanisms affect-
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.01.006
Is osteoporosis linked to vaccinations and Gulf War Syndrome? ing a novel group of vasoactive neuropeptides (VaNs) [6] and the sandfly salivary vasodilator maxadilan [7].
Osteoporosis and vasoactive neuropeptides Osteoporosis is the reduction in the mass of bone per unit volume. It is also used to define any degree of skeletal fragility sufficient to increase risk of bone fracture. Calcitonin decreases bone resorption and is used therapeutically in osteoporosis [8]. Calcitonin gene related protein is a widely distributed member of the vasoactive neuropeptide class of substances and is involved with calcitonin activity. It has numerous protective roles [9]. Neuropeptides such as VIP and CGRP have important roles in bone metabolism [10]. CGRP protects the skeleton from calcium stress including growth, pregnancy and lactation [11]. Plasma levels of CGRP and adrenomedullin (ADM) are increased in subjects with osteoporosis and may contribute to this disease [12]. Calcitonin gene related protein promotes cAMP accumulation in osteobalstic cells indicating the existence of functional receptors [13]. In this respect it mirrors the mechanism of action of other vasoactive neuropeptides. Recent studies have demonstrated the ability of receptor modifying proteins (RAMPs) to post-translationally modify the calcitonin receptor-like receptor (CRLR) presumably indicating the potential for receptor interference and compromise of function [14] which could result in calcitonin impairment and osteoporosis [15]. Endogenous vasoactive neuropeptides exert a wide spectrum of immunological functions and have a critical role in homeostasis of the immune system through different receptors expressed in various immunocompetent cells [16]. Disturbances in their function are recognised as potential causes of autoimmune disease [17]. Vasoactive neuropeptides are related to the secretin/glucagon superfamily and include pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), NAPVSIPG (NAP), CGRP and ADM amongst others. They are a relatively novel class of substances that function as highly potent immune regulators, neurotransmitte- rs, co-transmitters, hormones and neurotrophes. They are genetically highly preserved indicating crucial roles for survival over many hundreds of millions of years [18]. They act in extremely small concentrations, for example
671
nanomolar (VIP) and femtomolar (NAP) concentrations, respectively [19].
Immunological sequelae and vaccination Vasoactive neuropeptides have a role in protecting from autoimmune and inflammatory diseases [20] and they exert activity through inhibition of the production of macrophage-derived chemokines, effects on lymphocyte migration, antigen-induced cell apoptosis and on T-cell differentiation [21]. The development of autoantibodies to PACAP and VIP in mammalian tissues is known but not extensively documented. However autoantibody responses to this group of neuropeptides indicate immunological tolerance to them or their receptors may be readily broken [22] and result in further amplification of autoreactive immunological responses [23]. Monoclonal anti-VIP antibody has high affinity binding to VIP and displays protease-like catalysis of VIP [24]. The effect of vaccinations on vasoactive neuropeptide responses is not well documented in the literature. Any association between vaccination and dysfunction of VaN activity would depend on demonstrable evidence that immunisation acts in a similar stimulant way to infection and other known VaN stimuli. However VaN dysfunction may still arise de novo for reasons that are not completely understood. The role of adjuvants in vaccines in eliciting VaN dysfunction is also unclear. A shortage of research data has been suggested in anthrax vaccine used in Gulf War personnel [25]. High levels of IL-6, IL12, TNFalpha and lupus specific antibodies occurred in mice after intraperitoneal injection of the hydrocarbon oil pristane [26]. Squalene is an endogenous hydrocarbon and efficient adjuvant [27] and has been claimed to have been used in anthrax vaccines, although their presence is disputed [28]. Anti-squalene antibodies (ASA) have been detected in personnel [29]. Nevertheless, Gulf War veterans who received anthrax vaccine reported more reactions to vaccines than those who did not receive anthrax vaccine [30]. Vaccination has been raised as a possible contributing factor in GWS. Many vaccinations were given on arrival in the field rather than at home bases. Worse health outcome measures were found in Gulf War veterans who received vaccinations in the field [31]. This raises the interesting question as to whether vaccinations, particularly involving a large number of different and unusual vaccines in a compressed time period, whether in the field or at
672 home, may have had a role in eliciting vasoactive neuropeptide responses and predisposed autoimmune reaction to them.
Perverse immunological outcomes Interactions and potentially synergistic effects between exogenous infection and other antigenic substances such as vaccines, adjuvants, and sandfly vasodilating substances such as maxadilan may give rise to autoimmune mechanisms producing impaired vasoactive neuropeptide function. These effects might include disturbed calcium metabolism. Theoretically these mechanisms may have a role in causing osteoporosis, and potentially other GWS symptoms, in previously healthy service personnel, and may include those who received vaccines but were not deployed to the Persian Gulf. The role of vasoactive neuropeptides in responding to exogenous infection, vaccines and their adjuvants or other stimuli may be significant in developing perverse immunological responses to the neuropeptides themselves or their receptor binding sites.
Conclusion and future directions Osteoporosis is an unusual disorder in relatively young males. Assuming exclusion of other potential causes of osteoporosis, the theoretical link between certain vaccines, their adjuvants and multisymptom disorders like GWS and CFS in the context of vasoactive neuropeptide autoimmune dysfunction can not be dismissed. The role of vasoactive neuropeptides, their receptor binding sites and their potential agonists and antagonists such as sandfly maxadilan in causing autoimmune disorders should be investigated further.
References [1] Bieliauskas LA, Turner RS. What Persian Gulf Syndrome? Clin Neuropsychol 2000;14(3):341–3. [2] Proctor SP, Heaton KJ, White RF, Wolfe J. Chemical sensitivity and chronic fatigue in Gulf War veterans: a brief report. J Occup Environ Med 2001;43(3):259–64. [3] Tournier JN, Drouet E, Jouan A. The Gulf War Syndrome. Presse Med 2002;31(1 Pt 1):3–9. [4] Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Arch Neurol 2000;57(9):1280–5.
Staines [5] Jamal GA. Gulf War syndrome – a model for the complexity of biological and environmental interaction with human health. Adverse Drug React Toxicol Rev 1998;17(1): 1–17. [6] Staines DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry. Med Hypotheses 2004, in press. [7] Staines DR. Is Gulf War Syndrome an autoimmune disorder of endogenous neuropeptides, exogenous sandfly maxadilan and molecular mimicry. Med Hypotheses 2004, in press. [8] Harrison’s. Principles of internal medicine. 14th ed., McGraw-Hill; 1998, p. 2247–2253. [9] She F, Sun W, Mao JM, Wang X. Calcitonin gene-related peptide gene therapy suppresses reactive oxygen species in pancreas and prevents mice from autoimmune diabetes. Sheng Li Xue Bao 2003;55(6):625–32. [10] Garcia-Catellano JM, Diaz-Herrera P, Morcuende JA. Is bone a target – tissue for the nervous system? New advances on the understanding of their interactions. Iowa Orthop J 2000;20:49–58. [11] Wimalawansa SJ. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Crit Rev Neurobiol 1997;11(2–3):167–239. [12] Lin J, Lu C, Gao L. Study on the level of plasma calcitonin gene-related peptide and adrenomedullin in subjects with primary osteoporosis. Zhonghua Yi Xue Za Zhi 2001; 81(14):841–3. [13] Pondel M. Calcitonin and calcitonin receptors: bone and beyond. Int J Exp Pathol 2000;81(6):405–22. [14] Vignery A, McCarthy TL. The neuropeptide calcitonin generelated peptide stimulates insulin-like growth factor 1 production by primary fetal rat osteoblasts. Bone 1996;18(4):331–5. [15] MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M. Calcitonin and the peptides from the calcitonin gene. Clin Orthop 1987;(217):45–55. [16] Delgado M, Abad C, Martinez C, Juarranz MG, Leceta J, Ganea D, et al. PACAP in immunity and inflammation. Ann NY Acad Sci 2003;992:141–57. [17] Paul S. Catalytic activity of anti-ground state antibodies, antibody subunits, and human autoantibodies. Appl Biochem Biotechnol 1994;47(2-3):241–53. [18] Moretti C, Mencacci C, Frajese GV, Cerilli M, Frajese G. Growth hormone-releasing hormone and pituitary adenylate cyclase activating polypeptide in the reproductive system. Trends Endocrinol Metab 2002;13(10):428–35. [19] Brenneman DE, Glazner G, Hill JM, Hauser J, Davidson A, Gozes I. VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolaracting peptide. Ann NY Acad Sci 1998;865:207–12. [20] Delgado M, Jonakait GM, Ganea D. Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia. Glia 2002;39(2):148–61. [21] Vassiliou E, Jiang X, Delgado M, Ganea D. TH2 lymphocytes secrete functional VIP upon antigen stimulation. Arch Physiol Biochem 2001;109(4):365–8. [22] Takamori M, Maruta T. Receptor diseases in the field of neurology. Rinsho Byori 2000;48(5):385–95. [23] Bangale Y, Cavill D, Gordon T, Planque S, Taguchi H, Bhatia G. Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice. Peptides 2002;23(12): 2251–7. [24] Ikezaki H, Paul S, Alkan-Onyuksel H, Patel M, Gao XP, Rubenstein I. Vasodilation elicited by liposomal VIP is unimpeded by anti-VIP antibody in hamster cheek pouch. Am J Physiol 1998;275(1 Pt 2):R56–62.
Is osteoporosis linked to vaccinations and Gulf War Syndrome? [25] Turnbull PC. Current status of immunisation against anthrax: old vaccines may be here to stay a while. Curr Opin Infect Dis 2000;13(2):113–20. [26] Satoh M, Kuroda Y, Yoshida H, Behney KM, Mitzutani A, Akaogi J, et al. Induction of lupus autoantibodies by adjuvants. J Autoimmun 2003;21(1):1–9. [27] Allison AC. Squalene and squalene emulsions as adjuvants. Methods 1999;19(1):87–93. [28] Spanggord RJ, Wu B, Sun M, Lim P, Ellis WY. Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed. J Pharm Biomed Anal 2002;29(1-2):183–93.
673
[29] Asa PB, Wilson RB, Garry RF. Antibodies to squalene in recipients of anthrax vaccine. Exp Mol Pathol 2002;73(1): 19–27. [30] Schumm WR, Reppert EJ, Jurich AP, Bollman SR, Webb FJ, Castello CS, et al. Sel-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans. Psychol Rep 2002;90(2): 639–53. [31] Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. BMJ 2000;320(7246): 1363–7.
http://intl.elsevierhealth.com/journals/mehy
Is osteoporosis linked to vaccinations and Gulf War Syndrome?q Donald R. Staines* Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Queensland, Australia Received 20 January 2004; accepted 21 January 2004
Summary Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigations and lack of a biologically plausible aetiology. Assertions have been made that GWS may be the result of vaccinations given to serving military personnel in the Persian Gulf and may be associated with osteoporosis. Calcitonin gene related protein (CGRP) is a vasoactive neuropeptide that is synthesised in conjunction with calcitonin gene expression. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. This paper describes a biologically plausible mechanism for the development of osteoporosis in the context of GWS based on loss of immunological tolerance to the vasoactive neuropeptide CGRP or its receptors following a variety of antigenic events. c 2004 Elsevier Ltd. All rights reserved.
Introduction Gulf War Syndrome (GWS), a disabling fatigue-associated state acquired in armed services personnel during the Persian Gulf War, is a disorder of unknown aetiology and no proven biologically plausible mechanism [1]. GWS has been associated with multiple chemical sensitivity (MCS) and a range of neu-
q The author declares no grants or financial conflict of interest are relevant in the development of this paper. Abstracts from PubMed, National Library of Medicine, were used in the development of this paper. * Tel.: +61-7-55097202; mobile: +61-414-278-031; fax: +61-75561-1851. E-mail address: [email protected] (D.R. Staines).
ropsychiatric, somatic and behavioural disorders in addition to fatigue [2]. GWS has been possibly attributed to stress, vaccinations and their adjuvants, exposure to neurotoxic substances, and biological warfare agents [3]. Some presenting features of GWS are consistent with a neurological illness [4]. Diverse neurological symptoms have been reported [5]. Vaccinations are suggested to have contributed to osteoporosis in Gulf War veterans, as part of the syndrome constellation of GWS. An autoimmune process has been suggested however no published reports detailing an hypothesised mechanism are currently available. A biologically plausible link exists between the vasoactive neuropeptide, calcitonin gene related protein (CGRP), and osteoporosis. GWS may also be linked to chronic fatigue syndrome (CFS) through similar autoimmune mechanisms affect-
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.01.006
Is osteoporosis linked to vaccinations and Gulf War Syndrome? ing a novel group of vasoactive neuropeptides (VaNs) [6] and the sandfly salivary vasodilator maxadilan [7].
Osteoporosis and vasoactive neuropeptides Osteoporosis is the reduction in the mass of bone per unit volume. It is also used to define any degree of skeletal fragility sufficient to increase risk of bone fracture. Calcitonin decreases bone resorption and is used therapeutically in osteoporosis [8]. Calcitonin gene related protein is a widely distributed member of the vasoactive neuropeptide class of substances and is involved with calcitonin activity. It has numerous protective roles [9]. Neuropeptides such as VIP and CGRP have important roles in bone metabolism [10]. CGRP protects the skeleton from calcium stress including growth, pregnancy and lactation [11]. Plasma levels of CGRP and adrenomedullin (ADM) are increased in subjects with osteoporosis and may contribute to this disease [12]. Calcitonin gene related protein promotes cAMP accumulation in osteobalstic cells indicating the existence of functional receptors [13]. In this respect it mirrors the mechanism of action of other vasoactive neuropeptides. Recent studies have demonstrated the ability of receptor modifying proteins (RAMPs) to post-translationally modify the calcitonin receptor-like receptor (CRLR) presumably indicating the potential for receptor interference and compromise of function [14] which could result in calcitonin impairment and osteoporosis [15]. Endogenous vasoactive neuropeptides exert a wide spectrum of immunological functions and have a critical role in homeostasis of the immune system through different receptors expressed in various immunocompetent cells [16]. Disturbances in their function are recognised as potential causes of autoimmune disease [17]. Vasoactive neuropeptides are related to the secretin/glucagon superfamily and include pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), NAPVSIPG (NAP), CGRP and ADM amongst others. They are a relatively novel class of substances that function as highly potent immune regulators, neurotransmitte- rs, co-transmitters, hormones and neurotrophes. They are genetically highly preserved indicating crucial roles for survival over many hundreds of millions of years [18]. They act in extremely small concentrations, for example
671
nanomolar (VIP) and femtomolar (NAP) concentrations, respectively [19].
Immunological sequelae and vaccination Vasoactive neuropeptides have a role in protecting from autoimmune and inflammatory diseases [20] and they exert activity through inhibition of the production of macrophage-derived chemokines, effects on lymphocyte migration, antigen-induced cell apoptosis and on T-cell differentiation [21]. The development of autoantibodies to PACAP and VIP in mammalian tissues is known but not extensively documented. However autoantibody responses to this group of neuropeptides indicate immunological tolerance to them or their receptors may be readily broken [22] and result in further amplification of autoreactive immunological responses [23]. Monoclonal anti-VIP antibody has high affinity binding to VIP and displays protease-like catalysis of VIP [24]. The effect of vaccinations on vasoactive neuropeptide responses is not well documented in the literature. Any association between vaccination and dysfunction of VaN activity would depend on demonstrable evidence that immunisation acts in a similar stimulant way to infection and other known VaN stimuli. However VaN dysfunction may still arise de novo for reasons that are not completely understood. The role of adjuvants in vaccines in eliciting VaN dysfunction is also unclear. A shortage of research data has been suggested in anthrax vaccine used in Gulf War personnel [25]. High levels of IL-6, IL12, TNFalpha and lupus specific antibodies occurred in mice after intraperitoneal injection of the hydrocarbon oil pristane [26]. Squalene is an endogenous hydrocarbon and efficient adjuvant [27] and has been claimed to have been used in anthrax vaccines, although their presence is disputed [28]. Anti-squalene antibodies (ASA) have been detected in personnel [29]. Nevertheless, Gulf War veterans who received anthrax vaccine reported more reactions to vaccines than those who did not receive anthrax vaccine [30]. Vaccination has been raised as a possible contributing factor in GWS. Many vaccinations were given on arrival in the field rather than at home bases. Worse health outcome measures were found in Gulf War veterans who received vaccinations in the field [31]. This raises the interesting question as to whether vaccinations, particularly involving a large number of different and unusual vaccines in a compressed time period, whether in the field or at
672 home, may have had a role in eliciting vasoactive neuropeptide responses and predisposed autoimmune reaction to them.
Perverse immunological outcomes Interactions and potentially synergistic effects between exogenous infection and other antigenic substances such as vaccines, adjuvants, and sandfly vasodilating substances such as maxadilan may give rise to autoimmune mechanisms producing impaired vasoactive neuropeptide function. These effects might include disturbed calcium metabolism. Theoretically these mechanisms may have a role in causing osteoporosis, and potentially other GWS symptoms, in previously healthy service personnel, and may include those who received vaccines but were not deployed to the Persian Gulf. The role of vasoactive neuropeptides in responding to exogenous infection, vaccines and their adjuvants or other stimuli may be significant in developing perverse immunological responses to the neuropeptides themselves or their receptor binding sites.
Conclusion and future directions Osteoporosis is an unusual disorder in relatively young males. Assuming exclusion of other potential causes of osteoporosis, the theoretical link between certain vaccines, their adjuvants and multisymptom disorders like GWS and CFS in the context of vasoactive neuropeptide autoimmune dysfunction can not be dismissed. The role of vasoactive neuropeptides, their receptor binding sites and their potential agonists and antagonists such as sandfly maxadilan in causing autoimmune disorders should be investigated further.
References [1] Bieliauskas LA, Turner RS. What Persian Gulf Syndrome? Clin Neuropsychol 2000;14(3):341–3. [2] Proctor SP, Heaton KJ, White RF, Wolfe J. Chemical sensitivity and chronic fatigue in Gulf War veterans: a brief report. J Occup Environ Med 2001;43(3):259–64. [3] Tournier JN, Drouet E, Jouan A. The Gulf War Syndrome. Presse Med 2002;31(1 Pt 1):3–9. [4] Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Arch Neurol 2000;57(9):1280–5.
Staines [5] Jamal GA. Gulf War syndrome – a model for the complexity of biological and environmental interaction with human health. Adverse Drug React Toxicol Rev 1998;17(1): 1–17. [6] Staines DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry. Med Hypotheses 2004, in press. [7] Staines DR. Is Gulf War Syndrome an autoimmune disorder of endogenous neuropeptides, exogenous sandfly maxadilan and molecular mimicry. Med Hypotheses 2004, in press. [8] Harrison’s. Principles of internal medicine. 14th ed., McGraw-Hill; 1998, p. 2247–2253. [9] She F, Sun W, Mao JM, Wang X. Calcitonin gene-related peptide gene therapy suppresses reactive oxygen species in pancreas and prevents mice from autoimmune diabetes. Sheng Li Xue Bao 2003;55(6):625–32. [10] Garcia-Catellano JM, Diaz-Herrera P, Morcuende JA. Is bone a target – tissue for the nervous system? New advances on the understanding of their interactions. Iowa Orthop J 2000;20:49–58. [11] Wimalawansa SJ. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Crit Rev Neurobiol 1997;11(2–3):167–239. [12] Lin J, Lu C, Gao L. Study on the level of plasma calcitonin gene-related peptide and adrenomedullin in subjects with primary osteoporosis. Zhonghua Yi Xue Za Zhi 2001; 81(14):841–3. [13] Pondel M. Calcitonin and calcitonin receptors: bone and beyond. Int J Exp Pathol 2000;81(6):405–22. [14] Vignery A, McCarthy TL. The neuropeptide calcitonin generelated peptide stimulates insulin-like growth factor 1 production by primary fetal rat osteoblasts. Bone 1996;18(4):331–5. [15] MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M. Calcitonin and the peptides from the calcitonin gene. Clin Orthop 1987;(217):45–55. [16] Delgado M, Abad C, Martinez C, Juarranz MG, Leceta J, Ganea D, et al. PACAP in immunity and inflammation. Ann NY Acad Sci 2003;992:141–57. [17] Paul S. Catalytic activity of anti-ground state antibodies, antibody subunits, and human autoantibodies. Appl Biochem Biotechnol 1994;47(2-3):241–53. [18] Moretti C, Mencacci C, Frajese GV, Cerilli M, Frajese G. Growth hormone-releasing hormone and pituitary adenylate cyclase activating polypeptide in the reproductive system. Trends Endocrinol Metab 2002;13(10):428–35. [19] Brenneman DE, Glazner G, Hill JM, Hauser J, Davidson A, Gozes I. VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolaracting peptide. Ann NY Acad Sci 1998;865:207–12. [20] Delgado M, Jonakait GM, Ganea D. Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia. Glia 2002;39(2):148–61. [21] Vassiliou E, Jiang X, Delgado M, Ganea D. TH2 lymphocytes secrete functional VIP upon antigen stimulation. Arch Physiol Biochem 2001;109(4):365–8. [22] Takamori M, Maruta T. Receptor diseases in the field of neurology. Rinsho Byori 2000;48(5):385–95. [23] Bangale Y, Cavill D, Gordon T, Planque S, Taguchi H, Bhatia G. Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice. Peptides 2002;23(12): 2251–7. [24] Ikezaki H, Paul S, Alkan-Onyuksel H, Patel M, Gao XP, Rubenstein I. Vasodilation elicited by liposomal VIP is unimpeded by anti-VIP antibody in hamster cheek pouch. Am J Physiol 1998;275(1 Pt 2):R56–62.
Is osteoporosis linked to vaccinations and Gulf War Syndrome? [25] Turnbull PC. Current status of immunisation against anthrax: old vaccines may be here to stay a while. Curr Opin Infect Dis 2000;13(2):113–20. [26] Satoh M, Kuroda Y, Yoshida H, Behney KM, Mitzutani A, Akaogi J, et al. Induction of lupus autoantibodies by adjuvants. J Autoimmun 2003;21(1):1–9. [27] Allison AC. Squalene and squalene emulsions as adjuvants. Methods 1999;19(1):87–93. [28] Spanggord RJ, Wu B, Sun M, Lim P, Ellis WY. Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed. J Pharm Biomed Anal 2002;29(1-2):183–93.
673
[29] Asa PB, Wilson RB, Garry RF. Antibodies to squalene in recipients of anthrax vaccine. Exp Mol Pathol 2002;73(1): 19–27. [30] Schumm WR, Reppert EJ, Jurich AP, Bollman SR, Webb FJ, Castello CS, et al. Sel-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans. Psychol Rep 2002;90(2): 639–53. [31] Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. BMJ 2000;320(7246): 1363–7.