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Atherogenic role of protein-modified oxidized low-density lipoproteins and related autoantibodies
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
development in children with ASD. It is also important to note that for each antibody tested the number of autistic children showing positivity was far from 100%. It is also unclear whether individual autistic children are positive for more than one antibody. One must also keep in mind that for circulating autoantibodies to have access to the brain, there must be a breach, however transient, of the blood–brain barrier. Again, it can be inferred that increased autoimmunity may be confined to a subset of autistic patients. Indeed, large cohort studies with thoroughly defined, and specifically phenotyped autistic patient groups, containing controls carefully matched for age and sex, need to be performed to confirm the potential role of autoantibodies in the pathology of either all or subsets of patients with ASD. Moreover, the development of an animal model will be crucial to clarify the role of autoimmunity in the pathology of autism.
603
Acknowledgements
This work was supported in part by grants from the UC Davis MIND Institute and NIEHS 1 P01 ES11269-01; EPA Log Number HQ-R-000.
References [1] Korvatska E, Van de Water J, Anders TF, Gershwin ME. Genetic and immunologic considerations in autism. Neurobiol Dis 2002 (Mar);9(2):107 – 25. [2] Ashwood P, Van de Water J. A review of autism and the immune response. Clin Dev Immunol 2004 [in press].
doi:10.1016/j.autrev.2004.08.018
Atherogenic role of protein-modified oxidized low-density lipoproteins and related autoantibodies Eiji Matsuuraa, Kazuko Kobayashia, Yehuda Shoenfeldb, Luis R. Lopezc a
Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan b Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel c Corgenix, Inc., Westminster, Colorado, USA Available online 11 September 2004
Oxidative-stress is thought to be etiologically related to atherosclerosis, a vascular disorder of public health importance. The causal relationship between atherosclerosis and cholesterol is well established. However, newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions. In particular, experimental evidence has clearly shown that oxidation of lowdensity lipoprotein (LDL) is an early proatherogenic event that contributes to the formation of macrophage-derived foam cells. The increased cardiovascular morbidity and mortality recently recognized in patients with systemic
autoimmune disorders is possibly the consequence of their accelerated (or premature) development of atherosclerosis. These findings have suggested a contributing role of autoimmunity in atherogenesis. The antiphospholipid syndrome (APS) is characterized by venous and arterial thromboembolic complications associated with high serum levels of antiphospholipid antibodies, and is frequently diagnosed in the context of an autoimmune disease. However, the exact mechanism(s) by which anticardiolipin antibodies (aCL), lupus anticoagulants (LA) and/or other antiphospholipid antibodies promote thrombosis is not completely understood. It is now widely agreed that h2-glycoprotein I (h2GPI) plays a
604
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
central role in APS, and more importantly, represents a major antigenic target for antiphospholipid antibodies. Oxidized LDL (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with h2GPI and immunoreactive lymphocytes. It was also reported that aCL antibodies from patients with systemic lupus erythematosus (SLE) cross-reacted with malondialdehyde (MDA)modified LDL, and that anti-h2GPI antibodies were associated with arterial thrombosis. These findings further indicated the participation of antiphospholipid antibodies in atherogenesis. More recently, we have demonstrated that oxLDL binds to h2GPI to form complexes, and that these complexes can be found in the blood stream of patients with various autoimmune and chronic inflammatory diseases, such as SLE, APS, systemic sclerosis (SSc), chronic renal disease, diabetes mellitus (DM), as well as in some patients with bacuteQ myocardial infarction. Thus, it can be hypothesized that oxLDL/h2GPI complexes are associated to systemic and chronic inflammation of the vasculature that occurs in autoimmune patients. It has been widely suggested that elevated levels of high-sensitivity C-reactive protein (hsCRP) predict the risk of cardiovascular events and may be useful for detecting subclinical atherosclerosis. Our recent studies showed that CRP from SLE, APS and DM patients interacted with oxLDL and h2GPI to form circulating complexes. In contrast, CRP from rheumatoid arthritis (RA) patients did not form complexes with oxLDL or h2GPI. CRP of RA is synthesized in the liver while CRP of SLE, APS and DM is synthesized by activated macrophages in arterial intima. Thus, CRP/oxLDL/h2GPI complexes of SLE, APS and DM may be also formed in the intima of atherogenic arteries with oxLDL and h2GPI incorporated from the lumen. IgG antibodies to oxLDL/h2GPI complexes have been detected only in SLE and APS patients and were strongly associated with arterial thrombosis. Furthermore, immune complexes containing oxLDL, h2GPI and IgG anti-h2GPI antibodies
have also been detected in SLE and APS patients. Our recent in vitro experiments showed that oxLDL/h2GPI complexes were internalized by macrophages via an anti-h2GPI antibody-mediated phagocytosis. Thus, circulating IgG immune complexes containing oxLDL and h2GPI may be batherogenicQ. Recent reports have indicated that natural antioxLDL antibodies (mainly of the IgM class) derived from hyperlipidemic mice reduced the incidence of atherosclerosis in experimental models (bprotective antibodiesQ). In our study, RA patients had significantly higher IgM anti-oxLDL/h2GPI antibody levels compared to the controls, SLE and SSc patients. SSc IgM antibody levels were significantly higher that the controls, while SLE levels were not. The IgM anti-oxLDL/h2GPI antibody results of RA patients did not correlate with their IgM RF titers. IgM anti-oxLDL/h2GPI antibodies were detected but not associated with any clinical manifestation of APS. Thus, IgG anti-oxLDL/h2GPI antibodies appear to be useful serologic markers for atherosclerotic risk in autoimmune patients with high specificity for APS. The pattern of IgM anti-oxLDL/h2GPI antibodies observed in these autoimmune patients, different to that of IgG antibodies, suggest a different role. However, the exact clinical significance of IgM antibodies in atherogenesis needs to be further explored.
Further reading Kobayashi K, Kishi M, Atsumi T, Bertolaccini ML, Makino H, Sakairi N, et al. Circulating oxidized LDL forms complexes with h2-glycoprotein I: implication as an atherogenic autoantigen. J Lipid Res 2003;44:716 – 26. Lopez D, Garcia-Valladares I, Palafox-Sanchez C, Garcia De La Torre I, Kobayashi K, Matsuura E, et al. Oxidized low-density lipoprotein/h2-glycoprotein I complexes and autoantibodies to oxLig-1/h2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome. Am J Clin Pathol 2004;121:426 – 36. doi:10.1016/j.autrev.2004.08.019
development in children with ASD. It is also important to note that for each antibody tested the number of autistic children showing positivity was far from 100%. It is also unclear whether individual autistic children are positive for more than one antibody. One must also keep in mind that for circulating autoantibodies to have access to the brain, there must be a breach, however transient, of the blood–brain barrier. Again, it can be inferred that increased autoimmunity may be confined to a subset of autistic patients. Indeed, large cohort studies with thoroughly defined, and specifically phenotyped autistic patient groups, containing controls carefully matched for age and sex, need to be performed to confirm the potential role of autoantibodies in the pathology of either all or subsets of patients with ASD. Moreover, the development of an animal model will be crucial to clarify the role of autoimmunity in the pathology of autism.
603
Acknowledgements
This work was supported in part by grants from the UC Davis MIND Institute and NIEHS 1 P01 ES11269-01; EPA Log Number HQ-R-000.
References [1] Korvatska E, Van de Water J, Anders TF, Gershwin ME. Genetic and immunologic considerations in autism. Neurobiol Dis 2002 (Mar);9(2):107 – 25. [2] Ashwood P, Van de Water J. A review of autism and the immune response. Clin Dev Immunol 2004 [in press].
doi:10.1016/j.autrev.2004.08.018
Atherogenic role of protein-modified oxidized low-density lipoproteins and related autoantibodies Eiji Matsuuraa, Kazuko Kobayashia, Yehuda Shoenfeldb, Luis R. Lopezc a
Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan b Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel c Corgenix, Inc., Westminster, Colorado, USA Available online 11 September 2004
Oxidative-stress is thought to be etiologically related to atherosclerosis, a vascular disorder of public health importance. The causal relationship between atherosclerosis and cholesterol is well established. However, newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions. In particular, experimental evidence has clearly shown that oxidation of lowdensity lipoprotein (LDL) is an early proatherogenic event that contributes to the formation of macrophage-derived foam cells. The increased cardiovascular morbidity and mortality recently recognized in patients with systemic
autoimmune disorders is possibly the consequence of their accelerated (or premature) development of atherosclerosis. These findings have suggested a contributing role of autoimmunity in atherogenesis. The antiphospholipid syndrome (APS) is characterized by venous and arterial thromboembolic complications associated with high serum levels of antiphospholipid antibodies, and is frequently diagnosed in the context of an autoimmune disease. However, the exact mechanism(s) by which anticardiolipin antibodies (aCL), lupus anticoagulants (LA) and/or other antiphospholipid antibodies promote thrombosis is not completely understood. It is now widely agreed that h2-glycoprotein I (h2GPI) plays a
604
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
central role in APS, and more importantly, represents a major antigenic target for antiphospholipid antibodies. Oxidized LDL (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with h2GPI and immunoreactive lymphocytes. It was also reported that aCL antibodies from patients with systemic lupus erythematosus (SLE) cross-reacted with malondialdehyde (MDA)modified LDL, and that anti-h2GPI antibodies were associated with arterial thrombosis. These findings further indicated the participation of antiphospholipid antibodies in atherogenesis. More recently, we have demonstrated that oxLDL binds to h2GPI to form complexes, and that these complexes can be found in the blood stream of patients with various autoimmune and chronic inflammatory diseases, such as SLE, APS, systemic sclerosis (SSc), chronic renal disease, diabetes mellitus (DM), as well as in some patients with bacuteQ myocardial infarction. Thus, it can be hypothesized that oxLDL/h2GPI complexes are associated to systemic and chronic inflammation of the vasculature that occurs in autoimmune patients. It has been widely suggested that elevated levels of high-sensitivity C-reactive protein (hsCRP) predict the risk of cardiovascular events and may be useful for detecting subclinical atherosclerosis. Our recent studies showed that CRP from SLE, APS and DM patients interacted with oxLDL and h2GPI to form circulating complexes. In contrast, CRP from rheumatoid arthritis (RA) patients did not form complexes with oxLDL or h2GPI. CRP of RA is synthesized in the liver while CRP of SLE, APS and DM is synthesized by activated macrophages in arterial intima. Thus, CRP/oxLDL/h2GPI complexes of SLE, APS and DM may be also formed in the intima of atherogenic arteries with oxLDL and h2GPI incorporated from the lumen. IgG antibodies to oxLDL/h2GPI complexes have been detected only in SLE and APS patients and were strongly associated with arterial thrombosis. Furthermore, immune complexes containing oxLDL, h2GPI and IgG anti-h2GPI antibodies
have also been detected in SLE and APS patients. Our recent in vitro experiments showed that oxLDL/h2GPI complexes were internalized by macrophages via an anti-h2GPI antibody-mediated phagocytosis. Thus, circulating IgG immune complexes containing oxLDL and h2GPI may be batherogenicQ. Recent reports have indicated that natural antioxLDL antibodies (mainly of the IgM class) derived from hyperlipidemic mice reduced the incidence of atherosclerosis in experimental models (bprotective antibodiesQ). In our study, RA patients had significantly higher IgM anti-oxLDL/h2GPI antibody levels compared to the controls, SLE and SSc patients. SSc IgM antibody levels were significantly higher that the controls, while SLE levels were not. The IgM anti-oxLDL/h2GPI antibody results of RA patients did not correlate with their IgM RF titers. IgM anti-oxLDL/h2GPI antibodies were detected but not associated with any clinical manifestation of APS. Thus, IgG anti-oxLDL/h2GPI antibodies appear to be useful serologic markers for atherosclerotic risk in autoimmune patients with high specificity for APS. The pattern of IgM anti-oxLDL/h2GPI antibodies observed in these autoimmune patients, different to that of IgG antibodies, suggest a different role. However, the exact clinical significance of IgM antibodies in atherogenesis needs to be further explored.
Further reading Kobayashi K, Kishi M, Atsumi T, Bertolaccini ML, Makino H, Sakairi N, et al. Circulating oxidized LDL forms complexes with h2-glycoprotein I: implication as an atherogenic autoantigen. J Lipid Res 2003;44:716 – 26. Lopez D, Garcia-Valladares I, Palafox-Sanchez C, Garcia De La Torre I, Kobayashi K, Matsuura E, et al. Oxidized low-density lipoprotein/h2-glycoprotein I complexes and autoantibodies to oxLig-1/h2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome. Am J Clin Pathol 2004;121:426 – 36. doi:10.1016/j.autrev.2004.08.019