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Cardiovascular Research 2005 68(2):183-185; doi:10.1016/j.cardiores.2005.08.008
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Copyright © 2005, European Society of Cardiology

Complexity of antigenic determinants and humoral responses in vascular injury

Olivier Thaunatb, Guiseppina Caligiurib, Antonino Nicolettib and Jean-Baptiste Michela,*

aInserm Unit 698, Cardiovascular Hematology, Bioengineering and Remodeling, CHU Xavier Bichat, 46 rue Henri Huchard, 75018 Paris, France
bInserm Unit 681, Institut Biomedical des Cordeliers, 75006 Paris, France

* Corresponding author. Email address: jbmichel{at}bichat.inserm.fr

Received 29 August 2005; revised 29 August 2005; accepted 31 August 2005

See article by Shinohara et al. [1] (pages 249–258) in this issue.

Circulating antibodies, reacting with autoantigens in the vascular wall, are commonly harmless in healthy vessels but can turn pathogenic in the presence of vascular injury. The exact antigenic determinants and the role of such autoreactive antibodies remain unclear. In their present study appearing in this issue, Shinohara and coworkers [1] propose a xenogenic, vaccinal experimental approach in order to limit intimal proliferation in response to balloon-induced arterial wall injury in rabbits. Their observations suggest that the observed humoral response is responsible for the limitation of smooth muscle cell (SMC) migration and proliferation via an extracellular effect on the SMC response to growth factors and angiotensin II, as observed in vitro.

While the involvement of autoreactive antibodies in human autoimmune diseases and their vascular targeting are beyond the scope of the present editorial, the observations of Shinohara and coworkers merit some comments. The authors [1] used a mixture of specific and non-specific cellular xenoantigens shared by cultured rat SMC rendered inert for immunization. They also used a homogenized rabbit SMC preparation, including membrane-exposed and intracellular antigens, for exploring the autoreactive determinants of the response. Therefore, a precise identification of the molecular targets of the humoral response is difficult to evaluate. The presence of auto-antibodies, within the intima in vivo, was not presented in the study; nevertheless, the induced antibodies did not provoke apoptosis of SMC in vitro. One interesting point is that the humoral response specifically limited intimal proliferation but did not modify SMC content in the contralateral unballooned carotid. These data suggest that SMC cultured in vitro and proliferating intimal SMC in vivo share similar conserved neo-antigens. The effect was independent of the species and was probably associated with the proliferating secretory phenotype of SMC as compared with the contractile phenotype of resting SMC in healthy, untreated arteries.

These data raise the question of the pleiotropic role of circulating immunoglobulins in vascular biology. Circulating antibodies, which target arterial wall components, are involved in acute vascular rejection in xenotransplantation, in chronic rejection in allotransplantation, and in autoimmunity associated with vascular pathologies.


   1. Xenoantigens
Top
 1. Xenoantigens
2. Alloantigens
 3. Antibodies in atherosclerosis
 4. Conclusions
 References
 
The main mediators of hyperacute rejection in xenotransplantation, leading to diffuse arterial thrombosis, are carbohydrate xenoantigens expressed on the endothelium of the organ donor species that are spontaneously recognized by circulating natural immunoglobulins in the recipient species. The xenoantigen, shared by the endothelium of the donor, is mainly related to a repeated disaccharide residue Gal{alpha}1-3Gal [2]. The natural circulating antibodies of the recipient species spontaneously recognize this motif, bind to the xenogenic endothelium and activate the complement cascade and a procoagulant phenotype, leading to perivascular hemorrhages and intravascular coagulation. This detrimental effect of natural immunoglobulins has been combated by plasmapheresis-induced depletion of xenoreactive immunoglobulins in the recipient plasma by the use of complement inhibitors or by the use of knock-out transgenic animals as donors that are negative for the {alpha}1,3-galactosyltransferase (decrease in xenoantigens) [3]. In this latter system, the acute rejection was postponed, but thrombotic microangiopathy appeared in relation to other xenoantigens and other immunoglobulin specificities. These data suggest a development, in parallel with immunological approaches, of a direct targeting of procoagulant molecules at the surface of the endothelium [4].


   2. Alloantigens
Top
 1. Xenoantigens
 2. Alloantigens
3. Antibodies in atherosclerosis
 4. Conclusions
 References
 
Nowadays chronic rejection is the main cause of long-term allograft failure. Since the vascular cells of the graft are permanently exposed to the immune system of the recipient, they are an important target in the chronic rejection process. The immune injury of the vascular wall results in arterial remodeling known as graft arteriosclerosis. A neointimal proliferating response associated with the disappearance of medial SMC characterizes this remodeling. In an attempt to determine which arm of the immune response is involved in the development of chronic vascular rejection lesions, immunodeficient mice receiving a cardiac allograft were transfused with sera from mice allosensitized by a skin graft from the same donor. Under these conditions, chronic vascular rejection lesions developed in the grafts. This demonstrates that the humoral alloimmune response is sufficient to promote chronic vascular rejection [5]. Using the rat aortic interposition model, our group has shown that during the rejection of the arterial wall (i) the media remains devoid of inflammatory cell infiltration although IgGs are deposited at the site [6], (ii) alloantibodies directed against donor MHC I induce smooth muscle cells apoptosis [7], (iii) and the intimal proliferation is of recipient origin (cellular chimerism) [6,8]. Importantly, an allo-presensitization-induced humoral response was associated with an accelerated disappearance of allogenic SMC in the media and a limitation of isogenic SMC proliferation in the intima [9]. Nevertheless, a role for other non-specific antigens cannot be completely excluded. In contrast, Jin et al. [10] have reported that anti-MHC I antibodies stimulated the proliferation and induced the up-regulation of cell survival genes of donor endothelial cells. Further studies are therefore required to further explore the role and the targets of the antibodies in lesions of chronic vascular rejection.


   3. Antibodies in atherosclerosis
Top
 1. Xenoantigens
 2. Alloantigens
 3. Antibodies in atherosclerosis
4. Conclusions
 References
 
Autoreactive antibodies have been linked to atherosclerosis by both clinical and experimental studies. Indeed, the entire repertoire of circulating autoreactive antibodies is perturbed in atherosclerotic patients [11]. Although the recognized arterial epitopes are common in those healthy individuals, the affinity of autoimmune antibodies has been reported to be elevated and unmasked in patients [11]. Specifically, the reactivity against plaque-infiltrating modified lipoproteins (mLDL) by oxidative stress and/or proteolytic injury is recognized as a possible component of the atherosclerotic process. The serum titers of antibodies directed against mLDL are increased in patients with clinical manifestation of atherosclerosis as well as in atherosclerotic mice. The deleterious role evoked by the prognostic clinical studies has not been confirmed by the experimental studies in atherosclerotic-prone mice [12,13] and suggests a protective role for mLDL antibodies in atherogenesis, probably through an accelerated turn-over in the spleen as well as modified lipoprotein in the blood [13]. Intriguingly, anti-mLDL antibodies show a common reactivity to phosphorylcholine and hence may also react with apoptotic cells, increasing inflammatory response [14]. This latter mechanism may account for the deleterious role suggested by the clinical studies in which the risk associated with anti-mLDL antibody titers was reported. Thus, the autoreactive antibodies developed during atherogenesis may serve to protect from disease but may also induce pathogenic events as in the case of superimposed ischemia.


   4. Conclusions
Top
 1. Xenoantigens
 2. Alloantigens
 3. Antibodies in atherosclerosis
 4. Conclusions
References
 
In conclusion, the effects of circulating antibodies in vascular biology in vivo are pleiotropic, with either beneficial or detrimental actions on SMC survival and proliferation. Similarly, possible antigenic determinants are numerous and diversified (saccharides, MHC, metabolized lipoproteins, phospholipids, etc.), which probably limit human applications of such immunization protocols, as proposed by Shinohara and coworkers [1], in the future.


   References
Top
 1. Xenoantigens
 2. Alloantigens
 3. Antibodies in atherosclerosis
 4. Conclusions
 References
 

  1. Shinohara M., Kawashima S., Yamashita T., Takaya T., Toh R., Ishida T., et al. Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries. Cardiovasc Res (2005) 68:249–258.[Abstract/Free Full Text]
  2. Parker W., Lesher A.P. In pursuit of xenoreactive antibodies: where has it gotten us? Immunol Cell Biol (2005) 83:413–417.[CrossRef][Medline]
  3. Seveno C., Fellous M., Ashton-Chess J., Soulillou J.P., Vanhove B. On the acceptability of xenografts. Med Sci (Paris) (2005) 21:302–308.[Medline]
  4. Mendicino M., Liu M., Ghanekar A., He W., Koscik C., Shalev I., et al. Targeted deletion of Fgl-2/fibroleukin in the donor modulates immunologic response and acute vascular rejection in cardiac xenografts. Circulation (2005) 112:248–256.[Abstract/Free Full Text]
  5. Russell P.S., Chase C.M., Winn H.J., Colvin R.B. Coronary atherosclerosis in transplanted mouse hearts: II. Importance of humoral immunity. J Immunol (1994) 152:5135–5141.[Abstract]
  6. Plissonnier D., Nochy D., Poncet P., Mandet C., Hinglais N., Bariety J., et al. Sequential immunological targeting of chronic experimental arterial allograft. Transplantation (1995) 60:414–424.[Web of Science][Medline]
  7. Plissonnier D., Henaff M., Poncet P., Paris E., Tron F., Thuillez C., et al. Involvement of antibody-dependent apoptosis in graft rejection. Transplantation (2000) 69:2601–2608.[CrossRef][Web of Science][Medline]
  8. Shimizu K., Sugiyama S., Aikawa M., Fukumoto Y., Rabkin E., Libby P., et al. Host bone-marrow cells are a source of donor intimal smooth-muscle-like cells in murine aortic transplant arteriopathy. Nat Med (2001) 7:738–741.[CrossRef][Web of Science][Medline]
  9. Kolb F., Heudes D., Mandet C., Plissonnier D., Osborne-Pellegrin M., Bariety J., et al. Presensitization accelerates allograft arteriosclerosis. Transplantation (1996) 62:1401–1410.[CrossRef][Web of Science][Medline]
  10. Jin Y.P., Jindra P.T., Gong K.W., Lepin E.J., Reed E.F. Anti-HLA class I antibodies activate endothelial cells and promote chronic rejection. Transplantation (2005) 79:S19–S21.[CrossRef][Web of Science][Medline]
  11. Caligiuri G., Stahl D., Kaveri S., Irinopoulous T., Savoie F., Mandet C., et al. Autoreactive antibody repertoire is perturbed in atherosclerotic patients. Lab Invest (2003) 83:939–947.[CrossRef][Web of Science][Medline]
  12. Zhou X., Caligiuri G., Hamsten A., Lefvert A.K., Hansson G.K. LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis. Arterioscler Thromb Vasc Biol (2001) 21:108–114.[Abstract/Free Full Text]
  13. Caligiuri G., Nicoletti A., Poirier B., Hansson G.K. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest (2002) 109:745–753.[CrossRef][Web of Science][Medline]
  14. Shaw P.X., Goodyear C.S., Chang M.K., Witztum J.L., Silverman G.J. The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells. J Immunol (2003) 170:6151–6157.[Abstract/Free Full Text]

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