Buscar en
Revista Colombiana de Reumatología
Toda la web
Inicio Revista Colombiana de Reumatología Posible papel de la β2 glicoproteína I y la apoptosis durante la diseminación...
Información de la revista
Vol. 19. Núm. 1.
Páginas 52-58 (Marzo 2012)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 19. Núm. 1.
Páginas 52-58 (Marzo 2012)
DOI: 10.1016/S0121-8123(12)70039-7
Acceso a texto completo
Posible papel de la β2 glicoproteína I y la apoptosis durante la diseminación intermolecular de epítopes en lupus eritematoso sistémico
Possible role of β2-glycoprotein I and apoptosis during intermolecular epitope spreading in systemic lupus erythematous
Visitas
...
Mauricio Restrepo E.1,
Autor para correspondencia
mauresco90@hotmail.com

Correspondencia:.
, Carolina Muñoz G.1, Adriana L. Vanegas G.1, Luis Alonso González1, Gloria María Vásquez D.1
1 Sección de Reumatología. Departamento de Medicina Interna. Facultad de Medicina. Universidad de Antioquia. Medellín, Colombia
Información del artículo
Resumen

El lupus eritematoso sistémico (LES) es una enfermedad caracterizada por la pérdida de la tolerancia hacia antígenos propios que conlleva a la aparición de autoanticuerpos contra antígenos nucleares y daño de órganos asociado. Durante la apoptosis se expone al sistema inmune a múltiples antígenos nucleares y se piensa que alteraciones en la remoción de cuerpos apoptóticos pueden iniciar o perpetuar una respuesta autoinmune. Otra fuente de material nuclear expuesto al medio extracelular son las denominadas micropartículas, las cuales son liberadas de diferentes células no solo durante la apoptosis sino también durante la activación celular o el estrés mecánico. Se ha demostrado que los pacientes con LES presentan autoanticuerpos varios años antes de la fase clínica de la enfermedad, y esta aparición de autoanticuerpos tiende a seguir un curso predecible, con acumulación progresiva de autoanticuerpos específicos. Esta aparición consistentemente ordenada de autoanticuerpos, precediendo por varios años la aparición de la enfermedad clínica, apoya fuertemente las teorías de diseminación de epítopes en LES humano. Varios modelos múridos han tratado de reproducir la enfermedad humana utilizando cuerpos apoptóticos pero sin resultados contundentes. Un reciente modelo animal logra reproducir más fielmente la secuencia de autoanticuerpos y las manifestaciones clínicas del LES al utilizar a la β2GP-I como inmunógeno potenciado por una respuesta de célula T inducida por lipopolisacárido. Las micropartículas, rodeadas de fosfatidilserina y cargadas de material nuclear incluyendo DNA extracelular antigénicamente activo, son asimismo candidatas ideales para servir de plataforma para la diseminación de epítopes en un medio inflamatorio, con la posterior aparición secuencial de autoanticuerpos específicos patogénicos.

Palabras clave:
lupus eritematoso sistémico
apoptosis
micropartículas
β2 glicoproteína I
diseminación del epítope
Summary

Systemic lupus erythematosus (SLE) is a disease characterized by loss of tolerance to selfantigens leading to the development of autoantibodies against nuclear antigens and organ damage. During apoptosis, immune system is exposed to multiple nuclear antigens and is thought that alterations in the removal of apoptotic bodies could start or perpetuate an autoimmune response. Another source of nuclear material exposed to extracellular medium are called microparticles, which are released from various cells not only during apoptosis but also during cell activation or mechanical stress. It has been shown that patients with SLE already have autoantibodies several years before clinical phase of disease, and this appearance of autoantibodies tends to follow a predictable course, with progressive accumulation of specific autoantibodies. This steadily orderly appearance of autoantibodies preceding for several years the onset of clinical disease strongly supports theories of spreading epitopes in human SLE. Several mouse models have tried to replicate the human disease using apoptotic bodies but without conclusive results. A recent animal model can reproduce more closely the sequence of autoantibodies and clinical manifestations of SLE using the β2-glycoprotein I (β2GP-I) as an immunogen powered by a lipopolysaccharide induced T cell response. Microparticles, surrouded by phosphatidylserie and nuclear material loaded including antigenically active extracellular DNA, are also ideal candidates to serve as a platdorm for the epitopes dissemination in an inflammatory environment, with subsequent sequential appearance of pathogenic specific antibodies.

Key words:
systemic lupus erythematosus
apoptosis
microparticles
β2 glycoprotein I
epitope spreading
El Texto completo está disponible en PDF
Referencias
[1.]
D.P. D’Cruz, M.A. Khamashta, G.R.V. Hughes.
Systemic lupus erythematosus.
[2.]
A. Rahman, D.A. Isenberg.
Systemic Lupus Erythematosus.
N Engl J Med, 358 (2008), pp. 929-939
[3.]
G.C. Tsokos.
Systemic Lupus Erythematosus.
N Engl J Med, 365 (2011), pp. 2110-2121
[4.]
Y. Sherer, A. Gorstein, M.J. Fritzler, Y. Shoenfeld.
Autoantibody Explosion in Systemic Lupus Erythematosus: More than 100 Different Antibodies Found in SLE Patients.
Semin Arthritis Rheum, 34 (2004), pp. 501-537
[5.]
D.H. Solomon, A.J. Kavanaugh, P.H. Schur.
Evidence-based guidelines for the use of immunologic tests: Antinuclear antibody testing.
Arthritis Rheum, 47 (2002), pp. 434-444
[6.]
A.F. Kavanaugh, D.H. Solomon.
Guidelines for immunologic laboratory testing in the rheumatic diseases: Anti- DNA antibody tests.
Arthritis Rheum, 47 (2002), pp. 546-555
[7.]
M.T. McClain, M.R. Arbuckle, L.D. Heinlen, G.J. Dennis, J. Roebuck, M.V. Rubertone, et al.
The Prevalence Onset, and Clinical Significance of Antiphospholipid Antibodies Prior to Diagnosis of Systemic Lupus Erythematosus.
Arthritis Rheum, 50 (2004), pp. 1226-1232
[8.]
C.C. Mok, C.S. Lau.
Pathogenesis of systemic lupus erythematosus.
J Clin Pathol, 56 (2003), pp. 481-490
[9.]
R. Gualtierotti, M. Biggioggero, A.E. Penatti, P.L. Meroni.
Updating on the pathogenesis of systemic lupus erythematosus.
Autoimmun Rev, 10 (2010), pp. 3-7
[10.]
T.K. Means, A.D. Luster.
Toll-like receptor activation in the pathogenesis of systemic lupus erythematosus.
Ann N Y Acad Sci, 1062 (2005), pp. 242-251
[11.]
J.S. Navratil, J.M. Ahearn.
Apoptosis Clearance Mechanisms, and the Development of Systemic Lupus Erythematosus.
Curr Rheumatol Rep, 3 (2001), pp. 191-198
[12.]
L.M. Yassin, M. Rojas, L.A. Ramírez, L.F. García, G. Vásquez.
Monocyte activation by apoptotic cells removal in systemic lupus erythematosus patients.
Cell Immunol, 266 (2010), pp. 52-60
[13.]
B. Hugel, M.C. Martínez, C. Kunzelmann, J.M. Freyssinet.
Membrane Microparticles: Two Sides of the Coin.
Physiol, 20 (2005), pp. 22-27
[14.]
D.S. Pisetsky, J. Gauley, A.J. Ullal.
Microparticles as a source of extracellular DNA.
Immunol Res, 49 (2011), pp. 227-234
[15.]
S.P. Ardoin, D.S. Pisetsky.
The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation.
Mod Rheumatol, 18 (2008), pp. 319-326
[16.]
A.J. Ullal, C.F. Reich, M. Clowse, L.G. Criscione-Schreiber, M. Tochacek, M. Monestier, et al.
Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus.
J Autoimmun, 36 (2011), pp. 173-180
[17.]
D.S. Pisetsky, P.E. Lipsky.
Microparticles as autoadjuvants in the pathogenesis of SLE.
Nat Rev Rheumatol, 6 (2010), pp. 368-372
[18.]
R. Mejía-Romero, M. García-Carrasco, C. Galarza-Maldonado, P. Santos, C. Mendoza-Pinto, R.O. Escárcega, et al.
Primary antiphospholipid syndrome in Latin American mestizo patients: clinical and immunologic characteristics and comparison with European patients.
Clin Rheumatol, 27 (2008), pp. 891-897
[19.]
R. Cervera, J.C. Piette, J. Font, M.A. Khamashta, Y. Shoenfeld, M.T. Camps, et al.
Antiphospholipid syndrome. Clinical and Immunologic Manifestations and Patterns of Disease Expression in a Cohort of 1,000 Patients.
Arthritis Rheum, 46 (2002), pp. 1019-1027
[20.]
B. de Laat, K. Mertens, P.G. de Groot.
Mechanisms of disease: antiphospholipid antibodies-from clinical association to pathologic mechanism.
Nat Clin Pract Rheumatol, 4 (2008), pp. 192-199
[21.]
W.F. Baker, R.L. Bick.
The Clinical Spectrum of Antiphospholipid Syndrome.
Hematol Oncol Clin North Am, 22 (2008), pp. 33-52
[22.]
N.A. Sangle, K.J. Smock.
Antiphospholipid antibody syndrome.
Arch Pathol Lab Med, 135 (2011), pp. 1092-1096
[23.]
S. Miyakis, M.D. Lockshin, T. Atsumi, D.W. Branch, R.L. Brey, R. Cervera, R.H. Derksen, P.G. DE Groot, T. Koike, P.L. Meroni, G. Reber, Y. Shoenfeld, A. Tincani, P.G. Vlachoyiannopoulos, S.A. Krilis.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost, 4 (2006), pp. 295-306
[24.]
J.M. Grossman.
Primary versus secondary antiphospholipid syndrome: is this lupus or not?.
Curr Rheumatol Rep, 6 (2004), pp. 445-450
[25.]
M. Rottem, I. Krause, A. Fraser, L. Stojanovich, J. Rovensky, Y. Shoenfeld.
Autoimmune hemolytic anaemia in the antiphospholipid syndrome.
Lupus, 15 (2006), pp. 473-477
[26.]
L. Comellas-Kirkerup, G. Hernández-Molina, A.R. Cabral.
Antiphospholipid associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study.
Blood, 116 (2010), pp. 3058-3063
[27.]
K. Oku, T. Atsumi, M. Bohgaki, O. Amengual, H. Kataoka, T. Horita, et al.
Complement activation in patients with primary antiphospholipid syndrome.
Ann Rheum Dis, 68 (2009), pp. 1030-1035
[28.]
M. Ramos-Casals, M.T. Campoamor, A. Chamorro, G. Salvador, S. Segura, J.C. Botero, et al.
Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients.
Lupus, 13 (2004), pp. 777-783
[29.]
C.E. Builes, I.C. Durango, C.J. Velásquez.
Lupus eritematoso sistémico con anticuerpos antinucleares negativos y anemia hemolítica.
Acta Med Colomb, 35 (2010), pp. 179-182
[30.]
M. Restrepo.
Con relación al artículo: «Lupus eritematoso sistémico con anticuerpos antinucleares negativos y anemia hemolítica» Cartas al Editor.
Acta Med Colomb, 36 (2011), pp. 52
[31.]
M.R. Arbuckle, M.T. McClain, M.V. Rubertone, R.H. Scofield, G.J. Dennis, J.A. James, J.B. Harley.
Development of autoantibodies before the clinical onset of systemic lupus erythematosus.
N Engl J Med, 349 (2003), pp. 1526-1533
[32.]
C. Eriksson, H. Kokkonen, M. Johansson, G. Hallmans, G. Wadell, S. Rantapää-Dahlqvist.
Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden.
Arthritis Res Ther, 22;13 (2011), pp. R30
[33.]
J.S. Levine, R. Subang, S.H. Nasr, S. Fournier, G. Lajoie, J. Wither, J. Rauch.
Immunization with an apoptotic cell-binding protein recapitulates the nephritis and sequential autoantibody emergence of systemic lupus erythematosus.
J Immunol, 177 (2006), pp. 6504-6516
[34.]
F. Monneaux, S. Muller.
Epitope Spreading in Systemic Lupus Erythematosus.
Arthritis Rheum, 46 (2002), pp. 1430-1438
[35.]
C.L. Vanderlugt, S.D. Miller.
Epitope spreading in immune mediated diseases: implications for immunotherapy.
Nat Rev Immunol, 2 (2002), pp. 85-95
[36.]
U.S. Deshmukh, F. Gaskin, J.E. Lewis, C.C. Kannapell, S.M. Fu.
Mechanisms of autoantibody diversification to SLErelated autoantigens.
Ann N Y Acad Sci, 987 (2003), pp. 91-98
[37.]
R.S. Hotchkiss, A. Strasser, J.E. McDunn, P.E. Swanson.
Cell death.
N Engl J Med, 361 (2009), pp. 1570-1583
[38.]
L.E. Muñoz, C. Janko, C. Schulze, C. Schorn, K. Sarter, G. Schett, M. Herrmann.
Autoimmunity and chronic inflammation - two clearance-related steps in the etiopathogenesis of SLE.
Autoimmun Rev, 10 (2010), pp. 38-42
[39.]
L.E. Muñoz, K. Lauber, M. Schiller, A.A. Manfredi, M. Herrmann.
The role of defective clearance of apoptotic cells in systemic autoimmunity.
Nat Rev Rheumatol, 6 (2010), pp. 280-289
[40.]
J.S. Navratil, J.M. Ahearn.
Apoptosis and autoimmunity: complement deficiency and systemic lupus erythematosus revisited.
Curr Rheumatol Rep, 2 (2000), pp. 32-38
[41.]
A. Sheriff, U.S. Gaipl, R.E. Voll, J.R. Kalden, M. Herrmann.
Apoptosis and systemic lupus erythematosus.
Rheum Dis Clin North Am, 30 (2004), pp. 505-527
[42.]
B. Giannakopoulos, P. Mirarabshahi, S.A. Krilis.
New Insights into the Biology and Pathobiology of Beta2- Glycoprotein I.
Curr Rheumatol Rep, 13 (2011), pp. 90-95
[43.]
K. Gropp, N. Weber, M. Reuter, S. Micklisch, I. Kopka, T. Hallström, C. Skerka.
β2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator.
Blood, 118 (2011), pp. 2774-2783
[44.]
E. Matsuura, L. Shen, Y. Matsunami, N. Quan, M. Makarova, F.J. Geske, et al.
Pathophysiology of beta2-glycoprotein I in antiphospholipid syndrome.
Lupus, 19 (2010), pp. 379-384
[45.]
S. Miyakis, B. Giannakopoulos, S.A. Krilis.
Beta 2 glycoprotein I function in health and disease.
Thrombosis Research, 114 (2004), pp. 335-346
[46.]
K. Balasubramanian, S.N. Maiti, A.J. Schroit.
Recruitment of beta-2-glycoprotein 1 to cell surfaces in extrinsic and intrinsic apoptosis.
Apoptosis, 10 (2005), pp. 439-446
[47.]
A.A. Manfredi, P. Rovere, G. Galati, S. Heltai, E. Bozzolo, L. Soldini, J. Davoust, G. Balestrieri, A. Tincani, M.G. Sabbadini.
Apoptotic Cell Clearance In Systemic Lupus Erythematosus I. Opsonization by Antiphospholipid Antibodies.
[48.]
A.A. Manfredi, P. Rovere, S. Heltai, G. Galati, G. Nebbia, A. Tincani, G. Balestrieri, M.G. Sabbadini.
Apoptotic Cell Clearance In Systemic Lupus Erythematosus II. Role of β2-Glycoprotein I.
[49.]
D. Mevorach, J.L. Zhou, X. Song, K.B. Elkon.
Systemic exposure to irradiated apoptotic cells induces autoantibody production.
J Exp Med, 188 (1998), pp. 387-392
[50.]
M. Georgiev, L.M. Agle, J.L. Chu, K.B. Elkon, D. Ashany.
Mature dendritic cells readily break tolerance in normal mice but do not lead to disease expression.
Arthritis Rheum, 52 (2005), pp. 225-238

* Los autores declaran no presentar ningún conflicto de interés al momento de la redacción del manuscrito.

Copyright © 2012. Asociación Colombiana de Reumatología
Opciones de artículo
Herramientas