Anti-M₃ Muscarinic Acetylcholine Receptor Antibodies in Systemic Lupus Erythematosus

Silvia Reina^1,2, Cecilia Pisoni³, Alicia Eimon³, Carolina Carrizo³, Roberto Arana³, Enri Borda^1,2*

¹Pharmacology Unit, School of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.
²National Research Council of Argentina (CONICET), Buenos Aires, Argentina.
³Section of Rheumatology and Immunology, Department of Internal Medicine, CEMIC, Buenos Aires, Argentina.

DOI: 10.4236/pp.2015.61004                

Abstract

Background: Evidences have shown that anti-M₃ muscarinic acetylcholine receptor IgG (anti-M₃ mAChR IgG) are clinically useful autoantibody that exert a cholinergic pharmacologic effect binding and interacting with M₃ mAChR at the level of exocrine gland (salivary and ocular). Aims: The aim of this study was to determine the associations between serum level of anti-M₃ mAChR IgG in patients with systemic lupus erythematosus (SLE) and other autoantibodies, serum prostaglandin E₂ (PGE₂), and clinical manifestations. Methods: Serum autoantibodies against M₃ mAChR synthetic peptide were measured by enzyme-linked immuno absorbent assay (ELISA) using, as an antigen, a 25-mer peptide K-R-T-V-P-D-N-Q-C-F-I-Q-F-L-S-N-P-A-V-T-F-G-T-A-I corresponding to the amino acid sequence of the second extracellular loop of the human M₃ mAChR. Serum levels of antinuclear antibodies (ANA), anti-Smith (Sm) antibodies, anti-phospholipid (APL) antibodies, and PGE₂ were determined by ELISA in patients with SLE. Results: We found significantly enhanced titers of anti-M₃ mAChR IgG in sera from SLE patients compared with healthy individuals (control). In addition, serum levels of PGE₂ were significantly higher in SLE patients than in control patients and were significantly higher in active than in non-active SLE. No correlation was found with other autoantibodies present in SLE. By contrast, a positive correlation was found between anti-M₃ mAChR IgG and PGE₂ serum levels in SLE. Conclusions: As anti-M₃ mAChR antibodies present in the sera of SLE patients may be another factor in the pathogenesis of this disease, and the increment of PGE₂ in the sera of SLE has a modulatory action on the inflammatory process, suggesting that the presence of these autoantibodies against M₃ mAChR may contribute to sustained immune deregulation and the strong inflammatory component observed in SLE.

Keywords

Anti-M₃ mAChR Antibodies, Systemic Lupus Erythematosus, Prostaglandin E₂

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Deane, K.D. (2014) Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review. Current Rheumatology Report, 16, 419-422. http://dx.doi.org/10.1007/s11926-014-0419-6
[2]	Bizzaro, N. (2007) Autoantibodies as Predictors of Disease: The Clinical and Experimental Evidence. Autoimmunity Review, 6, 325-333. http://dx.doi.org/10.1016/j.autrev.2007.01.006
[3]	Bizzaro, N. (2008) The Predictive Significance of Autoanti-bodies in Organ-Specific Autoimmune Diseases. Clinical Reviews in Allergy & Immunology, 34, 326-331. http://dx.doi.org/10.1007/s12016-007-8059-5
[4]	Sherer, Y., Gorstein, A., Fritzler, M.J. and Shoenfeld, Y. (2004) Autoantibody Explosion in Systemic Lupus Erythematosus: More than 100 Different Antibodies Found in SLE Patients. Seminars in Arthritis and Rheumatism, 34, 501-537. http://dx.doi.org/10.1016/j.semarthrit.2004.07.002
[5]	Li, Q.Z., Zhou, J., Wandstrat, A.E., Carr-Johnson, F., Branch, V. and Karp, D.R. (2007) Protein Array Autoantibody Profiles for Insights into Systemic Lupus Erythematosus and Incomplete Lupus Syndromes. Clinical Experimental Immunology, 147, 60-70.
[6]	Mansour, R.B., Lassoued, S., Gargouri, B., El Gaid, A., Attia, H. and Fakhfakh, F. (2008) Increased Levels of Autoantibodies against Catalase and Superoxide Dismutase Associated with Oxidative Stress in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus. Scandinavian Journal of Rheumatology, 37, 103-108. http://dx.doi.org/10.1080/03009740701772465
[7]	Magalhaes, M.B., da Silva, L.M., Voltarelli, J.C., Donadi, E.A. and Louzada-Junior, P. (2007) Lymphocytotoxic Antibodies in Systemic Lupus Erythematosus Are Associated with Disease Activity Irrespective of the Presence of Neuropsychiatric Manifestations. Scandinavian Journal of Rheumatology, 6, 442-447. http://dx.doi.org/10.1080/03009740701482768
[8]	Braun, A., Sis, J., Max, R., Mueller, K., Fiehn, C., Zeier, M. and Andrassy, K. (2007) Anti-Chromatin and Anti-C1q Antibodies in Systemic Lupus Erythematosus Compared to Other Systemic Autoimmune Diseases. Scandinavian Journal of Rheumatology, 36, 291-298. http://dx.doi.org/10.1080/03009740701218717
[9]	D’Cruz, D.P., Khamashta, M.A. and Hughes, G.R. (2007) Systemic Lupus Erythematosus. Lancet, 369, 587-596. http://dx.doi.org/10.1016/S0140-6736(07)60279-7
[10]	Rahman, A. and Isenberg, D.A. (2008) Systemic Lupus Erythematosus. New England Journal of Medicine, 358, 929-939. http://dx.doi.org/10.1056/NEJMra071297
[11]	Pugh-Bernard, A.E. and Cambier, J.C. (2006) B Cell Receptor Signaling in Human Systemic Lupus Erythematosus. Current Opinion in Rheumatology, 18, 451-455. http://dx.doi.org/10.1097/01.bor.0000240353.99808.5f
[12]	Nagy, G., Koncz, A. and Perl, A. (2005) T- and B-Cell Abnormalities in Systemic Lupus Erythematosus. Critical Reviews in Immunology, 25, 123-140. http://dx.doi.org/10.1615/CritRevImmunol.v25.i2.30
[13]	Ishikawa, S., Akakura, S., Abe, M., Terashima, K., Chijiiwa, K., Nishimura, H., Hirose, S. and Shirai, T. (1998) A Subset of CD4+ T Cells Expressing Early Activation Antigen CD69 in Murine Lupus: Possible Abnormal Regulatory Role for Cytokine Imbalance. Journal of Immunology, 161, 1267-1273.
[14]	Bohm, I. (2004) Apoptosis: The Link between Autoantibodies and Leuko-/Lymphocytopenia in Patients with Lupus Erythematosus. Scandinavian Journal of Rheumatology, 33, 409-416. http://dx.doi.org/10.1080/03009740410006907
[15]	Reichlin, M. (1993) Antibodies to Defined Antigens in the Systemic Rheumatic Diseases. Bulletin on the Rheumatic Diseases, 42, 4-6.
[16]	Waltuck, J. and Buyon, J.P. (1994) Autoantibody-Associated Congenital Heart Block: Outcome in Mothers and Children. Annals of Internal Medicine, 120, 544-551. http://dx.doi.org/10.7326/0003-4819-120-7-199404010-00003
[17]	Aho, K., Koskela, P., Makitalo, R., Heliovaara, M. and Palosuo, T. (1992) Antinuclear Antibodies Heralding the Onset of Systemic Lupus Erythematosus. Journal of Rheumatology, 19, 1377-1379.
[18]	Heinlen, L.D., McClain, M.T., Merrill, J., Akbarali, Y.W., Edgerton, C.C., Harley, J.B. and James, J.A. (2007) Clinical Criteria for Systemic Lupus Erythematosus Precede Diagnosis, and Associated Autoantibodies Are Present before Clinical Symptoms. Arthritis & Rheumatism, 56, 2344-2351. http://dx.doi.org/10.1002/art.22665
[19]	McClain, M.T., Arbuckle, M.R., Heinlen, L.D., Dennis, G.J., Roebuck, J., Rubertone, M.V., Harley, J.B. and James, J.A. (2004) The Prevalence, Onset, and Clinical Significance of Antiphospholipid Antibodies Prior to Diagnosis of Systemic Lupus Erythematosus. Arthritis & Rheumatism, 50, 1226-1232. http://dx.doi.org/10.1002/art.20120
[20]	Heinlen, L.D., McClain, M.T., Ritterhouse, L.L., Bruner, B.F., Edgerton, C.C., Keith, M.P., James, J.A. and Harley, J.B. (2010) 60 kD Ro and nRNP A Frequently Initiate Human Lupus Autoimmunity. PLoS ONE, 5, e9599. http://dx.doi.org/10.1371/journal.pone.0009599
[21]	Arbuckle, M.R., McClain, M.T., Rubertone, M.V., Scofield, R.H., Dennis, G.J., James, J.A. and Harley, J.B. (2003) Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus. New England Journal of Medicine, 349, 1526-1533. http://dx.doi.org/10.1056/NEJMoa021933
[22]	Arbuckle, M.R., James, J.A., Kohlhase, K.F., Rubertone, M.V., Dennis, G.J. and Harley, J.B. (2001) Development of Anti-dsDNA Autoantibodies Prior to Clinical Diagnosis of Systemic Lupus Erythematosus. Scandinavian Journal of Immunology, 54, 211-219. http://dx.doi.org/10.1046/j.1365-3083.2001.00959.x
[23]	Jonsson, R., Theander, E., Sjöström, B., Brokstad, K. and Henriksson, G. (2013) Autoantibodies Present before Symptom Onset in Primary Sjögren Syndrome. JAMA, 310, 1854-1855. http://dx.doi.org/10.1001/jama.2013.278448
[24]	Tzioufas, A.G., Kapsogeorgou, E.K. and Moutsopoulos, H.M. (2012) Pathogenesis of Sjögren’s Syndrome: What We Know and What We Should Learn. Journal of Autoimmunity, 39, 4-8. http://dx.doi.org/10.1016/j.jaut.2012.01.002
[25]	Reina, S., Sterin-Borda, L., Orman, B. and Borda, E. (2004) Autoantibodies against Cerebral Muscarinic Cholinoceptors in Sjögren Syndrome: Functional and Pathological Implications. Journal of Neuroimmunology, 150, 107-115. http://dx.doi.org/10.1016/j.jneuroim.2004.01.019
[26]	Reina, S., Sterin-Borda, L. and Borda, E. (2012) Anti-M3 Peptide IgG from Sjögren’s Syndrome Triggers Apoptosis in A253 Cells. Cellular Immunology, 275, 33-41. http://dx.doi.org/10.1016/j.cellimm.2012.03.006
[27]	Chae, B.S., Shin, T.Y., Kim, D.K., Eun, J.S., Leem, J.Y. and Yang, J.H. (2008) Prostaglandin E2-Mediated Dysregulation of Proinflammatory Cytokine Production in Pristane-Induced Lupus Mice. Archives of Pharmacal Research, 31, 503-510. http://dx.doi.org/10.1007/s12272-001-1185-6
[28]	Abreu-Velez, A.M., Smith Jr., G. and Howard, M.S. (2011) Activation of the Signaling Cascade in Response to T Lymphocyte Receptor Stimulation and Prostanoids in a Case of Cutaneous Lupus. North American Journal of Medical Sciences, 3, 251-254. http://dx.doi.org/10.4297/najms.2011.3251
[29]	Tan, E.M., Cohen, A.S., Fries, J.F., Masi, A.T., McShane, D.J., Rothfield, N.F., Schaller, J.G., Talal, N. and Winchester, R.J. (1982) The 1982 Revised Criteria for the Classification of Systemic Lupus Erythematosus. Arthritis & Rheumatism, 25, 1271-1277. http://dx.doi.org/10.1002/art.1780251101
[30]	Bombardier, C., Gladman, D.D., Urowitz, M.B., Caron, D., Chang, C.H., et al., The Committee on Prognosis Studies in SLE (1992) Derivation of the Sledai. A Disease Activity Index for Lupus Patients. Arthritis & Rheumatism, 35, 630-640. http://dx.doi.org/10.1002/art.1780350606
[31]	Guzman, J., Cardiel, M.H., Arce-Salinas, A., Sánchez-Guerrero, J. and Alarcón-Segovia, D. (1992) Measurement of Disease Activity in Systemic Lupus Erythematosus. Prospective Validation of 3 Clinical Indices. Journal of Rheumatology, 19, 1551-1558.
[32]	Eriksson, C., Kokkonen, H., Johansson, M., Hallmans, G., Wadell, G. and Rantapaa-Dahlqvist, S. (2011) Autoantibodies Predate the Onset of Systemic Lupus Erythematosus in Northern Sweden. Arthritis Research & Therapy, 13, R30-R34. http://dx.doi.org/10.1186/ar3258
[33]	Tsai, C.Y., Wu, T.H., Tsai, S.T., Chen, K.H., Thajeb, P., Lin, W.M., Yu, H.S. and Yu, C.L. (1994) Cerebrospinal Fluid Interleukin-6, Prostaglandin E2, and Autoantibodies in Patients with Neuropsychiatric Systemic Lupus Erythematosus and Central Nervous System Infections. Scandinavian Journal of Rheumatology, 23, 57-63. http://dx.doi.org/10.3109/03009749409103028