Abstract
Introduction
Associations between systemic lupus erythematosus (SLE) and primary immunodeficiencies (PIDs) were analyzed to gain insight into the physiopathology of SLE. Some PIDs have been consistently associated with SLE or lupus-like manifestations: (a) homozygous deficiencies of the early components of the classical complement pathway in the following decreasing order: in C1q, 93% of affected patients developed SLE; in C4, 75%; in C1r/s, 57%; and in C2, up to 25%; (b) female carriers of X-linked chronic granulomatous disease allele; and (c) IgA deficiency, present in around 5% of juvenile SLE.
Discussion
In the first two groups, disturbances of cellular waste-disposal have been proposed as the main mechanisms of pathogenesis. On the other hand and very interestingly, there are PIDs systematically associated with several autoimmune manifestations in which SLE has not been described, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), immunedysregulation polyendocrinopathy enteropathy X-linked (IPEX), and autoimmune lymphoproliferative syndrome (ALPS), suggesting that mechanisms considered as critical players for induction and maintenance of tolerance to autoantigens, such as (1) AIRE-mediated thymic negative selection of lymphocytes, (2) Foxp3+ regulatory T cell-mediated peripheral tolerance, and (3) deletion of auto-reactive lymphocytes by Fas-mediated apoptosis, could not be relevant in SLE physiopathology. The non-description of SLE and neither the most characteristic SLE clinical features among patients with agammaglobulinemia are also interesting observations, which reinforce the essential role of B lymphocytes and antibodies for SLE pathogenesis.
Conclusion
Therefore, monogenic PIDs represent unique and not fully explored human models for unraveling components of the conundrum represented by the physiopathology of SLE, a prototypical polygenic disease.
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References
Geha RS, Notarangelo L, Casanova J-L, Chapel H, Conley ME, Fischer A, Hammarström L, Nonoyama S, Ochs HD, Puck JM, Roifman C, Seger R, Wedgwood J. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776–94.
Carneiro-Sampaio M, Coutinho A. Tolerance and autoimmunity: lessons at the bedside of primary immunodeficiencies. Adv Immunol 2007;95:51–82.
Navratil JS, Korb LC, Ahearn JM. Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance. Immunopharmacology 1999;42:47–52.
Pickering MC, Botto M, Taylor PR, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 2000;76:227–34.
Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 2004;22:431–56.
Sjöholm AG, Jönsson G, Braconier JH, Sturfelt G, Truedsson L. Complement deficiency and disease: an update. Mol Immunol 2006;43:78–85.
Koide M, Shirahama S, Tokura Y, Takigawa M, Hayakawa M, Furukawa F. Lupus erythematosus associated with C1 inhibitor deficiency. J Dermatol 2002;29:503–7.
Kemper C, Chan AC, Green J, Brett KA, Murphy KM, Atkinson P. Activation of human CD4+cells with CD3 and CD466 induces a T-regulatory cell 1 phenotype. Nature 2003;42:388–92.
Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79:155–69.
Cale CM, Morton L, Goldblatt D. Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. Clin Exp Immunol 2007;148:79–84.
Brown JR, Goldblatt D, Buddle J, Morton L, Thrasher AJ. Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease. J Leukoc Biol 2003;73:591–9.
Sanford AN, Suriano AR, Herche D, Dietzmann K, Sullivan KE. Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus. Rheumatology 2006;45:178–81.
Liblau RS, Bach JF. Selective IgA deficiency and autoimmunity. Int Arch Allergy Immunol 1992;99:16–27.
Rankin EC, Isenberg DA. IgA deficiency and SLE: prevalence in a clinic population and a review of the literature. Lupus 1997;6:390–4.
Cassidy JT, Kitson RK, Selby CL. Selective IgA deficiency in children and adults with systemic lupus erythematosus. Lupus 2007;16:647–50.
Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffié C, Hénin D, Benhamou M, Pretolani M, Blank U, Monteiro RC. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 2005;22:31–42.
Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829–36.
Betterle C, Greggio NA, Volpato M. Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998;83:1049–55.
Perheentupä J. Extensive Clinical experience: autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. J Clin Endocrinol Metab 2006;91:2843–50.
Perniola R, Falorni A, Clemente MG, Forini F, Accogli E, Lobreglio G. Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Eur J Endocrinol 2000;143:497–503.
Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of immune dysregulation, polyendocrinopathy, and X-linked inheritance (IPEX), a syndrome. J Med Genet 2002;39:537–45.
Ochs HD, Ziegler SF, Torgerson TR. FOXP3 acts as a rheostat of the immune response. Immunol Rev 2005;203:156–64.
Torgerson T. Regulatory T cells in human autoimmune diseases. Springer Semin Immun 2006;28:63–76.
Oliveira JB, Fleisher T. Autoimmune lymproliferative syndrome. Curr Opin Allergy Clin Immunol, 2004;4:497–503.
Oliveira JB, Bidère N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A 2007;104:8953–8.
Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 1996;98:1107–13.
Liphaus BL, Kiss MH, Carrasco S, Goldenstein-Schainberg C. Increased Fas and Bcl-2 expression on peripheral cells from patients with active juvenile-onset systemic lupus erythematosus. J Rheum 2007;34:1580–4.
Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Italian Pediatric Group for XLA-AIEOP. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 2002;104:221–30.
Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006;85:193–202.
Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, et al. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol 2006;118:201–8.
Fernandez-Castro M, Mellor-Pita S, Citores MJ, Muñoz P, Tutor-Ureta P, Silva L, Vargas JA, Yebra-Bango M, Andreu JL. Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum 2007;36:238–45.
Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun 2005;25:57–62.
Glocker E, Ehl S, Grimbacher B. Common variable immunodeficiency in children. Curr Opin Pediatr 2007;19:685–92.
Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH, Litzman J, Holm A, et al. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol 2004;113:234–40.
Salzer U, Chapel HM, Webster AD, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37:820–8.
Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997;131:47–54.
Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome. Medicine 2003;82:373–84.
Lougaris V, Badolato R, Ferrari S, Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 2005;203:48–66.
Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996;97:2063–73.
Durandy A, Notarangelo L, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 2005;203:67–79.
Melegari A, Mascia MT, Sandri G, Carbonieri A. Immunodeficiency and autoimmune phenomena in female hyper-IgM syndrome. Ann N Y Acad Sci 2007;1109:106–8.
Shrinath M, Walter JH, Haeney M, Couriel JM, Lewis MA, Herrick AL. Prolidase deficiency and systemic lupus erythematosus. Arch Dis Child 1997;76:441–4.
Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, et al. Autoimmunity in Wiskott–Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 2003;111:e622–7.
Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott–Aldrich syndrome. J Pediatr 1994;125:876–85.
Rosenzweig SD, Holland SM. Defects in the interferon-γ and interleukin 12 pathways. Immunol Rev 2005;3:38–47.
Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–52.
de Haas M, Kleijer M, van Zwieten R, Roos D, von dem Borne AEGK. Neutrophil FcγRIIIb deficiency, nature and clinical consequences: a study of 21 individuals from 14 families. Blood 1995;86:2403–13.
Acknowledgment
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (grant 2002/05880-4 to MC-S) and Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (grants 302469/2005-2 to CAAS and 34802/2005-0 to MC-S).
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Carneiro-Sampaio, M., Liphaus, B.L., Jesus, A.A. et al. Understanding Systemic Lupus Erythematosus Physiopathology in the Light of Primary Immunodeficiencies. J Clin Immunol 28 (Suppl 1), 34–41 (2008). https://doi.org/10.1007/s10875-008-9187-2
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DOI: https://doi.org/10.1007/s10875-008-9187-2