Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil

Paolo Ruggero Errante Sandro Félix Perazzio Josias Brito Frazão Neusa Pereira da Silva Luis Eduardo Coelho Andrade About the authors

Resumo

As imunodeficiências primárias (IDP) representam um grupo heterogêneo de doenças resultantes de defeitos hereditários no desenvolvimento, na maturação e na função normal de células do sistema imunológico; assim, tornam os indivíduos suscetíveis a infecções recorrentes, alergia, autoimunidade e doenças malignas. Neste estudo retrospectivo descrevem-se doenças autoimunes (DAI), em especial o lúpus eritematoso sistêmico (LES), que surgiram associadas ao curso das IDP. Classicamente, a literatura descreve três grupos de IDP associadas ao LES: (1) deficiência de componentes da via do complemento, (2) defeitos na síntese de imunoglobulinas e (3) doença granulomatosa crônica (DGC). Na atualidade, outras IDP têm sido descritas como manifestações clínicas do LES, como a síndrome de Wiskott-Aldrich (WAS), a poliendocrinopatia autoimune-candidíase-distrofia ectodérmica (APECED), a síndrome linfoproliferativa autoimune (ALPS) e a linfocitopenia idiopática CD4+. Também são apresentados achados de uma coorte de adultos do ambulatório da Divisão de Reumatologia da Universidade Federal de São Paulo. As manifestações de IDP encontradas pelo nosso grupo de estudo foram consideradas leves em termos de gravidade de infecções e mortalidade no início da vida. Assim, é possível que alguns estados de imunodeficiência sejam compatíveis com a sobrevivência em relação à suscetibilidade infecciosa; no entanto, esses estados podem representar um fator de predisposição forte para o desenvolvimento de doenças imunológicas, como observado no LES.

Palavras-chave:
Doença autoimune; Imunodeficiência primária; Lúpus eritematoso sistêmico; Deficiência de anticorpos

Abstract

Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott–Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4+ lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

Keywords:
Autoimmune disease; Primary immunodeficiency; Systemic lupus erythematosus; Antibodies deficiency

Introduction

Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells. PID often have an important genetic basis leading to different immune disorders associated with infections, autoimmune diseases and other malignancies in patients.11 Gupta S, Louis AG. Tolerance and autoimmunity in primary immunodeficiency disease: a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):162-9. Since these are congenital conditions, usually with well-defined genetic defects and mendelian inheritance, children are the most predominant patients. On the other hand, autoimmune diseases (AIDs) have a complex multifactorial polygenic etiology in which environmental triggers play an important role in their pathogenesis and represent a group of more than 70 known diseases.22 Moroni L, Bianchi I, Lleo A. Geoepidemiology, gender, and autoimmune disease. Autoimmun Rev. 2012;11(6-7):A386-92. Remarkably, AIDs represent one of the most common clinical phenotypes of many forms of PID, only overcome by the frequency of infections.33 Torgerson TR. Immunodeficiency diseases with rheumatic manifestations. Pediatr Clin North Am. 2012;59(2):493-507.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by a range of clinical manifestations that predominantly affects women in reproductive age. In SLE, polyclonal hypergammaglobulinemia and multiple autoantibodies are produced predominantly against nuclear antigens. These autoantibodies deposit on several organs, including kidneys, skin and joints, causing severe inflammation.44 Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929-39. Although SLE patients have hypergammaglobulinemia, they often present severe infections, especially while receiving immunosuppressive treatment.

Infections by opportunistic pathogens are commonly seen in patients with PID.55 Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010;71(5):317-28. These infections, either clinical or subclinical, may represent the primary trigger for the development of autoimmunity. In genetically predisposed individuals, chronic exposure to environmental factors can promote the development of autoantibodies many years before the disease onset. Patients with SLE present an increased susceptibility to infection in pre-clinical phase of disease.66 Dooley MA, Hogan SL. Environmental epidemiology and risk factors for autoimmune disease. Curr Opin Rheumatol. 2003;15(2):99-103. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components77 Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004;22:431-56.; (2) selective and partial defects in immunoglobulin synthesis (particularly isolated IgA and IgM deficiencies)88 Cassidy JT, Kitson RK, Selby CL. Selective IgA deficiency in children and adults with systemic lupus erythematosus. Lupus. 2007;16(8):647-50.,99. Carneiro-Sampaio M, Liphaus BL, Jesus AA, Silva CA, Oliveira JB, Kiss MH. Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies. J Clin Immunol. 2008;28 Suppl 1:S34-41.; and (3) chronic granulomatous disease (CGD).99. Carneiro-Sampaio M, Liphaus BL, Jesus AA, Silva CA, Oliveira JB, Kiss MH. Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies. J Clin Immunol. 2008;28 Suppl 1:S34-41.1212 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(1):79-84. However, among clinical observations, several other PID may also occasionally be associated with SLE or SLE-like syndrome manifestations. These include Wiskott–Aldrich syndrome (WAS),1313 Monteferrante G, Giani M, van den Heuvel M. Systemic lupus erythematosus and Wiskott-Aldrich syndrome in an Italian patient. Lupus. 2009;18(3):273-7. autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED),1414 Chebbi W Alaya W,Zantour B, Berriche O, Kamoun M, Sfar MH. Systemic lupus erythematosus with autoimmune polyendocrinopathy type II. Presse Med. 2011;40(7-8):772-4. autoimmune lymphoproliferative syndrome (ALPS),1515 Hong YH, Lee CK. Autoimmune lymphoproliferative syndrome-like syndrome presented as lupus-like syndrome with mycobacterial joint infection evolved into the lymphoma. Rheumatol Int. 2009;29(5):569-73. idiopathic CD4+ lymphocytopenia (ICL),1616 Coutant G, Algayres JP, Bili H, Daly JP. CD4 lymphocytopenia. Gougerot-Sjogren and systemic lupus erythematosus. Ann Med Interne (Paris). 1997;148(7):503-4. partial T cell immunodeficiency and hyper-immune dysregulation (including autoimmunity, inflammatory diseases and elevated IgE production).1717 Liston A, Enders A, Siggs OM. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat Rev Immunol. 2008;8(7):545-58.

Our group has reported that a broad fraction of juvenile SLE patients present one of the several forms of PID.1818 Jesus AA, Liphaus BL, Silva CA, Bando SY, Andrade LE, Coutinho A, et al. Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients. Lupus. 2011;20(12):1275-84. More recently, we documented that 28% of a consecutive cohort of 300 adult SLE patients present some form of PID, mainly related to immunoglobulin deficiency. In this review, we describe the various PID associations with SLE or SLE-like manifestations and also our experience from the outpatient clinic of the adult Rheumatology Division at Universidade Federal de São Paulo.

Classical and non-classical PID associated with SLE

PID are a heterogeneous group of diseases characterized by increased susceptibility to multiple and recurrent infections caused by virulent and non-virulent microorganisms. The literature ranks PID in classical and non-classical forms. Classical PID are defined on the basis of an overt immunologic phenotype, often leading to the identification of the disease-causing gene. The expert committee on Primary Immunodeficiency of the International Union of Immunological Societies (IUIS) recently updated the classification of human classical PID.1919 Al-Herz W Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. Non-classical PID are defined on the basis of a specific though unremarkable clinical phenotype, and never have been classified as a fully distinct phenotype out of PID classification. Additionally, they have not been included in the updated classification of PID, compiled by the ad hoc Expert Committee of the IUIS.2020 Casanova JL, Fieschi C, Bustamante J, Reichenbach J, Remus N, von Bernuth H, et al. From idiopathic infectious diseases to novel primary immunodeficiencies. J Allergy Clin Immunol. 2005;116(2):426-30. However, the fact that non-classical PID may not be associated with recurrent infections does not guarantee that these diseases do not predispose the development of autoimmune disorders. Therefore, in this paper, we describe the major classical and non-classical PID associated to SLE.

Complement deficiencies

The Complement system is composed by a group of plasma and surface cell-proteins with important role in innate and acquired humoral immune system, responsible for the destruction of microbial agents and clearance of circulating immune complexes.2121 Mizuno M. A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis. Curr Med Chem. 2006;13(14):1707-17. In SLE, the deposition of immune complexes containing multiple autoantibodies and activation of the Complement system mediate tissue damage.44 Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929-39. Paradoxically, deficiencies in components of early elements of the classical pathway (C1q, C1r, C1s, C4, and C2) are strongly associated with the development of SLE. In addition, deficiency in components of the late common pathway (C5, C6, C7, C8a and C8b) as well as some elements of the alternative pathway (C3 and Factor I) are only occasionally associated with SLE (Table 1).1919 Al-Herz W Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. Genetic deficiencies of these components might contribute towards SLE pathogenesis by decreasing immune complex clearance capacity. The literature is controversial in respect to mannose-binding lectin (MBL)2222 Glesse N, Monticielo OA, Mattevi VS, Brenol JC, Xavier RM, da Silva GK, et al. Association of mannose-binding lectin 2 gene polymorphic variants with susceptibility and clinical progression in systemic lupus erythematosus. Clin Exp Rheumatol. 2011;29(6):983-90.,2323 Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther. 2012;14(5):R218. and antibodies against MBL2424 Pradhan V, Mahant G, Rajadhyaksha A, Surve P Rajendran V, Patwardhan M, et al. A study on anti-mannose binding lectin (anti-MBL) antibodies and serum MBL levels in Indian systemic lupus erythematosus patients. Rheumatol Int. 2013;33(6):1533-9. in the pathogenesis of SLE. Some authors, and this includes our group, have described the presence of increased MBL deficiency in SLE patients (unpublished data). However, further studies should be conducted for a better elucidation of this association with SLE.

Table 1
Complement deficiencies associated with SLE or SLE-like manifestation.

Defects in immunoglobulin synthesis (antibody deficiencies)

Antibody deficiencies also referred as immunoglobulin deficiencies, represent a group of diseases (immune system disorders) characterized by low or absent levels of immunoglobulin in the blood. Immunoglobulins (Ig) are large y-shaped glycoprotein molecules produced by B cells that detect, bind and neutralize foreign substances (like bacteria, viruses, fungi, toxins and allergens). They also have the capability to signal immune cells to eliminate foreign substances. Antibody deficiencies represent a group of diseases and are considered the most common type of primary immune deficiencies in humans. Due to the fact that protective levels of IgG that are passively acquired by the newborns from the mother decreases during the first year of life, symptoms of this group of diseases only become symptomatic at the end of the first year of life. The spectrum of antibody deficiencies is broad, ranging from the absence of B cells and serum Igs (most severe type of antibody deficiency) to selective antibody deficiency with normal serum levels of total immunoglobulin. In addition to increased susceptibility to infections, clinical presentation of antibody deficiencies may also include other disease processes (e.g., autoimmunity and malignancies).

Common variable immunodeficiency disorders

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies diagnosed in humans, with broad clinical spectrum. CVID patients present history of hypogammaglobulinemia, recurrent respiratory tract infections, but the clinical spectrum may include autoimmune phenomena, bowel inflammatory or infectious disease, and granulomatous disease which can affect liver, spleen and lungs.2525 Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301-5. It has been postulated that persistent antigen stimulation, recurrent tissue damage, defective clearance of immune complexes and immune dysregulation contribute toward the development of autoimmunity, including SLE, but more frequently autoimmune cytopenia and endocrinopathy. Fernandez-Castro et al. described a series of 18 patients with SLE and CVID. Interestingly, up to 67% of them had the autoimmune disease controlled after the development of the immunodeficiency.2626 Fernandez-Castro M, Mellor-Pita S, Citores MJ, Munoz P, Tutor-Ureta P Silva L, et al. Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum. 2007;36(4):238-45. Genetic abnormalities described in CVID include defects in the inducible co-stimulator (ICOS), the membrane activator and calcium-modulator interactor (TACI), the B-cell activating factor receptor (BAFF-R), CD19, CD20 and CD81 (Table 2).1919 Al-Herz W Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. Although CVID has been described in patients after the diagnosis of SLE,2626 Fernandez-Castro M, Mellor-Pita S, Citores MJ, Munoz P, Tutor-Ureta P Silva L, et al. Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum. 2007;36(4):238-45.,2727 Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009;9(5):347-52. immunosuppressive agents used for SLE treatment can be the very cause of hypogammaglobulinemia development, turning the definitive diagnosis of CVID into a difficult task, since the diagnosis of CVID depends on exclusion of all other known causes of hypogammaglobulinemia.

Table 2
Primary immunodeficiencies frequently associated with SLE or SLE-like manifestation.

Selective IgA deficiency

Selective IgA deficiency (SIgAD) is the most common PID (ranging from 1:400 to 1:3000).99. Carneiro-Sampaio M, Liphaus BL, Jesus AA, Silva CA, Oliveira JB, Kiss MH. Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies. J Clin Immunol. 2008;28 Suppl 1:S34-41. Since the majority of patients are asymptomatic, this disorder may be unnoticed during childhood or even on adult phase. These patients present recurrent sino-pulmonary infections, allergy, gastrointestinal disease, endocrinopathy, malignancy and autoimmunity (Table 2). Eventually, patients with SIgAD evolve to CVID. SIgAD is frequently found in patients previously diagnosed with autoimmune disease such as Graves' disease (GD), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG), SLE, and rheumatoid arthritis (RA).2828 Wang N, Shen N, Vyse TJ, Anand V,Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Mol Med. 2011;17(11-12):1383-96. A high prevalence of SIgAD was described in juvenile SLE (5.2%) and in adult onset SLE (2.6%).88 Cassidy JT, Kitson RK, Selby CL. Selective IgA deficiency in children and adults with systemic lupus erythematosus. Lupus. 2007;16(8):647-50. It is hypothesized that the absence of mucosa IgA may reduce clearance and neutralization of antigen and pathogen, which serve as triggers for breaking immune tolerance. However, the association between SIgAD and SLE is not completely understood yet.

Hyper-IgM syndrome

Hyper-IgM syndrome (HIGM) is a non-classical PID characterized by antibody deficiency with the absence of IgG and IgA but normal or increased IgM levels. Different genetic mutations can cause this PID; including mutation of CD40 ligand gene (CD40LG gene, X-linked HIGM), CD40 gene, Activation-induced DNA-cytidine deaminase gene (AICDA gene, also known as AID) and uracil DNA glycosylase gene (UNG) (Table 2).1919 Al-Herz W Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54.,2929 Uygungil B, Bonilla F. Lederman H. Evaluation of a patient with hyper-IgM syndrome. J Allergy Clin Immunol. 2012;129(6), 1692-3 e4. Patients with HIGM usually present during childhood opportunistic infections and autoimmune diseases (autoimmune cytopenia, nephritis, inflammatory bowel disease, autoimmune hepatitis, arthritis, hypothyroidism and SLE). Autoimmune manifestation are more frequent in patients that present HIGM due to mutations in AID, however, autoimmune manifestations have also been reported in other types of HIGM.2929 Uygungil B, Bonilla F. Lederman H. Evaluation of a patient with hyper-IgM syndrome. J Allergy Clin Immunol. 2012;129(6), 1692-3 e4.,3030 Bussone G, Mouthon L. Autoimmune manifestations in primary immune deficiencies. Autoimmun Rev. 2009;8(4):332-6. There are very few cases reported on the coexistence of SLE and AID or UNG associated Hyper-IgM.3131 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.

Isolated IgG subclass deficiency

IgG subclass deficiency is defined as a serum IgG subclass level that is more than two standard deviations below the normal mean for age. IgG subclass deficiency can be associated with recurrent infections of the upper and lower respiratory tracts.3232 Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. Ann Allergy Asthma Immunol. 2007;99(3):281-3. Pathogens are generally limited to bacteria and respiratory viruses. Because IgG2 is important in the response to polysaccharide antigens, IgG2 subclass-deficient patients typically have infections with Haemophilus influenza or Streptococcus pneumoniae.3333 Maguire GA, Kumararatne DS, Joyce HJ. Are there any clinical indications for measuring IgG subclasses? Ann Clin Biochem. 2002;39 Pt 4:374-7. In adults, deficiency of IgG3 subclass is the most common, whereas in children IgG2 is the most prevalent IgG subclass deficiency. IgG subclass deficiency may be seen in conjunction with other primary immune deficiency disorders, such as ataxia-telangiectasia and IgA deficiency.3434 Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, et al. IgA deficiency: correlation between clinical and immunological phenotypes. J Clin Immunol. 2009;29(1):130-6. An IgG subclass deficiency might occur as an isolated single IgG subclass deficiency or as a deficiency of two or more IgG subclasses. The literature describes sporadic cases of autoimmune manifestation in patients with IgG subclass deficiency,35–38 like IgG1,3939 Lacombe C, Aucouturier PPreud'homme JL. Selective IgG1 deficiency. Clin Immunol Immunopathol. 1997;84(2):194-201. IgG44040 Kim JH, Park HJ, Choi GS, Kim JE, Ye YM, Nahm DH, et al. Immunoglobulin G subclass deficiency is the major phenotype of prima^ immunodeficiency in a Korean adult cohort. J Korean Med Sci. 2010;25(6):824-8. and combined IgG2 and IgG4 subclass deficiency.4141 Tamura A, Agematsu K, Urasawa R, Naganuma K, Komiyama A. Cardiac tamponade due to systemic lupus erythematosus in a 7-year-old boy with selective IgG subclass deficiency. Eur J Pediatr. 1998;157(6):475-8. The prevalence might be higher, however those cases might go unnoticed, since IgG subclasses serum level determination is not included in routine evaluation of SLE patients. Jesus et al. (2011) also showed the coexistence of IgG2 deficiency in 5.5% of the juvenile SLE patients studied, representing 21% of all PID cases in their series.1818 Jesus AA, Liphaus BL, Silva CA, Bando SY, Andrade LE, Coutinho A, et al. Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients. Lupus. 2011;20(12):1275-84.

IgM deficiency

The IgM deficiency (IgMD) has been reported in patients with several forms of autoimmune diseases. One reported case describes a 15-year-old female presenting a 22q11.2 deletion syndrome (partial DiGeorge Syndrome) who presented recurrent and chronic otitis media, developmental delay, not associated with any other immunologic defects.4242 Al-Herz W,McGeady SJ, Gripp KW. 22q11.2 deletion syndrome and selective IgM deficiency: an association of a common chromosomal abnormality with a rare immunodeficiency. Am J Med Genet A. 2004;127A(1):99-100. Patients with IgMD and 22q11.2 deletion syndrome may present sinopulmonary recurrent infections, which typically respond to conventional antibiotic therapy without the need of prolonged antibiotic use or intravenous immunoglobulin therapy (IVIg).4343 Kung SJ, Gripp KW, Stephan MJ, Fairchok MP, McGeady SJ. Selective IgM deficiency and 22q11.2 deletion syndrome. Ann Allergy Asthma Immunol. 2007;99(1):87-92. In IgMD patients, recurrent respiratory tract infections, asthma, allergic rhinitis, vasomotor rhinitis, angioedema, and anaphylaxis have been described.4444 Goldstein MF, Goldstein AL, Dunsky EH, Dvorin DJ, Belecanech GA, Shamir K. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006;97(6):717-30. Patients may present antinuclear antibodies (ANA).4545 Antar M, Lamarche J, Peguero A, Reiss A, Cole S. A case of selective immunoglobulin M deficiency and autoimmune glomerulonephritis. Clin Exp Nephrol. 2008;12(4):300-4. Few reports have focused their analysis on selective IgM deficiency however a detailed pathogenesis of this disorder still remains to be carefully analyzed. A study on a case report of a 37-year-old woman who presented selective IgM deficiency with concurrent IgG4 deficiency, various dermal symptoms and a bronchial polyp, serves as an observation of a not very clear association between a solitary polyp and IgM deficiency, however suggestions have been made for repeated IgM deficiency-related airway infections as a probable etiological factor for the inflammatory polyp.4646. Ideura G, Agematsu K, Komatsu Y, Hatayama O, Yasuo M, Tsushima K, et al. Selective IgM deficiency accompanied with IgG4 deficiency, dermal complications, and a bronchial polyp. Allergol Int. 2008;57(1):99-105. It is speculated that the reduction of secreted IgM production is related to the risk of progression of autoimmune diseases, such as autoimmune glomerulonephritis and SLE in humans. In fact, a few case reports or series show association of this disorder with autoimmune rheumatic diseases, including SLE,4444 Goldstein MF, Goldstein AL, Dunsky EH, Dvorin DJ, Belecanech GA, Shamir K. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006;97(6):717-30.,4747 Goldstein MF, Goldstein AL, Dunsky EH, Dvorin DJ, Belecanech GA, Shamir K. Pediatric selective IgM immunodeficiency. Clin Dev Immunol. 2008;2008:624850. especially in patients with disease of long duration.4848 Saiki O, Saeki Y,Tanaka T, Doi S, Hara H, Negoro S, et al. Development of selective IgM deficiency in systemic lupus erythematosus patients with disease of long duration. Arthritis Rheum. 1987;30(11):1289-92. Interestingly, disease remission did not correlate with elevation of IgM serum levels, indicating a deeper dysregulation of the immune system.

Congenital defects of phagocyte

Phagocytes such as monocytes/macrophages as well as granulocytes are the cells that engulf and destroy ingested pathogens during a process denominated phagocytosis. In certain conditions, either the number of phagocytes is reduced or their functional capacity is impaired.4949 Notarangelo LD, Fischer A, Geha RS, Casanova JL, Chapel H, Conley ME, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009;124(6):1161-78. Almost all PID due to phagocyte defects are a consequence of inherited mutations affecting the innate immune system. Most of these PID patients are identified at very young age based on their clinical phenotype of susceptibility to normally nonpathogenic bacteria or fungi, and in some cases, the infectious agents point to the disorder.5050 Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med. 2000;343(23):1703-14. Defects of these cells include decreased number of neutrophils caused by defects on granulocyte development or capability to exit into the circulation leading to neutropenia; or due to the presence of autoantibodies or isoantibodies directed against neutrophil membrane antigens. Other defects include abnormalities in granulocyte killing ability, opsonic capability secondary to deficiencies of antibody and complement factors, and chemotaxis.5050 Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med. 2000;343(23):1703-14.

Chronic granulomatous disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocytes, with X-linked or autosomal recessive inheritance. The X-linked form presents mutation in CYBB gene that encodes the heavy chain of cytochrome b558, or gp91-phox (56% of cases), an electron transport protein responsible for the oxidative burst of phagocytes. These patients present severe and recurrent infections of skin, respiratory system, gastrointestinal tract and adjacent lymphonodes, pancreas, bones and central nervous system. Persistence of microorganisms in phagolysosomes leads to granuloma formation that causes obstruction along the gastrointestinal or urinary tract. In the autosomal recessive form, genes affected include the other components of NADPH oxidase system: NCF1 (adapter protein p47-phox, 33% of cases); NCF2 (activator protein p67-phox, 5% of cases); and NCF4 (p40-phox), 6% of cases.5151 Stasia MJ, Li XJ. Genetics and immunopathology of chronic granulomatous disease. Semin Immunopathol. 2008;30(3):209-35. Patients with X-linked form present severe infections in the first year of life, and patients with the autosomal recessive form of CGD have less severe clinical manifestation, with late onset symptoms. Oral ulcers and autoimmune manifestation (antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous and systemic lupus erythematosus, and autoimmune pulmonary disease) are frequently seen in patients with CGD.5252 De Ravin SS, Naumann N, Cowen EW, Friend J, Hilligoss D, Marquesen M, et al. Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol. 2008;122(6):1097-103. Additionally, the mother's status of carrier of the affected gene is associated to higher frequency of discoid lupus lesions.1111 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(3):155-69. X-linked form can also present McLeod phenotype (a genetic disorder that may affect the blood, brain, peripheral nerves, muscle and heart, caused by a variety of recessively inherited mutations in the XK gene on the X chromosome, responsible for producing the Kx protein, a secondary supportive protein for the Kell antigen on the red blood cell surface, with compensated hemolysis, acanthocysis and progressive degenerative neuromuscular disorders).5353 Watkins CE, Litchfield J, Song E, Jaishankar GB, Misra N, Holla N, et al. Chronic granulomatous disease, the McLeod phenotype, and the contiguous gene deletion syndrome-a review. Clin Mol Allergy. 2011;9:13.

Well-defined PID and PID syndromes associated with SLE

Within the clinical framework of PID, the most common feature besides susceptibility to infections is represented by autoimmune manifestations. Recent advances in both fields have lead to the identification that associations of PID with AIDs are more frequent than previously appreciated.55 Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010;71(5):317-28.,5454 Carneiro-Sampaio M, Coutinho A. Tolerance and autoimmunity: lessons at the bedside of primary immunodeficiencies. Adv Immunol. 2007;95:51-82.,5555 Westerberg LS, Klein C, Snapper SB. Breakdown of T cell tolerance and autoimmunity in primary immunodeficiency-lessons learned from monogenic disorders in mice and men. Curr Opin Immunol. 2008;20(6):646-54. It became evident that different types of PID display consistent associations with distinct autoimmune disorders (including homozygous deficiencies of early components of the classical Complement pathway, selective and partial immunoglobulin deficiencies, particularly isolated IgA and IgM deficiencies, and X-linked and autosomal forms of chronic granulomatous disease), allowing the perception that the study of the association between PID and AIDs represents a unique opportunity for new insights and a better understanding of the pathophysiology as well as the genetic basis of autoimmunity.

Wiskott–Aldrich syndrome

The Wiskott–Aldrich syndrome (WAS) is a PID caused by mutation in the WAS gene, that encodes a protein associated to the process of cell locomotion, immunological synapse formation, apoptosis and phagocytosis. Mutations in the WAS gene can lead to severe clinical manifestations (classical WAS), light manifestations (X-linked thrombocytopenia/XLT) and X-linked neutropenia (neutropenia and thrombocytopenia without myelodysplasia or immunodeficiency). Patients usually present elevated IgA and IgE serum levels, normal IgG, and slightly decreased IgM. The cytotoxic activity of NK cells and CD8 T lymphocytes is impaired. Infections are common since six months of age, with the development of otitis media, sinusitis, pneumonia and diarrhea. Viral infections are common, especially for chickenpox, herpes simplex and molluscum contagiosum. Clinical presentation is normally variable, with symptoms appearing soon after birth or in early life. Patients with WAS have small platelets, lacking specific granules, reduced numbers of organelles in the cytoplasm, defective platelet aggregation and ineffective thrombocytopoiesis. The appearance of petechiae, bruising, bleeding and severe cases of thrombocytopenia hemorrhage of central nervous system are frequent.5656 Puck JM, Candotti F. Lessons from the Wiskott-Aldrich syndrome. N Engl J Med. 2006;355(17):1759-61.,5757 Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N. Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant. 2009;15 1 Suppl:84-90. Eczema, recurrent infections, autoimmune diseases (hemolytic anemia, vasculitis, nephropathy, purpura resembling Henoch–Schonlein, inflammatory bowel disease, SLE, and IgA nephropathy) and malignancies (lymphoma, leukemia) are not rare manifestations.1313 Monteferrante G, Giani M, van den Heuvel M. Systemic lupus erythematosus and Wiskott-Aldrich syndrome in an Italian patient. Lupus. 2009;18(3):273-7.,5858 Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209.

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy

Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED) or autoimmune polyendocrine syndrome type I (APS1) is a PID that harbors autoimmunity within its very essence. There is a wide variation in the clinical features and course of APECED, even among patients sharing the same mutation in the autoimmune regulator gene (AIRE), involved in the disorder and whose encoded protein is responsible for presenting several self-antigens in thymus medullae. While specific mutations in the AIRE gene have not been associated with disease phenotype, associations with specific HLA haplotypes have been noted for some of the autoimmune manifestations of APECED, including alopecia, T1D, and Addison's disease. Chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure are the classic triad of findings that characterize this syndrome.5959 Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kampe O, et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. 2002;87(6):2568-74. Other autoimmune endocrinopathies can be present, including insulin-dependent diabetes mellitus, autoimmune thyroiditis, premature ovarian failure, and hypergonadotropic hypogonadism. Immune-mediated gastrointestinal diseases, autoimmune dermatologic conditions, ectodermal dystrophy, keratoconjunctivitis, iridocyclitis, hemolytic anemia, oral and esophageal cancers, chronic hepatitis, nephritis, cholelithiasis and SLE have also been seen associated to APECED.6060 Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843-50.,6161 Smith CJ, Oscarson M, Ronnblom L, Alimohammadi M, Perheentupa J, Husebye ES, et al. TSGA10 - A target for autoantibodies in autoimmune polyendocrine syndrome type 1 and systemic lupus erythematosus. Scand J Immunol. 2011;73(2):147-53.

Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is an autosomal dominant disorder caused by abnormalities in Fas-mediated lymphocyte apoptosis, with clinical features of splenomegaly and lymphadenopathy, and various autoimmune manifestations. ALPS caused by heterozygous mutations in the Fas gene (TNFRSF6; ALPS Type Ia) make up the majority of identified cases. ALPS caused by mutations in other factors involved in the Fas apoptosis pathway have been identified, including FasL (TNFSF6; ALPS Type Ib), Caspase 8 (NRAS) and Caspase 10 (CASP10) (the latter two, ALPS Type II). There is also a subgroup of patients with ALPS phenotype, abnormal Fas-mediated apoptosis, but no identified mutation in the Fas pathway (ALPS Type III).6262 Sneller MC, Dale JK, Straus SE. Autoimmune lymphoproliferative syndrome. Curr Opin Rheumatol. 2003;15(4):417-21.,6363 Teachey DT. New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome. Curr Opin Pediatr. 2012;24(1):1-8. Immunological abnormalities characteristic of ALPS include the presence of increased number of circulating CD4CD8 α/β+ lymphocytes (double negative), as well as T- and B-cell lymphocytosis and polyclonal hypergammaglobulinemia. Autoimmune hemolytic anemia and immune thrombocytopenia are the most common autoimmune features seen in ALPS. Autoimmune neutropenia and the presence of anticardiolipin antibodies are also often present, whereas autoimmune hepatitis, uveitis, and glomerulonephritis are much less common manifestations in these patients.6363 Teachey DT. New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome. Curr Opin Pediatr. 2012;24(1):1-8. The literature describes a case of SLE-like syndrome in a 59-year-old woman with arthritis, low fever, intermittent hypotension, confusion, macular skin rash with telangiectasia and perivascular lymphocyte infiltration, cytopenia without abnormal cells, hepatosplenomegaly, pericardial and pleural effusion, cervical lymph node enlargements and diffuse large B cell lymphoma. This patient was described with autoimmune lymphoproliferative syndrome-like syndrome.1515 Hong YH, Lee CK. Autoimmune lymphoproliferative syndrome-like syndrome presented as lupus-like syndrome with mycobacterial joint infection evolved into the lymphoma. Rheumatol Int. 2009;29(5):569-73.

Idiopathic CD4+ lymphocytopenia

Idiopathic CD4+ lymphocytopenia (ICL) is a non-classical PID characterized by a T CD4+ lymphocyte cell count below 300/mm3 or 20% of total T lymphocyte cell count in the absence of identified cause, including human immunodeficiency virus (HIV) or human lymphocytotropic virus (HTLV) infections, and absence of causative drug.6464 Regent A, Kluger N, Berezne A, Lassoued K, Mouthon L. Lymphocytopenia: aetiology and diagnosis, when to think about idiopathic CD4(+) lymphocytopenia? Rev Med Interne. 2012;33(11):628-34. Recently, a mutation in patients with ICL was described,6565 Gorska MM, Alam R. Consequences of a mutation in the UNC119 gene for T cell function in idiopathic CD4 lymphopenia. Curr Allergy Asthma Rep. 2012;12(5):396-401. but further studies are needed for definitive conclusion since the etiology still remains poorly understood and inadequately defined. Mechanisms implicated in CD4+ lymphocyte reduction may include decreased production, increased destruction, and tissue sequestration of these cells. Clinical presentation includes Cryptococcus spp. opportunistic infections and non-mycobacterial infections. Presence of malignancies is common, frequently due to opportunistic pathogens with an oncogenic potential (human papillomavirus/HPV, Kaposi's sarcoma by HHV8+).6666 Richetta A, Amoruso GF, Ascoli V, Natale ME, Carboni V, Carlomagno V, et al. PEL, Kaposi's sarcoma HHV8+ and idiopathic T-lymphocitopenia CD4+ Clin Ter. 2007;158(2):151-5.,6767 Alisjahbana B, Dinata R, Sutedja E, Suryahudaya I, Soedjana H, Hidajat NN, et al. Disfiguring generalized verrucosis in an indonesian man with idiopathic CD4 lymphopenia. Arch Dermatol. 2010;146(1):69-73. Autoimmune diseases observed in a series of 39 cases of ICL include SLE, antiphospholipid syndrome, psoriasis, Hashimoto's thyroiditis, Graves disease, ulcerative colitis and vitiligo.6868. Zonios D, Sheikh V Sereti I. Idiopathic CD4 lymphocytopenia: a case of missing, wandering or ineffective T cells. Arthritis Res Ther. 2012;14(4):222.,6969 Zonios DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, et al. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood. 2008;112(2):287-94.

Clinical characteristics of patients with SLE and PID manifestations followed by the outpatient clinic of the Rheumatology Division at Universidade Federal de São Paulo

Between 2009 and 2011, our group followed 315 consecutive adult SLE patients at the Rheumatology Division outpatient clinic of the University Hospital of Universidade Federal de São Paulo. The purpose of the study was to systematically track a comprehensive array of PID in a large cohort. Once the disease activity could influence the results, all patients were followed until achieving disease quiescence. Fifteen patients remained with active disease throughout the follow-up and were, therefore, excluded from the analysis. Patients followed were predominantly females (16 males and 284 females), with 39.58 ± 12.54 mean years-old (age ranging from 18 to 61 years), mean disease duration of 10.74 ± 8.15 years (disease duration from 1 to 53 years) and mean age at SLE onset of 28.79 ± 10.89 years-old (SLE onset from 3 to 69 years). Total frequency of infections in SLE patients was 28 (9.33%). Those patients were classified using the warning signals for primary immunodeficiency recently revised.7070 Costa-Carvalho BT, Grumach AS, Franco JL, Espinosa-Rosales FJ, Leiva LE, King A, et al. Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice. J Clin Immunol. 2014;34(1):10-22. Unfortunately the cross-sectional design of our study could not allow the calculi of mortality rate. Nine patients had recurrent airway infections, whereas 15 presented recurrent urinary tract infections and three, skin furunculosis. Two patients presented recurrent oral/genital Herpes simplex and two others had Herpes zoster infection. Additionally, two patients manifested mycobacterial infection: one had pulmonary tuberculosis and the other hanseniasis (Table 3). In the present series, other autoimmune diseases were observed in 47 individuals (15.66%) [including rheumatic autoimmune diseases (n = 32) and non-rheumatic autoimmune diseases (n = 20)], some of which presenting more than one autoimmune condition. Eighty-four patients (28%) were identified with immunity defects compatible with classical PID (Table 3), and in four patients (1.3%) more than one associated PID were identified (SIgAD + IgG2; SIgAD + IgG4; IgMD + IgG2 in 2 patients). Differently from our results, the literature describes one case of SIgMD accompanied with IgG4 deficiency (Ideura et al.4646. Ideura G, Agematsu K, Komatsu Y, Hatayama O, Yasuo M, Tsushima K, et al. Selective IgM deficiency accompanied with IgG4 deficiency, dermal complications, and a bronchial polyp. Allergol Int. 2008;57(1):99-105.). Interestingly, one patient presented a respiratory burst profile impaired enough to be classified as a CGD gene carrier but no patient presented the profile compatible with full-blown disease. Our clinical and laboratory findings have demonstrated that the PID observed in SLE patients are considered mild in terms of severity of infections and mortality. We speculate that those PID are compatible with apparently normal life, but that the consequent long-standing antigenic burden may be a risk factor for the development of AIDs, represented in this cohort by SLE. Generally, severe forms of PID are diagnosed at early stage of life, while non-severe or mild forms of PID manifestations are mostly asymptomatic.2020 Casanova JL, Fieschi C, Bustamante J, Reichenbach J, Remus N, von Bernuth H, et al. From idiopathic infectious diseases to novel primary immunodeficiencies. J Allergy Clin Immunol. 2005;116(2):426-30. We found that 28% of our cohort of adult SLE patients was constituted by mild PID which allowed a longer survival rate, passing unnoticed during childhood. This could possibly explain the absence of illnesses such as CVID, CGD and HIGM. Surprisingly, in our cohort the presence of IgMD, a non-classical form of PID, was very frequent. We also observed in our cohort a large number of SLE patients with IgG subclass deficiency, while literature reports only some cases of isolated deficiency of IgG2 and IgG4.1818 Jesus AA, Liphaus BL, Silva CA, Bando SY, Andrade LE, Coutinho A, et al. Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients. Lupus. 2011;20(12):1275-84.,4141 Tamura A, Agematsu K, Urasawa R, Naganuma K, Komiyama A. Cardiac tamponade due to systemic lupus erythematosus in a 7-year-old boy with selective IgG subclass deficiency. Eur J Pediatr. 1998;157(6):475-8.,7171 Hanson LA, Soderstrom R, Avanzini A, Bengtsson U, Bjorkander J, Soderstrom T. Immunoglobulin subclass deficiency. Pediatr Infect Dis J;1. 1988;7 5 Suppl:S17-21.,7272 Suyama K, Kawasaki Y Abe Y, Watanabe M, Ohara S, Oikawa T, et al. Development of common variable immunodeficiency in IgA- and IgG2-deficientpatients with systemic lupus erythematosus. Pediatr Nephrol. 2012;27(3):489-92. In our study, all patients with IgG4 deficiency and 75% of those with IgG3 deficiency had lupus nephropathy, which is above the ∼50% frequency in the whole cohort. In addition, patients with IgMD presented lower frequency of oral ulcers. Apart from IgG4 and IgG3 deficient patients, the remaining patients did not present a much severe phenotype regarding the presence of infections and lupus manifestations.

Table 3
Autoimmune diseases, primary immunodeficiencies and infections found in 300 Brazilian SLE patients.

Our findings regarding the association of immunoglobulin deficiency and the development of autoimmune disease could be partially explained based on the 'waste disposal' hypothesis, which postulates that defects on the clearance of dying cells increases the risk of developing autoimmunity since these cells provide the source of auto antigens responsible for driving autoantibody production in SLE.77 Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004;22:431-56. Additionally, because SLE is associated with a humoral exacerbated response, the presence of a primary dysfunction of B lymphocytes may be considered as a predisposing factor for unbalanced IgG subclasses synthesis, which may be considered as a factor for the development of SLE. These results suggest that mild immunologic defects might be compatible with patient survival, but at the expense of some chronic overload and future consequences to the immune system, which could lead to the development of immune disorders characteristic of SLE in the adulthood. The study findings give ground to further investigations that could deeply explore the participation of PID in the pathogenesis of SLE and other autoimmune rheumatic and non-rheumatic disease.

Conclusion

PID are a group of monogenic diseases in which mutations of certain genes can lead to increased susceptibility to infections but may also result in loss of central and/or peripheral tolerance. Therefore, AIDs are common among patients with a diverse array of PID. Immunoglobulin deficiency forms a peculiar group of PID, in which the inheritance appears to be polygenic and there is a wide severity spectrum, with mild forms that usually remain unnoticed. Our findings in adult patients with SLE suggest that AIDs can present a higher frequency of less severe forms of PID without severe infections. The presence of some forms of PID was associated with certain phenotypic peculiarities in SLE patients. The literature and our findings show that PID and AIDs frequently coexist and patients with autoimmune diseases should be carefully monitored for the presence of PID and vice versa.

  • Funding
    Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Publication Dates

  • Publication in this collection
    Jan-Feb 2016

History

  • Received
    12 Mar 2014
  • Accepted
    8 Mar 2015
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