Advances in Dental Research http://adr.sagepub.com/ The Association Between Immunodeficiency and the Development of Autoimmune Disease J.W. Sleasman ADR 1996 10: 57 DOI: 10.1177/08959374960100011101 The online version of this article can be found at: http://adr.sagepub.com/content/10/1/57 Published by: http://www.sagepublications.com On behalf of: International and American Associations for Dental Research Additional services and information for Advances in Dental Research can be found at: Email Alerts: http://adr.sagepub.com/cgi/alerts Subscriptions: http://adr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Downloaded from adr.sagepub.com by guest on July 18, 2011 For personal use only. No other uses without permission. THE ASSOCIATION BETWEEN IMMUNODEFICIENCY AND THE DEVELOPMENT OF AUTOIMMUNE DISEASE J.W. SLEASMAN aradoxically, individuals with primary or acquired immunodeficiency disease have an increased Division of Pediatric Immunology and Allergy incidence of autoimmunity. Human primary University of Florida College of Medicine immunodeficiency disease can be classified as Box 100296, 1600 SW Archer Road P disorders of cell-mediated immunity, humoral immunity, Gainesville, Florida 32610-0296 phagocytic cell function, and the complement system (Barrett and Sleasman, 1990). Cell-mediated and humoral immunity Adv Dent Res 10(l):57-61, April, 1996 comprise the adaptive arm of the immune response, which is antigen-specific and confers immunologic memory. The innate immune response, which is antigen-nonspecific, is Abstract—There is a paradoxical relationship between composed of phagocytic cells and the inflammatory peptides. immunodeficiency diseases and autoimmunity. While not all Not all individuals with inherited immunodeficiency develop individuals with immunodeficiency develop autoimmunity, autoimmunity, nor are all individuals with autoimmune nor are all individuals with autoimmunity immunodeficient, disease immunodeficient. Defects within particular defects within certain components of the immune system components of the immune response carry a higher risk for carry a high risk for the development of autoimmune disease. autoimmune disease than others. An understanding of the Inherited deficiencies of the complement system have a high immune defects that may contribute to the development of incidence of systemic lupus erythematosus (SLE), autoimmune disease provides an insight into the nature of the glomerulonephritis, and vasculitis. Carrier mothers of autoimmune process. children with chronic granulomatous disease, an X-linked defect of phagocytosis, often develop discoid lupus. Several SPECIFIC IMMUNODEFICIENCY DISORDERS antibody deficiencies are associated with autoimmune ASSOCIATED WITH AUTOIMMUNITY disease. Autoimmune cytopenias are commonly observed in individuals with selective IgA deficiency and common The most commonly observed association between disorders variable immune deficiency. Polyarticular arthritis can be of innate immunity and an increased risk for the development seen in children with X-linked agammaglobulinemia. of autoimmunity is in individuals with inherited defects in Combined cellular and antibody deficiencies, such as the complement cascade (Frank, 1995). Low serum Wiskott-Aldrich syndrome, carry an increased risk for complement levels found in patients with autoimmune juvenile rheumatoid arthritis and autoimmune hemolytic disease generally reflect increased consumption of anemia. Several hypothetical mechanisms have been complement proteins as a result of immune complex- proposed to explain the associations between autoimmunity mediated inflammation. Clinical manifestations of the and immunodeficiency. Immunologic defects may result in a inherited deficiencies of complement components include failure to exclude microbial antigens, resulting in chronic both an increased incidence of infection and autoimmunity. immunologic activation and autoimmune symptoms. There The complement cascade can be organized into three may be shared genetic factors, such as common HLA alleles, components: the classical pathway, initiated by the binding which predispose an individual to both autoimmunity and of Cl to immunoglobulin Fc receptor; the alternative immunodeficiency. Defects within one component of the pathway, initiated by microbial proteins binding to C3 and immune system may alter the way a pathogen induces an the membrane attack complex; and the final common immune response and lead to an inflammatory response pathway, consisting of C5 through C9, leading to cytolysis directed at self-antigens. An understanding of the (Fig. 1). immunologic defects that contribute to the development of Inherited deficiencies in the components of the classic autoimmunity will provide an insight into the pathogenesis of cascade carry with them a risk for the development of the autoimmune process. systemic lupus erythematosus (SLE), anaphylactoid purpura, and juvenile arthritis. Though rare, nearly 85% of patients Key words: Autoimmunity, immunodeficiency, T-cells, reported to have homozygous C4 deficiency have clinical antibody, complement. manifestations of autoimmunity. Approximately one-half of the individuals with symptomatic C2 deficiency have autoimmune disease (Hauptmann et al., 1988). Recurrent This was presented at the Conference on Oral and Ocular infections are uncommon in C2 deficiency compared with Manifestations of Autoimmune Diseases, January 20-21, other complement disorders, but an increased incidence of 1995, at the University of Florida, Gainesville. bacterial pneumonia, meningitis, and sepsis has been 57 Downloaded from adr.sagepub.com by guest on July 18, 2011 For personal use only. No other uses without permission. 58 SLEASMAN ADV DENT RES APRIL 1996 COMPLEMENT DEFICIENCIES organisms results in granuloma formation. In this way, the Classical immune response compensates for the defect in leukocyte function. While autoimmunity has not been reported in C1 Ag/Antibody Complex Autoimmunity affected male children, the genetic defect is associated with a C1 INH HANE SLE, GN, HSP high incidence of discoid lupus erythematosus (DLE) in C2 carrier mothers (Humbert et al., 1976). Superoxide C3- C3b C56789 membrane attack complex generation in carrier mothers is reduced but not absent. .. * - Cytolysis Studies of women with DLE who are not CGD carriers Pyogeimytmec tion Neissenal Infections indicate that leukocyte bactericidal activity is generally Autoimmunity C3,B,D,P normal (Humbert et al, 1976). Defects of adaptive immunity consist primarily of disorders of T-cell and B-cell function. Alternative Autoimmunity is uncommon in patients with pure T-cell immunodeficiency (Rosen, 1987). Children with X-linked Fig. 1—Complement deficiencies and their association with severe combined immunodeficiency exhibit T-cell maturation infection and autoimmunity. The classic pathway is activated arrest within the thymus (Sleasman et al, 1994). B-cell by antigen/antibody complexes binding to Cl. Loss of Cl numbers are normal, and immunoglobulin secretion can inhibitor {Cl INH) leads to Hereditary Angioneurotic Edema occur in the presence of normal T-cell help. Although this is (HANE). Defects in components of the classic pathway carry the most common form of human SCID, autoimmunity has an increased risk of SLE, glomerulonephritis, and HSP. not been reported in these patients, perhaps a result of early Deficiencies in the alternative pathway are generally treatment with bone marrow transplantation or death in early associated with recurrent infections with pyogenic bacteria. infancy due to infection. While opportunistic infections are a Defects within the components of the membrane attack prominant feature of both adults and children with idiopathic complex carry a risk of neisserial infections and autoimmune or congenital CD4+ T lymphocytopenia, autoimmune disease nephritis has not been associated with this newly described immunodeficiency of CD4+ T lymphocytes (Sleasman et al, reported. A deficiency of Cl inhibitor results in uncontrolled 1990; Duncan et al, 1993; Ho et al, 1993; Smith et al, activation of the classic pathway components and 1993; Spira et al, 1993). In contrast to purely T-cell consumption of C2 and C4. This deficiency leads to recurrent deficiencies, defects in immunoregulatory peptides involved episodes of angioedema of the viscera, soft tissues, and in cell-to-cell interactions are commonly associated with airway, and a high risk of SLE, Crohn's disease, and autoimmune disease. Children with Wiskott-Aldrich Sjogren's syndrome (Brickman et al, 1986a,b). Syndrome, an X-linked immunodeficiency characterized by Defects in the alternative complement pathway are more low expression of sialophorin (CD43), demonstrated a high commonly associated with recurrent pyogenic infections, incidence of Coombs-positive hemolytic anemia, juvenile particularly infections with Neisseria meningitidis and rheumatoid arthritis, and severe eczema (Amman and Hong, Streptococcus pneumoniae; SLE, systemic vasculitis, and 1989). glomerulonephritis have been reported in 15 to 20% of Unlike T-cell defects, humoral immunodeficiencies carry patients with C3 deficiency (Borzy et al, 1988). Cytolysis by a high risk of autoimmunity. Children with X-linked terminal complement components (C5 through C9) are agammaglobulinemia have little detectable immunoglobulin important in host defense against Gram-negative organisms, production due to a