Abstract
Primary immune deficiencies are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. In many immune deficiencies, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmune lymphoproliferative syndrome, immunodyregulation polyendocrinopathy enteropathy X-linked, IL-10/IL-10 receptor deficiencies, and PLCG2-associated antibody deficiency and immune dysregulation are disorders in which autoimmunity is a hallmark of the clinical disease presentation. In contrast, adaptive and innate immune deficiencies, which are typically defined by their infectious susceptibilities, can be associated with variable rates of autoimmune manifestations, predominantly autoimmune cytopenias. This review describes the immune dysregulation and autoimmune manifestations that may be encountered in various immune deficiencies.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Al-Herz W et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162. The most current and complete listing of primary immune deficiencies.
Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27:497–502.
Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. 1992;29:824–6.
Rosatelli MC et al. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum Genet. 1998;103:428–34.
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.
Puel A et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291–7.
Kisand K et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207:299–308.
Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843–50.
Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29.
Kisand K et al. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41:1517–27.
Sneller MC et al. Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997;89:1341–8.
Holzelova E et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004;351:1409–18.
Magerus-Chatinet A et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Invest. 2011;121:106–12.
Chun HJ et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002;419:395–9.
Teachey DT. New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome. Curr Opin Pediatr. 2012;24:1–8.
Sneller MC, Dale JK, Straus SE. Autoimmune lymphoproliferative syndrome. Curr Opin Rheumatol. 2003;15:417–21.
Oliveira JB et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116:e35–40.
Neven B et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118:4798–807.
Teachey DT et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005;105:2443–8.
Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood. 2010;115:2142–5.
Straus SE, Sneller M, Lenardo MJ, Puck JM, Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999;130:591–601.
Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr. 2001;13:533–8.
Gambineri E et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008;122:1105–12.
Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39:537–45.
Peake JE, McCrossin RB, Byrne G, Shepherd R. X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea. Arch Dis Child Fetal Neonatal Ed. 1996;74:F195–9.
Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatr Res. 2000;48:6–11.
Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A. 1997;94:3168–71.
Goudy K et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146:248–61.
Bernasconi A et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics. 2006;118:e1584–92.
Cohen AC et al. Cutting edge: decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. J Immunol. 2006;177:2770–4.
Boisson-Dupuis S et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24:364–78.
Liu L et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208:1635–48.
Uzel G et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131:1611–23. Describes an alternative phenotype for STAT1 GOF mutations, namely IPEX-like autoimmunity.
Glocker EO et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–45.
Glocker EO et al. Infant colitis—it’s in the genes. Lancet. 2010;376:1272.
Kotlarz D et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012;143:347–55.
Engelhardt KR et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;131:825–30. Demonstrates failure of conventional antiinflammatory therapy vs disease resolution with HSCT in inflammatory bowel disease due to IL-10 signaling defects.
Ombrello MJ et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med. 2012;366:330–8. Describes the new PLAID syndrome, also named FCAS3.
Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119:1650–7. Identified lymphoma, hepatitis, inflammatory lung complications, and gastrointestinal disease as risk factors for increased mortality in CVID.
Chapel H et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
Zhang L et al. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol. 2007;120:1178–85.
Quartier P et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin Immunol. 2004;110:22–9.
Duarte-Rey C, Bogdanos DP, Leung PS, Anaya JM, Gershwin ME. IgM predominance in autoimmune disease: genetics and gender. Autoimmun Rev. 2012;11:A404–12.
Jesus AA, Duarte AJ, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol. 2008;28 Suppl 1:S62–6.
Lacroix-Desmazes S et al. Defective self-reactive antibody repertoire of serum IgM in patients with hyper-IgM syndrome. J Immunol. 1999;162:5601–8.
Lee AH, Levinson AI, Schumacher Jr HR. Hypogammaglobulinemia and rheumatic disease. Semin Arthritis Rheum. 1993;22:252–64.
Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clin Immunol. 2004;111:93–7.
Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. 2014;13:163–77.
Cavadini P et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J Clin Invest. 2005;115:728–32.
Cassani B et al. Defect of regulatory T cells in patients with Omenn syndrome. J Allergy Clin Immunol. 2010;125:209–16.
Dupuis-Girod S 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.
Adriani M et al. Impaired in vitro regulatory T cell function associated with Wiskott-Aldrich syndrome. Clin Immunol. 2007;124:41–8.
Marangoni F et al. WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J Exp Med. 2007;204:369–80.
Nikolov NP et al. Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein. Blood. 2010;116:740–7.
Becker-Herman S et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med. 2011;208:2033–42.
Recher M et al. B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood. 2012;119:2819–28.
Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in Wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209.
Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology. 1998;199:265–85.
Pickering MC, Walport MJ. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology (Oxford). 2000;39:133–41.
Barilla-LaBarca ML, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol. 2003;15:55–60.
Jonsson G et al. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford). 2007;46:1133–9.
Ogden CA et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001;194:781–95.
Davies KA et al. Splenic uptake of immune complexes in man is complement-dependent. J Immunol. 1993;151:3866–73.
Compliance with Ethics Guidelines
Conflict of Interest
Dr Lehman declares no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Basic and Applied Science
Rights and permissions
About this article
Cite this article
Lehman, H.K. Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders. Curr Allergy Asthma Rep 15, 53 (2015). https://doi.org/10.1007/s11882-015-0553-x
Published:
DOI: https://doi.org/10.1007/s11882-015-0553-x