Autoimmunity in patients with primary immunodeficiency
- Markus G Seidel, MD
Markus G Seidel, MD
- Professor of Translational Pediatric Hematology and Immunology
- Medical University of Graz
- Section Editor
- E Richard Stiehm, MD
E Richard Stiehm, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Immunology and Immunodeficiency
- Distinguished Research Professor of Pediatrics
- David Geffen School of Medicine at UCLA
- Deputy Editors
- Anna M Feldweg, MD
Anna M Feldweg, MD
- Director, Editorial Management — UpToDate
- Deputy Editor — Allergy and Immunology
- Assistant Professor of Medicine, Part-time
- Harvard Medical School
- Monica Ramirez Curtis, MD, MPH
Monica Ramirez Curtis, MD, MPH
- Deputy Editor — Rheumatology
- Instructor of Medicine, Part-time
- Harvard Medical School
Patients with primary immunodeficiency (PID) have dysregulated immune processes, which can result in an increased susceptibility to infectious diseases, autoimmune disorders, and malignancies.
This topic will discuss the most common manifestations of autoimmunity in patients with PID and review the autoimmune disorders associated with the most prevalent PID disorders. Malignancies in patients with PID are reviewed separately. (See "Malignancy in primary immunodeficiency".)
CLASSIFICATION OF PID
Primary immunodeficiencies (PID) are classified into nine major categories of disorders :
●Combined immunodeficiencies without syndromic features. (See "Combined immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview".)
●Combined immunodeficiencies with syndromic features. (See "Syndromic immunodeficiencies".)
- Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol 2015; 35:696.
- Carneiro-Sampaio M, Coutinho A. Early-onset autoimmune disease as a manifestation of primary immunodeficiency. Front Immunol 2015; 6:185.
- Farmand S, Baumann U, von Bernuth H, et al. [Interdisciplinary AWMF guideline for the diagnostics of primary immunodeficiency]. Klin Padiatr 2011; 223:378.
- Feske S. Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci 2011; 1238:74.
- Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123:1989.
- Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a model of immune dysregulation. Curr Opin Allergy Clin Immunol 2002; 2:481.
- Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol 2007; 120:227.
- Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun 2005; 25 Suppl:56.
- Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood 2014; 124:2337.
- Al-Herz W, Bousfiha A, Casanova JL, 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.
- Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program 2012; 2012:301.
- Buchbinder D, Nugent DJ, Fillipovich AH. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet 2014; 7:55.
- Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci 2012; 69:17.
- Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014; 20:1410.
- Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345:1623.
- Lopez-Herrera G, Tampella G, Pan-Hammarström Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet 2012; 90:986.
- Seidel MG, Hirschmugl T, Gamez-Diaz L, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol 2015; 135:1384.
- Burns SO, Zenner HL, Plagnol V, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol 2012; 130:1428.
- Alangari A, Alsultan A, Adly N, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol 2012; 130:481.
- Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 2015; 349:436.
- Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 2013; 25:708.
- 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.
- Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057.
- De Martino L, Capalbo D, Improda N, et al. APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Front Immunol 2013; 4:331.
- Ahonen P. Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet 1985; 27:535.
- Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol 2015; 35:463.
- Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 2012; 143:347.
- Salzer E, Kansu A, Sic H, et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J Allergy Clin Immunol 2014; 133:1651.
- Leiding JW, Holland SM. Chronic granulomatous disease. In: GeneReviews, Pagon RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2012.
- Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 2008; 112:277.
- Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 2011; 117:1522.
- Guerrerio AL, Frischmeyer-Guerrerio PA, Lederman HM, Oliva-Hemker M. Recognizing gastrointestinal and hepatic manifestations of primary immunodeficiency diseases. J Pediatr Gastroenterol Nutr 2010; 51:548.
- Huppmann AR, Leiding JW, Hsu AP, et al. Pathologic Findings in NEMO Deficiency: A Surgical and Autopsy Survey. Pediatr Dev Pathol 2015; 18:387.
- Todoric K, Koontz JB, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Curr Allergy Asthma Rep 2013; 13:361.
- Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood 2002; 99:2694.
- Saifi M, Wysocki CA. Autoimmune Disease in Primary Immunodeficiency: At the Crossroads of Anti-Infective Immunity and Self-Tolerance. Immunol Allergy Clin North Am 2015; 35:731.
- Grimbacher B, Warnatz K, Yong PF, et al. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol 2016; 137:3.
- Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 2015; 136:703.
- Ghosh S, Bienemann K, Boztug K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. J Clin Immunol 2014; 34:892.
- Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency: an update. Arthritis Res Ther 2012; 14:223.
- Rensing-Ehl A, Warnatz K, Fuchs S, et al. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. Clin Immunol 2010; 137:357.
- Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 2012; 63:233.
- Veillette A, Pérez-Quintero LA, Latour S. X-linked lymphoproliferative syndromes and related autosomal recessive disorders. Curr Opin Allergy Clin Immunol 2013; 13:614.
- Salzer E, Daschkey S, Choo S, et al. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica 2013; 98:473.
- van Montfrans JM, Hoepelman AI, Otto S, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol 2012; 129:787.
- CLASSIFICATION OF PID
- MANIFESTATIONS OF AUTOIMMUNITY AND IMMUNE DYSREGULATION IN PID
- GENERAL PRINCIPLES OF AUTOIMMUNITY IN PID
- Autoimmune disorders in common forms of PID
- - Cytopenias
- - Endocrinopathies
- - Enteropathies
- WHEN TO SUSPECT AN UNDERLYING PID
- Early-onset autoimmunity
- Multiorgan involvement
- WHEN TO REFER
- POSSIBLE PATHOGENIC MECHANISMS
- Immune dysregulation
- MONITORING FOR AUTOIMMUNITY
- Considering alternative etiologies
- SUMMARY AND RECOMMENDATIONS