Novel Developments in Primary Immunodeficiencies (PID)—a Rheumatological Perspective

  • Helen Leavis
  • Jochen Zwerina
  • Bernhard Manger
  • Ruth D. E. Fritsch-StorkEmail author
Orphan Diseases (B Manger, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Orphan Diseases


Purpose of Review

The purpose of this review is to provide an overview of the most relevant new disorders, disease entities, or disease phenotypes of primary immune deficiency disorders (PID) for the interested rheumatologist, using the new phenotypic classification by the IUIS (International Union of Immunological Societies) as practical guide.

Recent Findings

Newly recognized disorders of immune dysregulation with underlying mutations in genes pertaining to the function of regulatory T cells (e.g., CTLA-4, LRBA, or BACH2) are characterized by multiple autoimmune diseases—mostly autoimmune cytopenia—combined with an increased susceptibility to infections due to hypogammaglobulinemia. On the other hand, new mutations (e.g., in NF-kB1, PI3Kδ, PI3KR1, PKCδ) leading to the clinical picture of CVID (common variable immmune deficiency) have been shown to increasingly associate with autoimmune diseases.


The mutual association of autoimmune diseases with PID warrants increased awareness of immunodeficiencies when diagnosing autoimmune diseases with a possible need to initiate appropriate genetic tests.


CVID NF-kB deficiency CTLA-4 haploinsufficiency LRBA indusfficiency APDS DADA2 


Compliance with Ethical Standards

Conflict of Interest

Dr. Leavis reports grants and other from Shire and personal fees and other from Novartis, other from Sobi, outside the submitted work.

Dr. Fritsch-Stork has nothing to disclose.

Dr. Zwerina has nothing to disclose.

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.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jonkman-Berk BM, van den Berg JM, Ten Berge IJ, Bredius RG, Driessen GJ, Dalm VA, et al. Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy. Clinical immunology (Orlando, Fla). 2015;156(2):154–62.CrossRefGoogle Scholar
  2. 2.
    Marschall K, Hoernes M, Bitzenhofer-Gruber M, Jandus P, Duppenthaler A, Wuillemin WA, et al. The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years' activity from 2008 to 2014. Clinical and experimental immunology. 2015;182(1):45–50.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Shillitoe B, Bangs C, Guzman D, Gennery AR, Longhurst HJ, Slatter M, et al. The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017. Clinical and experimental immunology. 2018;192(3):284–91.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mahlaoui N, Jais J-P, Brosselin P, Mignot C, Beaurain B, Brito C, et al. Prevalence of primary immunodeficiencies in France is underestimated. Journal of Allergy and Clinical Immunology. 2017;140(6):1731–3.CrossRefPubMedGoogle Scholar
  5. 5.
    Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N. members of the CFPIDsg. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388–93 e8.CrossRefPubMedGoogle Scholar
  6. 6.
    • Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. Journal of clinical immunology. 2018;38(1):96–128 This is the latest report oft he IUIS listing 354 primary immunodeficiencies with their characteristic immunological and clinical features. CrossRefPubMedGoogle Scholar
  7. 7.
    •• Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. Journal of clinical immunology. 2018;38(1):129–43 This report combines a list of 320 single-gene inborn errors of immunity published in 2017 by the IUIS (ref #6) with the clinical phenotype and groups the diseases in categories for easier clinical use.CrossRefPubMedGoogle Scholar
  8. 8.
    Jeddane L, Ouair H, Benhsaien I, Bakkouri JE, Bousfiha AA. Primary immunodeficiency classification on smartphone. Journal of clinical immunology. 2017;37(1):1–2.CrossRefPubMedGoogle Scholar
  9. 9.
    Alghamdi M. Autoinflammatory disease-associated vasculitis/vasculopathy. Current rheumatology reports. 2018;20(12):87.CrossRefPubMedGoogle Scholar
  10. 10.
    Pereira LF, Sapina AM, Arroyo J, Vinuelas J, Bardaji RM, Prieto L. Prevalence of selective IgA deficiency in Spain: more than we thought. Blood. 1997;90(2):893.PubMedGoogle Scholar
  11. 11.
    Kanoh T, Mizumoto T, Yasuda N, Koya M, Ohno Y, Uchino H, et al. Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis. Vox sanguinis. 1986;50(2):81–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmunity reviews. 2014;13(2):163–77.CrossRefPubMedGoogle Scholar
  13. 13.
    El-Sayed ZA, Abramova I, Aldave JC, Al-Herz W, Bezrodnik L, Boukari R, et al. X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world. The World Allergy Organization journal. 2019;12(3):100018.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Matamoros Flori N, Mila Llambi J, Espanol Boren T, Raga Borja S, Fontan CG. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. Journal of clinical immunology. 1997;17(4):333–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Selenius JS, Martelius T, Pikkarainen S, Siitonen S, Mattila E, Pietikäinen R, et al. Unexpectedly high prevalence of common variable immunodeficiency in Finland. Frontiers in immunology. 2017;8:1190.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    •• Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clinical and experimental immunology. 2013;174(2):203–11 Clinically practical diagnostic criteria for CVID with guidance for the practitioner to initiate immunoglobuline substitution. PubMedPubMedCentralGoogle Scholar
  17. 17.
    Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): common variable immunodeficiency disorders. The journal of allergy and clinical immunology In practice. 2016;4(1):38–59.CrossRefPubMedGoogle Scholar
  18. 18.
    Warnatz K, Wehr C, Drager R, Schmidt S, Eibel H, Schlesier M, et al. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206(5):502–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111(1):77–85.CrossRefPubMedGoogle Scholar
  20. 20.
    Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clinical immunology (Orlando, Fla). 2004;113(2):161–71.CrossRefGoogle Scholar
  21. 21.
    Isnardi I, Ng Y-S, Menard L, Meyers G, Saadoun D, Srdanovic I, et al. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood. 2010;115(24):5026–36.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Glauzy S, Boccitto M, Bannock JM, Delmotte FR, Saadoun D, Cacoub P, et al. Accumulation of antigen-driven lymphoproliferations in complement receptor 2/CD21(−/low) B cells from patients with Sjogren’s syndrome. Arthritis & rheumatology (Hoboken, NJ). 2018;70(2):298–307.CrossRefGoogle Scholar
  23. 23.
    Ameratunga R, Brewerton M, Slade C, Jordan A, Gillis D, Steele R, et al. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Frontiers in immunology. 2014;5:415.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. The Journal of clinical investigation. 2010;120(1):214–22.CrossRefPubMedGoogle Scholar
  25. 25.
    van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ, et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. The New England journal of medicine. 2006;354(18):1901–12.CrossRefPubMedGoogle Scholar
  26. 26.
    van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. The Journal of clinical investigation. 2010;120(4):1265–74.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wentink MW, Lambeck AJ, van Zelm MC, Simons E, van Dongen JJ, IJspeert H, et al. CD21 and CD19 deficiency: two defects in the same complex leading to different disease modalities. Clinical immunology (Orlando, Fla). 2015;161(2):120–7.CrossRefGoogle Scholar
  28. 28.
    Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4(3):261–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature genetics. 2005;37(8):829–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J, et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(33):13945–50.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Journal of medical genetics. 2016;53(9):575–90.CrossRefPubMedGoogle Scholar
  32. 32.
    van Montfrans JM, Hoepelman AI, Otto S, van Gijn M, van de Corput L, de Weger RA, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol. 2012;129(3):787–93.e6.CrossRefPubMedGoogle Scholar
  33. 33.
    Chen K, Coonrod E, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, et al. Germline mutations in NFKB2 implicate the noncanonical NF-kB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812–24CrossRefPubMedGoogle Scholar
  34. 34.
    Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-kappaB1 Subunit p50 in common variable immunodeficiency. American journal of human genetics. 2015;97(3):389–403.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, et al. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. The Journal of allergy and clinical immunology. 2018;142(4):1285–96.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, et al. NF-kappaB1 haploinsufficiency causing immunodeficiency and EBV-driven lymphoproliferation. Journal of clinical immunology. 2016;36(6):533–40.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science (New York, NY). 2013;342(6160):866–71.CrossRefGoogle Scholar
  38. 38.
    Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. The Journal of clinical investigation. 2014;124(9):3923–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. The New England journal of medicine. 2012;366(4):330–8.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, et al. Loss of B cells in patients with heterozygous mutations in IKAROS. The New England journal of medicine. 2016;374(11):1032–43.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta. Blood. 2013;121(16):3112–6.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Loss-of-function of the protein kinase C delta (PKCdelta) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117–25.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Belot A, Kasher PR, Trotter E, Foray A-P, Debaud A-L, Rice GI, et al. Protein kinase C deficiency causes Mendelian systemic lupus erythematosus With B cell-defective apoptosis and hyperproliferation.Arthritis Rheum. 2013;65(8):2161–71CrossRefGoogle Scholar
  44. 44.
    Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, et al. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol. 2018;141(3):1036–49.e5.CrossRefPubMedGoogle Scholar
  45. 45.
    Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Mannurita SC, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clinical Immunology. 2013;146(3):248–61.CrossRefPubMedGoogle Scholar
  46. 46.
    Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science (New York, NY). 2014;345(6204):1623–7.CrossRefGoogle Scholar
  47. 47.
    Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature medicine. 2014;20(12):1410–6.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P, Trujillo-Vargas Claudia M, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. The American Journal of Human Genetics. 2012;90(6):986–1001.CrossRefPubMedGoogle Scholar
  49. 49.
    Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30.CrossRefPubMedGoogle Scholar
  50. 50.
    Afzali B, Grönholm J, Vandrovcova J, O'Brien C, Sun H-W, Vanderleyden I, et al. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nature Immunology. 2017;18:813.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hwa V. STAT5B deficiency: impacts on human growth and immunity. Growth Hormone & IGF Research. 2016;28:16–20.CrossRefGoogle Scholar
  52. 52.
    Fabre A, Marchal S, Barlogis V, Mari B, Barbry P, Rohrlich P-S, et al. Clinical aspects of STAT3 gain-of-function germline mutations: A Systematic Review. The Journal of Allergy and Clinical Immunology: In Practice. J Allergy Clin Immunol Pract. 2019;7(6):1958–1969.e9PubMedGoogle Scholar
  53. 53.
    Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. The Journal of experimental medicine. 2011;208(8):1635–48.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Odnoletkova I, Kindle G, Quinti I, Grimbacher B, Knerr V, Gathmann B, et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet journal of rare diseases. 2018;13(1):201.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Cereser L, Girometti R, d'Angelo P, De Carli M, De Pellegrin A, Zuiani C. Humoral primary immunodeficiency diseases: clinical overview and chest high-resolution computed tomography (HRCT) features in the adult population. Clinical radiology. 2017;72(7):534–42.CrossRefPubMedGoogle Scholar
  58. 58.
    • Hurst JR, Verma N, Lowe D, Baxendale HE, Jolles S, Kelleher P, et al. British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders. The journal of allergy and clinical immunology In practice. 2017;5(4):938–45 The largest consensus report of clinical experts on how to diagnose and treat granulamotous disease in CVID. CrossRefPubMedGoogle Scholar
  59. 59.
    Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). Journal of clinical immunology. 2013;33(1):30–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Tashtoush B, Memarpour R, Ramirez J, Bejarano P, Mehta J. Granulomatous-lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency. The clinical respiratory journal. 2018;12(1):337–43.CrossRefPubMedGoogle Scholar
  61. 61.
    Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.CrossRefPubMedGoogle Scholar
  62. 62.
    Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. The Journal of experimental medicine. 2014;211(13):2537–47.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606.e4.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210–8.e9.CrossRefPubMedGoogle Scholar
  65. 65.
    Rao VK, Webster S, Dalm V, Sediva A, van Hagen PM, Holland S, et al. Effective “activated PI3Kdelta syndrome”—targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017;130(21):2307–16.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Kiykim A, Ogulur I, Bariş S, Salzer E, Karakoc-Aydiner E, Ozen A, et al. Potentially beneficial effect of hydroxychloroquine in a patient with a novel mutation in protein kinase Cδ deficiency. J Clin Immunol. 2015;35(6):523–6CrossRefPubMedGoogle Scholar
  67. 67.
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science (New York, NY). 2002;298(5597):1395–401.CrossRefGoogle Scholar
  68. 68.
    Oftedal BE, Hellesen A, Erichsen MM, Bratland E, Vardi A, Perheentupa J, et al. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity. 2015;42(6):1185–96.CrossRefPubMedGoogle Scholar
  69. 69.
    Ferre EM, Rose SR, Rosenzweig SD, Burbelo PD, Romito KR, Niemela JE, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight. 2016;1(13). e88782Google Scholar
  70. 70.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature genetics. 2001;27(1):20–1.CrossRefPubMedGoogle Scholar
  71. 71.
    • Cepika AM, Sato Y, Liu JM, Uyeda MJ, Bacchetta R, Roncarolo MG. Tregopathies: monogenic diseases resulting in regulatory T-cell deficiency. J Allergy Clin Immunol. 2018;142(6):1679–95 Good overview over the pathogenetic mechanisms, clinical presentation, diagnosis, and current and future treatments of major known Tregopathies. CrossRefPubMedGoogle Scholar
  72. 72.
    Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science (New York, NY). 2011;332(6029):600–3.CrossRefGoogle Scholar
  73. 73.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology. 2013;13:227.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Wang CJ, Heuts F, Ovcinnikovs V, Wardzinski L, Bowers C, Schmidt EM, et al. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(2):524–9.CrossRefPubMedGoogle Scholar
  75. 75.
    • Schwab C, Gabrysch A, Olbrich P, Patino V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932–46 Description of the largest known cohort of CTLA4 mutation carriers guiding the clinician in diagnosis and treatment. CrossRefPubMedGoogle Scholar
  76. 76.
    Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M, et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature. 2013;498(7455):506–10.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Zhou Y, Wu H, Zhao M, Chang C, Lu Q. The Bach family of transcription factors: a comprehensive review. Clinical reviews in allergy & immunology. 2016;50(3):345–56.CrossRefGoogle Scholar
  79. 79.
    Gadina M, Johnson C, Schwartz D, Bonelli M, Hasni S, Kanno Y, et al. Translational and clinical advances in JAK-STAT biology: the present and future of jakinibs. Journal of Leukocyte Biology. 2018;104(3):499–514.CrossRefPubMedGoogle Scholar
  80. 80.
    Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 Mutations in the Hyper-IgE Syndrome. New England Journal of Medicine. 2007;357(16):1608–19.CrossRefPubMedGoogle Scholar
  81. 81.
    Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nature genetics. 2014;46:812.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Zheng J, van de Veerdonk FL, Crossland KL, Smeekens SP, Chan CM, Al Shehri T, et al. Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). European journal of immunology. 2015;45(10):2834–46.CrossRefPubMedGoogle Scholar
  83. 83.
    Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science (New York, NY). 2015;349(6246):436–40.CrossRefGoogle Scholar
  84. 84.
    Khoury T, Molho-Pessach V, Ramot Y, Ayman AR, Elpeleg O, Berkman N, et al. Tocilizumab promotes regulatory T-cell alleviation in STAT3 gain-of-function−associated multi-organ autoimmune syndrome. Clinical Therapeutics. 2017;39(2):444–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO molecular medicine. 2017;9(6):737–40.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Fox TA, Chakraverty R, Burns S, Carpenter B, Thomson K, Lowe D, et al. Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Blood. 2018;131(8):917–31.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Bienias M, Bruck N, Griep C, Wolf C, Kretschmer S, Kind B, et al. Therapeutic approaches to type I interferonopathies. Current rheumatology reports. 2018;20(6):32.CrossRefPubMedGoogle Scholar
  88. 88.
    Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. The New England journal of medicine. 2014;370(10):921–31.CrossRefPubMedGoogle Scholar
  89. 89.
    Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. The New England journal of medicine. 2014;370(10):911–20.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the phenotype, genetics, pathogenesis, and treatment. Journal of clinical immunology. 2018;38(5):569–78.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, et al. Deficiency of adenosine deaminase 2 causes antibody deficiency. Journal of clinical immunology. 2016;36(3):179–86.CrossRefPubMedGoogle Scholar
  92. 92.
    • Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, et al. Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis & rheumatology (Hoboken, NJ). 2017;69(8):1689–700 Recent report of a new phenotypes of DADA2 deficiency and possible treatment options. CrossRefGoogle Scholar
  93. 93.
    Skrabl-Baumgartner A, Plecko B, Schmidt WM, Konig N, Hershfield M, Gruber-Sedlmayr U, et al. Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatric rheumatology online journal. 2017;15(1):67.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Hashem H, Kumar AR, Muller I, Babor F, Bredius R, Dalal J, et al. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood. 2017;130(24):2682–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Helen Leavis
    • 1
  • Jochen Zwerina
    • 2
  • Bernhard Manger
    • 3
  • Ruth D. E. Fritsch-Stork
    • 2
    • 4
    Email author
  1. 1.Department of Rheumatology and Clinical ImmunologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
  2. 2.Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical DepartmentHanusch HospitalWienAustria
  3. 3.Department of Internal Medicine 3, Universitätsklinikum ErlangenFriedrich-Alexander-Universität Erlange-NürnbergErlangenGermany
  4. 4.Sigmund Freud UniversityViennaAustria

Personalised recommendations