Skip to main content

Advertisement

SpringerLink
Log in

Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency—a Report from the Slovenian National Registry

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

An abnormal regulation of immune responses leads to autoimmune and inflammatory manifestations in patients with primary immunodeficiencies (PIDs). The objective of our study was to evaluate the frequency of non-infectious and non-malignant manifestations in a large cohort of patients included in the Slovenian national PID registry and to assess the time of manifestation onset with respect to the time of PID diagnosis. Medical records of registered patients were reviewed. Data on autoimmunity, lymphoproliferation, autoinflammation, allergies, PID diagnosis, and underlying genetic defects were collected and analyzed. The time of each manifestation onset was determined and compared with the time of PID diagnosis. As of May 2015, 247 patients with 50 different PIDs were registered in the Slovenian national PID registry (147 males, 100 females; mean age 20 years). Mean disease duration was 14 years; 78 % of patients were younger than 18 years; and 22 % of patients were adults. Diagnosis of PID was genetically confirmed in 51 % of patients. Non-infectious and non-malignant manifestations were present in 69/235 (29 %) patients, including autoimmune manifestations in 52/235 (22 %), lymphoproliferative/granulomatous in 28/235 (12 %), autoinflammatory in 12/247 (5 %), and allergic manifestations in 10/235 (4 %) of all registered patients. Autoimmune manifestations were present in all patients whose PIDs were classified as diseases of immune dysregulation, 47 % of patients with chronic granulomatous disease, and 38 % of patients with predominantly antibody immune deficiencies. A high prevalence of non-infectious and non-malignant manifestations among patients in the Slovenian national PID registry suggests common genetic factors of autoimmunity, inflammation, and immunodeficiency. Patients with PID should be routinely screened for autoimmune and inflammatory manifestations at the time of PID diagnosis and during the long-term follow up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Al-Herz W, Notarangelo LD. Classification of primary immunodeficiency disorders: one-fits-all does not help anymore. Clin Immunol. 2012;144:24–5.

  2. Maggadottir SM, Sullivan KE. The intersection of immune deficiency and autoimmunity. Curr Opin Rheumatol. 2014;26:570–8.

    Article  CAS  PubMed  Google Scholar 

  3. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009;27:621–68.

  4. Zhang H, Kong H, Zeng X, Guo L, Sun X, He S. Subsets of regulatory T cells and their roles in allergy. J Transl Med. 2014;12:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010;71:317–28.

    Article  CAS  PubMed  Google Scholar 

  6. Ballanti E, Perricone C, Greco E, Ballanti M, Di Muzio G, Chimenti MS, et al. Complement and autoimmunity. Immunol Res. 2013;56:477–91.

    Article  CAS  PubMed  Google Scholar 

  7. Goyal R, Bulua AC, Nikolov NP, Schwartzberg PL, Siegel RM. Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Curr Opin Rheumatol. 2009;21:78–84.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.

  9. Blazina Š, Markelj G, Debeljak M, Jeverica AK, Toplak N, Bratanič N, et al. Slovene national registry of patients with primary immunodeficiency. Zdrav Vestn. 2015;84:797–808.

  10. Pirrone A, Markelj G, Piscianz E, Jeverica AK, Valencic E, Debeljak M, et al. Primary immunodeficiency diseases in two neighboring pediatric centers: registry data bring out a wide spectrum of diseases with complex clinical presentations. Cent J Immunol. 2012;37:365–70.

    Article  Google Scholar 

  11. Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, 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. 2014;5:162.

    PubMed  PubMed Central  Google Scholar 

  12. Angulo I, Vadas O, Garçon F, Banham-hall E, Leahy TR, Baxendale H, et al. Europe PMC Funders Group Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2014;342:866–71.

  13. Sinožić D, Toplak N, Milotić I. Tumor necrosis factor receptor-associated periodic fever syndrome in a 58-year-old man: caution not to discount TRAPS as a diagnosis in older patients. J Clin Rheumatol. 2011;17:325–8.

    Article  PubMed  Google Scholar 

  14. Picard C, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, 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;35:696–726.

  15. 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.

  16. Melki I, Crow YJ. Novel monogenic diseases causing human autoimmunity. Curr Opin Immunol. 2015;37:1–5.

  17. Barsalou J, Saint-Cyr C, Drouin E, Le Deist F, Haddad E. High prevalence of primary immune deficiencies in children with autoimmune disorders. Clin Exp Rheumatol. 2011;29:125–30.

  18. Podkrajšek KT, Milenković T, Odink RJ, Claasen-van der Grinten HL, Bratanič N, Hovnik T, et al. Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1. Eur J Endocrinol. 2008;159:633–9.

    Article  CAS  PubMed  Google Scholar 

  19. Bratanic N, Kisand K, Avbelj Stefanija M, Battelino T, Trebusak Podkrajsek K. Clinical, genetic and immunological characteristics of paediatric autoimmune polyglandular syndrome type 1 patients in Slovenia/Klinične, Genetske nn Imunološke Značilnosti Otrok In Mladostnikov Z Avtoimunskim Poliglandularnim Sindromom Tipa 1 V Sloveni. Slov J Public Health. 2015;54:112–8.

    Google Scholar 

  20. Bleesing JJH. Autoimmune lymphoproliferative syndrome (ALPS). Curr Pharm Des. 2003;9:265–78.

    Article  CAS  PubMed  Google Scholar 

  21. 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;20:646–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014;133:1099–108.

    Article  CAS  PubMed  Google Scholar 

  23. Felgentreff K, Perez-Becker R, Speckmann C, Schwarz K, Kalwak K, Markelj G, et al. Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clin Immunol. 2011;141:73–82.

    Article  CAS  PubMed  Google Scholar 

  24. Davies K, Stiehm ER, Woo P, Murray KJ. Juvenile idiopathic polyarticular arthritis and IgA deficiency in the 22q11 deletion syndrome. J Rheumatol. 2001;28:2326–34.

    CAS  PubMed  Google Scholar 

  25. Davies JK, Telfer P, Cavenagh JD, Foot N, Neat M. Autoimmune cytopenias in the 22q11.2 deletion syndrome. Clin Lab Haematol. 2003;25:195–7.

    Article  CAS  PubMed  Google Scholar 

  26. Chen M, Daha MR, Kallenberg CGM. The complement system in systemic autoimmune disease. J Autoimmun. 2010;34:276–86.

  27. Walport MJ, Davies KA, Morley BJ, Botto M. Complement deficiency and autoimmunity. Ann N Y Acad Sci. 1997;815:267–81.

    Article  CAS  PubMed  Google Scholar 

  28. De Jesus AA, Goldbach-Mansky R. Newly recognized Mendelian disorders with rheumatic manifestations. Curr Opin Rheumatol. 2015;27:511–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was partially supported by the research grant of the University Medical Center Ljubljana No. 20140208.

Author information

Authors and Affiliations

  1. Department of Allergology, Rheumatology and Clinical Immunology, Children’s Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia

    Štefan Blazina, Gašper Markelj, Anja Koren Jeverica, Nataša Toplak & Tadej Avčin

  2. Department of Paediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    Nataša Toplak, Janez Jazbec & Tadej Avčin

  3. Department of Endocrinology, Diabetes and Metabolic Diseases, Children’s Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia

    Nevenka Bratanič

  4. Department of Haematology and Oncology, Children’s Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia

    Janez Jazbec

  5. University Clinic of Pulmonary and Allergic Diseases Golnik, Golnik, Slovenia

    Peter Kopač

  6. Department of Special Laboratory Diagnostics, Children’s Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia

    Maruša Debeljak

  7. Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    Alojz Ihan

Authors
  1. Štefan Blazina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gašper Markelj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anja Koren Jeverica
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nataša Toplak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nevenka Bratanič
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Janez Jazbec
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Kopač
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maruša Debeljak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alojz Ihan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tadej Avčin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Štefan Blazina.

Ethics declarations

All patients or their legal guardians gave informed consent to be entered in the national PID registry. Data collection was approved by the National Medical Ethics Committee.

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blazina, Š., Markelj, G., Jeverica, A.K. et al. Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency—a Report from the Slovenian National Registry. J Clin Immunol 36, 764–773 (2016). https://doi.org/10.1007/s10875-016-0330-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-016-0330-1

Keywords

Search

Navigation