Main Article Content
immune dysregulation, autoimmunity, IPEX-like, ALPS-like, APDS1-2, CTLA-4 haploinsufficiency, LRBA deficiency, RAG1-2
Primary immunodeficiencies (PIDs) are inherited disorders classically characterized by increased susceptibility to infections. Nevertheless, in the last two decades, genomic analysis (such as NGS) coupled with biochemical and cellular studies led to a more accurate definition for a growing number of novel genetic disorders associated with PIDs. This revealed new aspects of the immune system and its function and regulation within these diseases. In particular, it has been clarified that the clinical features of PIDs are much broader that originally thought and extend beyond an increased susceptibility to infections. More specifi- cally, immune dysregulation is very often described in novel characterized PIDs and can lead to multiple autoimmune diseases, lymphoproliferation and malignancies. If not promptly diagnosed, these could negatively impact patient’s prognosis. The aim of this review is to increase the awareness of recently discovered PIDs, characterized predominantly by immune dysregulation phenotypes. Findings highlighted in this review suggest screening for immunodeficiency in patients with lymphoproliferation or early onset/multiple autoimmune diseases. Prompt diagnosis would potentially allow most successful treatment and clinical outcome for patients with PIDs.
2. Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: A new paradigm is needed for the 21st century. Ann N Y Acad Sci 2011;1238:7–14.
3. Fischer A, Provot J, Jais J-P, Alcais A et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol 2017;140:1388-1393.e8.
4. Delmonte OM, Castagnoli R, Calzoni E, Notarangelo LD. Inborn errors of immunity with immune dysregulation: from bench to bedside. Front Pediatr 2019;7:353.
5. Delmonte OM. Immunodeficiency and disorders of immune dysregulation. Pediatr Allergy Immunol 2020;31:8–10.
6. Leavis H, Zwerina J, Manger B, Fritsch-Stork RDE. Novel Developments in Primary Immunodeficiencies (PID)—a Rheumatological Perspective. Curr Rheumatol Rep 2019;21:55.
7. Notarangelo LD, Uzel G, Rao VK. Primary immunodeficiencies: novel genes and unusual presentations. Hematology Am Soc Hematol Educ Program 2019;2019:443-448.
8. Daley SR, Koay HF, Dobbs K, et al. Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices. J Allergy Clin Immunol 2019;144:333-336.
9. Delmonte OM, Schuetz C, Notarangelo LD. RAG Deficiency: Two Genes, Many Diseases. J Clin Immunol 2018;38:646–655.
10. Villa A, Notarangelo LD. RAG gene defects at the verge of immunodeficiency and immune dysregulation. Immunol Rev 2019;287:73–90.
11. Montin D, Marolda A, Licciardi F et al. Immunophenotype anomalies predict the development of autoimmune cytopenia in 22q11.2 Deletion Syndrome. J Allergy Clin Immunol Pract 2019;7:2369–2376.
12. Constantine GM, Lionakis MS. Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev 2019;287:103–120.
13. Gambineri E, Ciullini Mannurita S, Hagin D et al. Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. Front Immunol (2018) 9:
14. Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Research 2017;6:1928.
15. Coulter TI, Chandra A, Bacon CM et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol 2017;139:597-606.e4.
16. Lucas CL, Kuehn HS, Zhao F et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol 2014;15:88–97.
17. Khailaie S, Rowshanravan B, Robert PA et al. Characterization of CTLA4 trafficking and implications for its function. Biophys J 2018;115:1330–1343.
18. Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev 2019;287:33–49.
19. Habibi S, Zaki-Dizaji M, Rafiemanesh H et al. Clinical, immunologic, and molecular spectrum of patients with lps-responsive beige-like anchor protein deficiency: a systematic review. J Allergy Clin Immunol Pract 2019;7:2379-2386.e5.
20. Hou TZ, Verma N, Wanders J et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood 2017;129:1458–1468.
21. Notarangelo LD, Fleisher TA. Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders. J Allergy Clin Immunol 2017;139:715–723.
22. Delmonte OM, Notarangelo LD. Targeted therapy with biologicals and small molecules in primary immunodeficiencies. Med Princ Pract 2020;29:101–112.
23. Maccari ME, Abolhassani H, Aghamohammadi A et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol 2018;9:1–8.
24. Schwab C, Gabrysch A, Olbrich P et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. J Allergy Clin Immunol 2018;142:1932–1946.
25. Tesch VK, Abolhassani H, Shadur B et al. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol 2020;145:1452-1463.
26. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 2008;28:581–587.
27. George LA, Teachey DT. Optimal management of autoimmune lymphoproliferative syndrome in children. Pediatr Drugs (2016) 18:261–272.
28. Rao VK, Webster S, Dalm VASH et al. Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017;130:2307–2316.
29. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front Pediatr 2019;7:295.