Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Dec 19:15:1497921.
doi: 10.3389/fimmu.2024.1497921. eCollection 2024.

Unmasking inborn errors of immunity: identifying the red flags of immune dysregulation

Manuela Cortesi  1 , Laura Dotta  1 , Marco Cattalini  1 , Vassilios Lougaris  1 , Annarosa Soresina  1 , Raffaele Badolato  1
Affiliations
Review

Unmasking inborn errors of immunity: identifying the red flags of immune dysregulation

Manuela Cortesi et al. Front Immunol. .

Abstract

Inborn errors of immunity (IEI) are rare diseases that affect the immune system. According to the latest International Union of Immunological Societies (IUIS) classification, 485 different IEI have been identified. Even if increased susceptibility to infections is the best-known symptom, IEI are no longer defined by the higher likelihood of infections alone. Immune dysregulation with autoimmune disease and hyperinflammation, lymphoproliferation, and malignancy are common manifestations and could be the only symptoms of IEI that must be recognized. An exclusive focus on infection-centered warning signs would miss around 25% of patients with IEI who initially present with other manifestations. Timely and appropriate diagnosis and treatment are essential to enhance the quality of life (QoL) and, in some cases, survival, as patients are susceptible to life-threatening infections or autoimmunity. In addition, the advantage of early diagnosis in IEI with immune dysregulation (i.e. CTLA4 deficiency, LRBA deficiency, NF-kB1/NF-kB2 deficiency, activated phosphoinositide 3-kinase delta syndrome -APDS-) is the initiation of targeted therapies with precise re-balancing of the dysregulated immune pathways (i.e., biologicals, selective inhibitors) or definitive therapy (i.e., HSCT).

Keywords: APDs; autoimmunity; immune dysregulation; inborn errors of immunity; warning signs.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Clinical spectrum of Inborn Errors of Immunity as a continuum. 22q11.2DS, 22q11.2 deletion syndrome; ALPS, autoimmune lymphoproliferative syndrome; APDS, Activated Phosphoinositide 3-kinase-d-syndrome; CVID, Common variable immunodeficiency; SCID, Severe combined immunodeficiency; CID, Combined Immunodeficiency; XLA, X-linked agammaglobulinemia; A-T, Ataxia-teleangiectasia; DADA-2, deficiency of adenosine deaminase 2; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked stndrome; XLP-1/2, SAP e XIAP deficiency.
Figure 2
Figure 2
Critical approach to patients with autoimmune cytopenias.
Figure 3
Figure 3
Inborn errors of immunity associated with non-malignant pediatric lymphoproliferative disorders. The figure was generated using Python and the NetworkX library.
See this image and copyright information in PMC

References

    1. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. . Human inborn errors of immunity: 2019 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. (2020) 40:24–64. doi: 10.1007/s10875-019-00737-x - DOI - PMC - PubMed
    1. Miyamoto S, Umeda K, Kurata M, Nishimura A, Yanagimachi M, Ishimura M, et al. . Hematopoietic cell transplantation for severe combined immunodeficiency patients: a Japanese retrospective study. J Clin Immunol. (2021) 41:1865–77. doi: 10.1007/s10875-021-01112-5 - DOI - PMC - PubMed
    1. Hosaka S, Kido T, Imagawa K, Fukushima H, Morio T, Nonoyama S, et al. . Vaccination for patients with inborn errors of immunity: a nationwide survey in Japan. J Clin Immunol. (2022) 42:183–94. doi: 10.1007/s10875-021-01160-x - DOI - PubMed
    1. Wood P, Stanworth S, Burton J, Jones A, Peckham DG, Green T, et al. . Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol. (2007) 149:410–23. doi: 10.1111/j.1365-2249.2007.03432.x - DOI - PMC - PubMed
    1. Thalhammer J, Kindle G, Nieters A, Rusch S, Seppänen MRJ, Fischer A, et al. . Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. (2021) 148:1332–1341.e5. doi: 10.1016/j.jaci.2021.04.015 - DOI - PubMed

MeSH terms

LinkOut - more resources