**Table 3.** *Cont.*


#### **Table 3.** *Cont.*

Abbreviations: AML—acute myelogenous leukemia; CMML—chronic myelomonocytic leukemia; EBV—Epstein–Barr virus; HPV—human papillomavirus; MDS—myelodysplastic syndrome; NHL—non-Hodgkin lymphoma; and T-ALL—T-cell acute lymphoblastic leukemia.

#### **6. Diseases of Immune Dysregulation**

Diseases of immune dysregulation are a separate and independent category of IEI in IUIS classification [1]. This category includes i.a. familial hemophagocytic lymphohistiocytosis (FHL syndromes), FHL syndromes with hypopigmentation, regulatory T cell defects, autoimmunity with or without lymphoproliferation, immune dysregulation with colitis, ALPS, and a susceptibility to EBV and lymphoproliferative conditions. This category is often the most difficult to define clinically and to diagnose without extensive sequencing since there is a significant phenotypic overlap between different genetic causes, the evolution of features over time, and phenotypic heterogeneity. On the other hand, these diseases have improved our understanding of the pathways that drive autoimmunity in IEI.

Early-onset autoimmunity, autoimmunity that involves multiple organs, a strong family history of autoimmunity, autoimmunity in combination with susceptibility to infection, or significant lymphoproliferation all suggest an immune dysregulation defect.

Diseases of immune dysregulation, according to IUIS classification, are summarized in Table S1.

Over the years, the wide application of whole-exome sequencing/whole-genome sequencing has significantly promoted the discovery and further study of new IEI and its number has doubled from 2009 to 2019 [1,140]. It is worth mentioning that the number of cases for any particular IEI is usually few, and because of that, a large-scale study of IEI can hardly be conducted [140]. Furthermore, there are several difficulties in identifying IEI connected with immune dysregulation. There are still countries where genetic tests are not widespread and freely available, mostly because of their costs. Moreover, in some patients more than one mutation is present, which makes it even more difficult to find [140,141]. In addition, phenotypes of the same mutation vary between patients, ranging from mild or uncharacteristic symptoms to even life-threatening manifestations [140,142,143]. In conclusion, patients with immune dysregulation should be examined scrupulously, and genetic diagnostics should be conducted in cases when it is necessary and possible [140]. Early and proper diagnosis seems crucial when we consider IEI patients. In cases of IEI patients with immune dysregulation, it is even more important.

The treatment is often challenging and sometimes requires balancing between increased susceptibility to infection and the additional suppression of the immune system [144]. Not so long ago, treatment options for IEI patients remained limited. They included the intensive treatment of infections; IRT; and bone marrow transplant in some cases. IRT has been a standard, often live-saving treatment for IEI that has affected antibody production for the past four decades. Both intravenous (IVIg) and subcutaneous (SCIg) immunoglobulins are often suitable for lifelong therapy. High-dose IVIg, together with corticosteroids, is a standard therapy for ITP [144]. A significant increase in the field of clinical immunology, including molecular biology techniques, gene therapy, or the use of immune modulators, allowed the development of modern and precise therapies [145]. Equally, having better knowledge of IEI pathophysiology enables the implementation of targeted therapy. IEI is an excellent example of disease where such "precision medicine" can be applied. Precision medicine is an approach based on advances in genetic research and data analysis. It offers breakthroughs in the treatment of the disease and has the potential to overturn traditional methods of practicing medicine.

Such medicines (new or repurposed) modify intracellular pathways whose function is disturbed because of specific genetic defect [144]. Thanks to precision medicine, the treatment can selectively influence a specific cell function instead of affecting the entire immune system. Moreover, the adverse side effects that affect other tissues are possible to avoid.

Although the term "precision medicine" is relatively new, it has been part of healthcare for many years. For example, a person who needs a blood transfusion does not receive blood from a randomly selected donor; instead, the donor's blood group is matched to that of the recipient to reduce the risk of complications. Precision medicine is already used in the treatment of diabetes and cancer. It is especially useful in cases of breast, lung, skin, colon, prostate, and pancreatic cancer. Its other promising applications include cardiology, signs of aging, rare childhood diseases, cystic fibrosis, and HIV.

In the context of immunedysregulation, the usage of small molecules and biologics effectively helps with reversing the clinical manifestations of immunedysregulation and hyperinflammation. Knowledge about the genetic etiology of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) allowed one to explore PI3Kδ inhibition as a precision medicine [146,147]. Leniolisib, a small-molecule, selective PI3Kδ inhibitor, causes the dose-dependent suppression of PI3Kδ pathway hyperactivation. Clinical trials are currently underway to establish the safety and efficacy of selective PI3K δ inhibitors as a possible therapeutic option in patients with APDS. One is related to the oral administration of leniolisib (NCT02435173), the other to the inhaled administration of nemiralisib (NCT02593539). So far, the 12-week dose escalation of leniolisib has been shown to be safe and effective in reducing lymphadenopathy, splenomegaly, and cytopenia [144,147].

#### **7. Conclusions**

IEI is a group of rare diseases that can be camouflaged or not considered because of the predominant clinical features of atopy, autoimmunity, or lymphoproliferation. Consequently, some patients will remain undiagnosed. This risk impairs their quality of life, morbidity, and mortality, especially when exposed to agents reducing the immune competence. An underlying IEI should be particularly considered, especially in severe cases of atopic disease with concomitant signs of autoimmunity and unusual, recurrent or severe infections, so appropriate treatment regimens can be initiated and inappropriate immune suppression avoided.

In terms of the scientific evidence, it is still debatable whether allergy and cancer should be considered as risk factors or rather the consequences of the underlying IEI. Autoimmunity, as well as malignancy, worsen the IEI patients' prognosis. Another important issue in IEI is their exact pathogenesis, as well as the gene–phenotype relationship. The recent advances in genetics also revolutionized the field of IEI. Until now, the increased use of new sequencing techniques allowed for the identification of different monogenic causes of IEI. They enabled the better understanding of genotype–phenotype correlations and consequently led to better therapeutic strategies targeting the immune dysregulation in IEI [45]. The unmet needs include the unified nomenclature; the pathophysiological

mechanisms assessment, for example, the lymphoma' genesis in IEI patients; and better, more personalized treatment strategies [148].

Novel diagnostic approaches, as well as evidence-based treatment guidelines that consider the underlying immunodeficiency rather than using extrapolation from non-IEI settings, are necessary. The recommendations for validated screening of cohorts at risk of allergy, autoimmunity, and malignancy are of the utmost importance.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/jcm11144220/s1, Table S1: Diseases of immune dysregulation according to IUIS classification. Accessed on 8 July 2022.

**Author Contributions:** K.P.-S. and G.P. wrote the initial draft of this paper, which was critically ´ revised by A.L.-U. and M.J. All the authors contributed to conceptualizing this work. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was financially supported by The Ministry of Health subvention according to number of STM.A020.20.063 from the IT Simple system of Wrocław Medical University.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
