Immunodeficiency

Immunodeficiency occurs due to impairment of the immune system, and diseases associated with it may result from the aberrant activation of cellular signaling pathways, including PI3K, NFκB, and CXCR4 signaling pathways (1). Immunodeficiency may be primary or secondary, resulting from defects in immune system function or components such as lymphocytes, phagocytes, and the complement system (2). Because of these immune system defects, people with immunodeficiency are prone to having long-lasting, severe, and recurring infections and other diseases (3).

Primary immunodeficiencies are inherent immune system defects resulting from genetic mutations present at birth. It can be classified into two broad types:

1. Disorders of adaptive immunity, resulting from T-cell deficiency, B-cell deficiency, and both T-cell and B-cell deficiency; and
2. Disorders of innate immunity, occurring due to complement and phagocyte deficiency.

There are over 250 disorders in the spectrum of primary immunodeficiencies, and they include severe combined immunodeficiency disease, Bruton disease, Wiskott-Aldrich syndrome, chronic granulomatous disease, DiGeorge syndrome, and major histocompatibility complex deficiency (4).

Secondary immunodeficiency, which is more common than primary immunodeficiency, describes acquired defects in immune system function resulting from factors such as prolonged use of anti-inflammatory, immunomodulatory, and immunosuppressive drugs, infections such as HIV infection, measles, and influenza A virus, nutrient deficiency or undernutrition, advanced age, and diseases such as diabetes, chronic uremia, and cancer (5, 6).

Aberrant PI3Kδ signaling has been identified to be pivotal to immunodeficiency, particularly primary immunodeficiency (7). The PI3K signaling pathway is involved in cellular functions, such as cell growth, differentiation, migration, proliferation, survival, and metabolism (8). The dynamic regulation of  PI3Kδ activity is essential for normal immune cell function and differentiation. Underactivation and overactivation of PI3Kδ activity caused by loss of function (LOF) and gain of function (GOF) mutations in PI3K genes results in immune system impairment and dysregulation (7).

Overactive PI3Kδ signaling results in activated PI3Kδ syndrome (APDS), a primary immunodeficiency disorder, characterized by recurrent infections, lymphoproliferation, autoimmunity, bronchiectasis (a condition that occurs with damage in the airways in the lungs), and an increased risk of B-cell malignancies (9). Conversely, significantly reduced PI3Kδ activity leads to impaired T and B cell function associated with frequent infections and colitis.

PI3Kδ pathway is a relevant target in drug development. Researchers suggest that PI3Kδ inhibition may be therapeutic to APDS (8). A small 2023 study found that PI3Kδ inhibitor leniolisib improved symptoms such as swollen lymph nodes and clinical outcomes in patients with APDS (10).

Another signaling pathway playing an essential role in immunodeficiencies is the NFκB pathway. NF-κB is a family of transcription factors that contributes to regulating genes involved in immune responses (11). The precise regulation of this signaling pathway is vital for various innate and adaptive immune functions (12, 13). Underactivation and overactivation of NFκB signaling due to mutations in NFκB genes are responsible for immunodeficiencies such as common variable immunodeficiency, ectodermal dysplasia with immunodeficiency (EDA-ID), and severe combined immunodeficiency and immune dysregulation. Researchers suggest that developing therapeutic agents that efficiently restore balance in defective NF-κB activity may be beneficial for treating these immunodeficiency disorders (14).

CXCR4 is a G protein-coupled receptor (GPCR) and has just one ligand, CXCL12, also called stromal cell-derived factor-1 (SDF-1). CXCR4 is expressed by hematopoietic stem cells, endothelial and epithelial cells, and neurons and is significantly involved in physiological processes such as immune response, angiogenesis, and hematopoiesis and pathological conditions including immunodeficiencies and cancer (15).

CXCR4 modulates innate and adaptive immune responses by regulating how leukocytes move and spread out in tissues. It is also involved in lymph node organization and supports the formation and stability of immunological synapses, contributing to B  and T cell function. Defective CXCR4 signaling due to mutations of CXCR4 may result in a primary immunodeficiency called WHIM syndrome, characterized by warts, neutropenia (abnormally low neutrophil count), B cell lymphopenia (lower-than-usual lymphocyte count), myelokathexis (retention of neutrophils in the bone marrow), hypogammaglobulinemia (a disorder caused by lack of immunoglobulin), and recurrent infections. (16, 17).

Researchers suggest the potential of using Plerixafor, a CXCR4 inhibitor approved to be used with granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell mobilization and transplantation to treat WHIM syndrome but also recognize the need for new therapies due to the complexity of this approach (16).

References

1. British Society for Immunology https://www.immunology.org/policy-and-public-affairs/briefings-and-position-statements/immunodeficiency (accessed August 8, 2023)
2. Justiz Vaillant AA, Qurie A. Immunodeficiency. [Updated 2022 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
3. ScienceDirect https://www.sciencedirect.com/topics/medicine-and-dentistry/immunodeficiency (accessed August 8, 2023)
4. McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61. Published 2018 Sep 12.
5. Ballow M, Sánchez-Ramón S, Walter JE. Secondary Immune Deficiency and Primary Immune Deficiency Crossovers: Hematological Malignancies and Autoimmune Diseases. Front Immunol. 2022;13:928062. Published 2022 Jul 18.
6. Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S195-S203.
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9. Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-983.
10. Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-983.
11. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023-.
12. Scott O, Roifman CM. NF-κB pathway and the Goldilocks principle: Lessons from human disorders of immunity and inflammation [published correction appears in J Allergy Clin Immunol. 2019 Aug;144(2):626]. J Allergy Clin Immunol. 2019;143(5):1688-1701.
13. Boztug H, Hirschmugl T, Holter W, et al. NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation. J Clin Immunol. 2016;36(6):533-540.
14. Dabbah-Krancher G, Snow AL. Mistuned NF-κB signaling in lymphocytes: lessons from relevant inborn errors of immunity. Clin Exp Immunol. 2023;212(2):117-128.
15. Busillo JM, Benovic JL. Regulation of CXCR4 signaling. Biochim Biophys Acta. 2007;1768(4):952-963.
16. Milanesi S, Locati M, Borroni EM. Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom's Macroglobulinemia. Int J Mol Sci. 2020;21(16):5696. Published 2020 Aug 8.
17. Pozzobon T, Goldoni G, Viola A, Molon B. CXCR4 signaling in health and disease. Immunol Lett. 2016;177:6-15.