Death of immunocytes as a cause of immunodeficiency
The classic factors causing massive death of immune cells are ionizing radiation and cytotoxic drugs.
Lymphocytes possess abnormally high sensitivity to DNA damage. Upon accumulation of unrepaired breaks, ATM kinase is activated and transmits a signal to the p53 protein, triggering apoptosis. The biological purpose of this process is to protect the organism from cells with genetic mutations and prevent tumor formation.
Unlike most other cells, lymphocytes show low expression of anti-apoptotic proteins Bcl-2 and Bcl-X_L. Consequently, lymphocytes are susceptible to interphase death even in a resting state (at radiation doses of 1–3 Gy). In contrast, mitotic death of dividing cells of various types occurs at a dose of about 1 Gy, whereas interphase death of non-lymphoid cells requires doses exceeding 10 Gy.
Effects of radiation on the immune system
Radiation acts in two ways: it disrupts natural barriers (mucous membranes), paving the way for infections, and selectively destroys lymphocytes, their precursors, and dividing cells.
- Early stages: An acute shortage of neutrophils (myeloid lineage) develops. This leads to weakening of the first line of defense and often becomes the primary cause of death.
- Acute effects on lymphoid tissue: More than 90% of lymphoid cells die, and their migration (homing) is disrupted.
Cell radiosensitivity varies greatly. Cortical thymocytes and resting B and T cells are the most vulnerable. Formed effectors (e.g., plasma cells) are radioresistant. Cellular immunity is generally more resistant to radiation than humoral immunity.
Fun fact: Low doses of radiation (0.1–0.5 Gy) can exert an immunostimulatory effect due to the generation of reactive oxygen species. However, such stimulation is not adaptive and leads to immune imbalance.
Non-radiation-induced cell death and functional disorders
Bacterial and viral infections can also lead to massive lymphocyte death. This often occurs due to the action of superantigens (e.g., staphylococcal exotoxin). They bind to T-cell receptors (TCR) in a non-standard way, causing non-clonal activation of a vast number of CD4+ T lymphocytes. Hyperproduction of cytokines is followed by massive apoptosis and severe lymphopenia.
In addition to cell death, secondary immunodeficiencies can be associated with impaired cell function:
- Tumor growth: In the tumor microenvironment, T cells lose expression of receptor $\zeta$-chains, preventing their activation upon antigen contact.
- IDO enzyme (indoleamine 2,3-dioxygenase): Produced by dendritic and stromal cells. IDO degrades tryptophan and accumulates kynurenine, which blocks the T-lymphocyte cell cycle and suppresses immunity.
- Thymic hormone deficiency: Leads to functional inadequacy of T cells associated with elevated intracellular cAMP levels. A similar effect is observed in zinc deficiency.
Physiological immunodeficiencies (stress and aging)
Stress causes elevated glucocorticoid levels.
- Moderate stress leads only to the redistribution of lymphocytes in the body.
- Intense and prolonged stress triggers massive apoptosis of cortisone-sensitive cells (primarily immature thymocytes) due to low levels of the anti-apoptotic protein Bcl-2. This suppresses humoral immunity and accelerates immune system aging.
Age-related changes:
- Early postnatal period: Immunodeficiency is associated with immaturity of the immune system. The newborn is temporarily protected by maternal IgG antibodies crossing the placenta and secretory IgA supplied via breast milk.
- Aging: Accompanied by decreased thymic activity and T-cell dysfunction.
Briefly: answers to topical questions
Which specific cytotoxic drugs (cytostatics) cause secondary immunodeficiency?
Sources mention cisplatin, cyclophosphamide, azathioprine, asparaginase, methotrexate, and mycophenolate mofetil among antineoplastic and immunosuppressive drugs. Cisplatin is classified as a cytotoxic agent that damages lymphocyte DNA; for cyclophosphamide, azathioprine, and other drugs, sources indicate immunosuppressive or antineoplastic use. Cyclophosphamide, mycophenolate, and azathioprine can suppress immunity as part of immunosuppressive therapy.
Which viral infections lead to marked secondary immunodeficiency?
Marked secondary immunodeficiency in viral infections develops most significantly in HIV infection. HIV infection is characterized by a sharp drop in circulating CD4+ T lymphocytes; damage to the immune system forms the basis of AIDS pathogenesis.
What opportunistic infections are characteristic of T-cell secondary immunodeficiencies?
T-cell secondary immunodeficiencies are characterized by opportunistic infections, including Pneumocystis pneumonia, candidiasis, cryptococcosis, aspergillosis, toxoplasmosis, and strongyloidiasis. In HIV infection, these conditions are associated with a marked decrease in CD4+ T lymphocytes; toxoplasmosis and strongyloidiasis further exacerbate cellular immunodeficiency.
Class and exam questions
Why are lymphocytes so sensitive to radiation?
Resting lymphocytes show low expression of anti-apoptotic defense factors (Bcl-2 and Bcl-X_L proteins). Therefore, upon DNA damage by radiation, p53-dependent apoptosis is rapidly triggered in them.
How is the T-cell pool restored after radiation injury?
Recovery proceeds via two pathways: through the differentiation of new cells from blood stem cells (involving the thymus) and via homeostatic proliferation of surviving mature T lymphocytes driven by the cytokine IL-7.
What is the danger of superantigens?
Superantigens activate up to 20–30% of all CD4+ T cells simultaneously without requiring prior processing. Such massive activation results in exhaustion and massive apoptosis of these cells, leading to T-cell immunodeficiency.
What else to study on this topic
- Mechanisms of homeostatic proliferation and acquisition of memory cell phenotype by T cells
- Spatial reorganization of the immune system following irradiation (differences between lymph nodes and spleen)
- Causes of increased frequency of autoimmune processes following radiation injury
- Interaction of regulatory T cells (Tregs) with dendritic cells via CTLA-4 and induction of IDO
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