Autoimmune lymphoproliferative syndrome (ALPS)
The pathogenesis of ALPS is based on the inability of immune system cells to initiate receptor-mediated apoptosis in a timely manner. Lymphocytes that have completed their function do not die, but continue to accumulate in the body.
- Genetics: In most cases, a mutation occurs in the TNFSFR6 gene located on chromosome 10q. It encodes the Fas receptor (CD95). Much less commonly, defects involve the Fas ligand or caspases 8 and 10. Important nuance: the disease develops only if the mutation alters the intracellular region of the CD95 molecule, blocking the apoptotic signal transduction.
- Immunological markers: Patients' blood shows hypergammaglobulinemia and a pathognomonic pool of T lymphocytes lacking both CD4 and CD8 co-receptors (so-called double-negative cells: CD3+ CD4- CD8-).
- Clinical presentation: Characterized by benign (non-malignant) lymphoproliferation and multiple autoimmune processes.
IPEX and APECED: Collapse of Immunological Tolerance
These two syndromes clearly demonstrate what happens when central and peripheral mechanisms of immunological tolerance break down. Both manifest as severe autoimmune endocrinopathies.
IPEX syndrome (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
- Mechanism: A mutation on the X chromosome affects the master gene FOXP3, which is critically required for the maturation of regulatory T cells. Without them, autospecific lymphocyte clones are disinhibited in the periphery.
- Manifestations: Boys become ill in the first year of life. Type 1 diabetes mellitus, thyroiditis, severe enteropathy (with cachexia), eczema, hemolytic anemia, and thrombocytopenia develop. Elevated IgE levels and eosinophilia are characteristic. The prognosis is extremely poor.
APECED syndrome (Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)
- Mechanism: The AIRE gene is responsible for the expression of organ-specific antigens in the thymic medulla. This is necessary to eliminate T cells aggressive to self-tissues during negative selection. When this gene is defective, autoreactive lymphocytes enter the periphery unhindered.
- Target organs: Parathyroid glands, adrenal glands, thyroid gland, gonads, and pancreatic islets (leading to diabetes) are affected. Severe candidiasis frequently develops.
X-linked lymphoproliferative syndrome (XLP)
A rare immunodeficiency in which the immune system mounts a distorted, life-threatening response to a specific infectious trigger — the Epstein-Barr virus (EBV).
- Molecular defect: A mutation in the SH2D1A gene leads to the absence or dysfunction of the SAP adaptor protein. Normally, this protein facilitates the transmission of activation signals via the SLAM receptor using the Fyn tyrosine kinase.
- Consequence: Without the SAP protein, the SH-2 phosphatase binds freely to the SLAM receptor, dephosphorylating it and silencing the signal. As a result, T lymphocytes and NK cells (the main defenders against viruses) cannot be activated.
- Pathogenesis: EBV enters B lymphocytes (by binding the gp150 molecule to the CD21 receptor). Due to a lack of control, the virus begins to replicate unhindered, and B cells undergo polyclonal activation.
- Clinical features: Fulminant infectious mononucleosis develops. EBV-infected B cells, along with inadequately functioning T cells, infiltrate the liver. This leads to massive hepatic tissue necrosis, which becomes the main cause of patient death. Dysgammaglobulinemia and a high risk of malignant lymphoproliferative disorders are also characteristic.
Briefly: answers to topical questions
What types of mutations in the TNFSFR6 gene lead to the development of ALPS?
Autoimmune lymphoproliferative syndrome is caused by mutations in the TNFSFR6 (TNFRSF6) gene that cause alterations in the intracellular domain of the CD95 molecule (Fas receptor). This results in impaired expression of the encoded molecules or complete failure of apoptotic signal transmission. This disrupts receptor-mediated apoptosis of immune system cells.
Clinical and laboratory manifestations include:
- Lymphoproliferation (non-malignant) — excessive proliferation of lymphocytes.
- Hypergammaglobulinemia — elevated levels of immunoglobulins.
- Autoimmune processes — aggression against self-tissues.
- Accumulation of specific cells — an increase in the blood content of CD3+ CD4- CD8- T cells.
What are the standard treatment methods for IPEX syndrome?
The treatment of choice for IPEX syndrome is bone marrow transplantation. The disease is a primary immunodeficiency with autoimmune aggression, manifesting at an early age.
Main manifestations of the syndrome:
- Endocrine system — involvement of the pancreas and thyroid gland, including type 1 diabetes mellitus.
- Gastrointestinal tract — severe enteropathy and intestinal damage.
The prognosis is extremely poor: affected children die within the first year of life from recurrent severe infections.
To remember the defect in IPEX: FOX ate regulatory T cells (FOXP3 mutation). For APECED: AIRE (air) in the thymus — cells do not "see" their own antigens, selection does not work.
Class and exam questions
Which cellular marker in a blood test indicates ALPS?
Accumulation in peripheral blood of so-called "double-negative" T lymphocytes with the CD3+ CD4- CD8- phenotype.
Why do patients with X-linked lymphoproliferative syndrome die from liver damage?
Massive infiltration of the liver occurs by B cells proliferating uncontrollably under the action of the Epstein-Barr virus, which causes extensive hepatocyte necrosis.
What is the role of regulatory T cells in IPEX syndrome?
Normally, they prevent the development of autoimmune processes. In IPEX syndrome, due to a defect in the FOXP3 gene, these cells are absent, leading to multiple endocrine gland and intestinal lesions in children.
What else to study on this topic
- Chromosome breakage syndromes: Ataxia-telangiectasia (Louis-Bar syndrome) and Nijmegen breakage syndrome.
- Wiskott-Aldrich syndrome: the role of the WASP protein in actin polymerization and immune synapse formation.
- Common variable immunodeficiency (CVID) and mechanisms of skewing toward Th1.
- Severe combined immunodeficiency (SCID) and the role of IL-7 receptor deficiency.
- AIDS as an independent acquired immunodeficiency disease.
Master the entire topic in the "Immunology" course
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Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
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