Genetic control of the immune response
Genetic control determines the variation in the severity of immune response components. A key role here is played by major histocompatibility complex molecules (MHC, in humans — HLA).
- Presentation mechanism: The level of responsiveness directly depends on how well a specific antigenic peptide (T-epitope) fits into the antigen-binding cleft of an MHC-II molecule on the surface of antigen-presenting cells. High affinity ensures a strong response.
- Ir-1 gene: Historically the first described immune response gene (identical to H-2I genes in mice). It has been established that the allele determining a high response level is dominant. Mutations in the exon encoding the variable region of the molecule change the phenotype from high responsiveness to low.
- Antigen processing: In addition to MHC molecules themselves, the strength of the response is influenced by complex genes that control peptide preparation: LMP genes (encoding proteasome components) and TAP genes (encoding transport systems for delivering peptides to the endoplasmic reticulum).
Association of genotype with diseases
The specificity of peptide insertion into allelic variants of MHC molecules determines individual predisposition to pathologies.
- Resistance to infections: Occurs when pathogen peptides have high affinity for HLA molecules. For example, influenza virus peptides have high affinity for HLA-B27 and HLA-A2 alleles, which is why their carriers possess genetically determined resistance to the virus.
- Autoimmune diseases: If self (autoantigenic) peptides bind too well to HLA molecules, the risk of an attack on own tissues increases sharply. For instance, the HLA-B27 allele increases the relative risk of ankylosing spondylitis by more than 200 times. The HLA-B8 and HLA-DR3 alleles are associated with type 1 diabetes mellitus and Hashimoto's thyroiditis.
- Allergies (atopy): The development of a Th2-dependent response is controlled by genes unlinked to MHC. The main predisposition locus is located on the 5th chromosome, where the cytokine gene cluster (IL-4, IL-5, IL-13) resides.
Neuroendocrine regulation
Hormones and autonomic nervous system mediators affect cells of the immune system via specific receptors. They are divided into two opposing groups:
- Inhibitory (suppressive) factors: Glucocorticoids, adrenocorticotropic hormone (ACTH), androgens, estrogens, catecholamines (norepinephrine). They reduce lymphocyte proliferation, suppress cytokine secretion, and promote thymic involution.
- Stimulating factors: Growth hormone (somatotropin), insulin, thyroxine, prolactin. They enhance cell proliferation and differentiation, and stimulate the synthesis of thymic hormones.
A special place is occupied by glucocorticoids (cortisol). In physiological doses, they regulate differentiation, while in elevated doses, they trigger lymphocyte apoptosis. Cortical thymocytes and B-centroblasts are most sensitive to them. Cortisol destroys clones during selection periods when cells have reduced expression of anti-apoptotic Bcl-2 factors.
Sex steroids and thymic hormones
Sex hormones cause age-related thymic involution, which starts from puberty.
- Androgens exert a strong suppressive effect on immunocytes. Therefore, the mass of lymphoid organs and immune activity are on average higher in females.
- Estrogens act more weakly than androgens, but they actively suppress regulatory T cells (Treg), which is one of the reasons for the increased susceptibility of women to autoimmune diseases.
The thymus itself performs an important endocrine function. Its epithelial cells produce thymulin, thymosins, and thymopoietins. They are critical for the ability of T lymphocytes to secrete IL-2 and proliferate. The secretion of thymic hormones is suppressed by glucocorticoids and sex steroids, but stimulated by prolactin and growth hormone.
Briefly: answers to topical questions
What mechanisms ensure the autoregulation of the immune response?
Autoregulation of the immune response is implemented with the participation of factors from the immune system itself. The main mechanisms include:
- Autocrine regulation — self-maintenance of T-helper subpopulations using specific key cytokines.
- Mutual inhibition — the ability of Th1 and Th2 cells to suppress the development and functioning of each other.
- Inducible regulatory T cells — restrain immune responses to prevent autoaggression. These include:
- Type 1 regulatory T cells (Tr1) — produce interleukin-10.
- Th3 cells (Th3) — secrete transforming growth factor beta (TGFβ).
What is the difference between the pathways of antigen processing and presentation for MHC class I and class II molecules?
The difference between processing and presentation pathways lies in the source of antigens, the site of complex formation, and the target cells.
| Characteristic | MHC I | MHC II |
|---|---|---|
| Source of antigen | Intracellular (endogenous) proteins | Extracellular (exogenous) proteins |
| Site of cleavage | Cellular proteasome | Early and late endosomes |
| Site of binding | Endoplasmic reticulum | Combined vesicle (MIIC granule) |
| Target cells | Cytotoxic T lymphocytes (CD8+) | T helpers (CD4+) |
Which cytokines carry out cross-regulation between the Th1 and Th2 branches of the immune response?
Cross-regulation and mutual inhibition between the branches of the immune response are carried out by specific key cytokines of T-helper subpopulations. They are responsible for suppressing the development of cells of the opposite type:
- Interferon-gamma (IFNγ) — a key cytokine of Th1 cells that suppresses the development of the Th2-dependent response.
- Interleukin-4 (IL-4) — a key cytokine of Th2 cells that strictly directs differentiation along the Th2 pathway and inhibits Th1.
- Interleukin-10 (IL-10) — a product of Th2 cells that plays an important role in inhibiting Th1 cells.
To quickly recall groups of hormones: "Stress and sex (cortisol, ACTH, androgens) — suppress immunity, while growth and metabolism (GH, thyroxine, insulin) — stimulate it."
Class and exam questions
What do experiments on Biozzi mice prove?
These mice, bred on the basis of high or low antibody synthesis, showed that a strong humoral response (Th2 type) is often combined with a low ability of macrophages to destroy intracellular infections (Th1 type). This proves the genetically fixed opposing nature of different branches of the immunity.
How are MHC molecules linked to the development of autoimmune diseases?
If the structure of the antigen-binding cleft of a certain allele (e.g., HLA-B27) is ideally suited for binding the body's own peptides, the immune system begins to recognize them and attack tissues, which vastly increases the relative risk of developing the disease.
What else to study on this topic
- Genetics of the allergic response and the role of the 5th and 6th chromosomes
- Mechanisms of lymphocyte selection and expression of Bcl-2 factors
- Effect of neuropeptides on allergic reactions (VIP and substance P)
- Molecular mechanisms of LMP and TAP gene function in antigen processing
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