Foreignness as a danger marker
The main task of the immune system is defense against biological aggression, both external (pathogens) and internal (tumors). Foreign molecules serve as an early danger signal.
It is important to understand that foreignness is relative: the same molecule can be an antigen for one organism and cause no reaction in another. The greater the "evolutionary distance" between the donor and the recipient (and the more differences in the primary structure of proteins), the higher the immunogenicity. Antibodies are capable of detecting even single amino acid substitutions, which forms the basis of intraspecific polymorphism and rejection phenomena in allotransplantation.
Foreignness is not always absolute. Under normal conditions and in pathology, autoantibodies (against self-tissues) can be formed. This happens for several reasons:
- Reaction to "immune-privileged tissues" that the immune system initially considers foreign.
- Molecular mimicry (cross-reactivity), when antibodies to a pathogen react with similar structures of self-tissues.
- Physiological processes: production of low-affinity autoantibodies by B-1 cells for homeostasis, elimination of old molecules, and immune regulation (e.g., anti-antibodies).
Immunogenicity and the role of haptens
Immunogenicity is the ability of an antigen to independently induce an immune response (engage the cellular ensemble of lymphocytes).
Based on this characteristic, substances are divided into two groups:
- Complete antigens (proteins, large carbohydrates) — possess both immunogenicity and specificity.
- Incomplete antigens, or haptens (lipids, nucleic acids, small organic molecules). They do not trigger a reaction on their own. To become immunogenic, they require a large carrier protein. In such a complex, the protein provides immunogenicity, while the hapten determines the specificity of recognition.
Structural and chemical factors
The strength of the immune response is influenced by the physicochemical properties of the molecule itself. To become a strong antigen, a molecule requires structural diversity.
| Factor | Effect on immunogenicity |
|---|---|
| Molecular mass | The larger the polymer, the higher the immunogenicity. Large aggregates are actively phagocytosed, which is critical for presentation to T helper cells. |
| Epitope density | An increase in the number of recognizable groups enhances the response, but an excess leads to steric hindrance and decreased immunogenicity. |
| Conformational rigidity | Stabilization of the structure (e.g., by aromatic amino acids) increases immunogenicity, whereas an excess of proline or hydrophobic residues decreases it. |
| Degradability | If the organism lacks enzymes to degrade the polymer, it will be a weak antigen because it cannot be fragmented for T cells. |
Recipient genetics
Immunogenicity depends not only on the structure of the molecule, but also on the genetic apparatus of the organism.
The major histocompatibility complex (MHC) plays a key role. The level of the immune response directly depends on how effectively allelic variants of MHC molecules can bind antigen peptide fragments and present them to T cells. For structurally simple antigens, the ability to mount a response is strictly controlled by a single dominant gene. For complex antigens, this control becomes polygenic.
Briefly: answers to topical questions
What is antigen specificity, and which molecular structures determine it?
Antigen specificity is the selectivity of interaction between inducers and products of immune processes, in particular, antigens and antibodies. Specific interaction occurs with a relatively small surface area of the molecule — the epitope (antigenic determinant). In complex antigens, specificity is determined predominantly by the hapten.
The following structures determine specificity:
- Conformational determinants — formed by the secondary structure (e.g., $\alpha$-helix) of linear polypeptides.
- Linear (sequential) determinants — located on the branches of branched polypeptides.
For antigen recognition, not only the amino acid sequence but also the spatial configuration of the molecule is critically important.
Which organs and tissues of the body are considered "immune-privileged"?
Immune-privileged structures are those that are isolated by hemato-tissue barriers during prenatal ontogenesis and have no contact with immunocompetent lymphocytes. In the postnatal period, the immune system perceives them as "foreign," although genetically they are "self."
Examples of immune-privileged (antigenically foreign) structures:
- Spermatozoal proteins.
- Lens of the eye.
- Myelin (nervous tissue).
- Thyroid gland colloid cells.
Breach of the integrity of hemato-tissue barriers leads to contact between these antigens and immune system cells, abrogation of tolerance, and autoaggression.
How does antigen processing occur inside an antigen-presenting cell?
Antigen processing inside an antigen-presenting cell occurs via two main pathways depending on its origin:
- Endogenous pathway — intracellular proteins are degraded in proteasomes into peptide fragments, transported into the endoplasmic reticulum, and embedded into MHC class I molecules.
- Endocytic pathway — exogenous proteins are captured via endocytosis and degraded into peptides in endosomes. Then the endosome fuses with the MIIC granule, where the peptide replaces the invariant chain (CLIP) residue in the MHC class II molecule with the participation of HLA-DM.
There is also cross-presentation, in which exogenous proteins enter the MHC class I processing pathway.
Which classes of MHC molecules participate in antigen presentation, and to which T lymphocyte subpopulations do they present them?
MHC class I and class II molecules participate in antigen presentation. Antigen recognition by T lymphocytes strictly obeys the restriction rule:
| MHC molecule class | T lymphocyte subpopulation | Coreceptor |
|---|---|---|
| MHC-I | Cytotoxic T lymphocytes (T killers) | CD8+ |
| MHC-II | T helper cells | CD4+ |
MHC class I molecules are localized on all nucleated cells and present endogenous peptides. MHC class II molecules are expressed on antigen-presenting cells and present exogenous antigens. CD8 and CD4 co-receptors bind to the corresponding MHC molecules, increasing the affinity of the receptor complex for the ligand.
To evaluate the properties of a strong antigen, use the "MEDS" rule: Mass (large), Epitopes (optimal density), Rigidity (stable conformation), Degradation (susceptibility to enzymatic cleavage).
Class and exam questions
What is the difference between PAMPs and antigens?
PAMPs (pathogen-associated molecular patterns) are recognized by innate immunity receptors and serve as primary danger signals. Antigens, however, are recognized by specific receptors of T and B lymphocytes, triggering an adaptive immune response.
Why might immunogenicity decrease as the number of epitopes increases?
When epitope density on a molecule is too high, steric (spatial) hindrance occurs. Recognizing groups mutually mask and block each other, making it difficult for them to bind to receptors.
Can a substance be non-immunogenic due to the absence of enzymes in the body?
Yes. To trigger a thymus-dependent response, the antigen molecule must be cleaved (processed) into small fragments. If the organism lacks suitable enzymes, the degradation process is impossible, and the substance will not provoke a strong immune response.
What else to study on this topic
- Mechanisms of autoimmune pathologies and molecular mimicry
- Antigen processing and presentation to T cells
- Structure and functions of the major histocompatibility complex (MHC)
- Cooperation of T-helper and B-lymphocytes
- Effect of adjuvants on immunogenicity
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