Evolution of concepts of "non-self" recognition
Until the late 1980s, the prevailing scientific view was that the ability to recognize foreign agents belonged exclusively to lymphocytes. It was believed that they react specifically to individual antigens, whereas myeloid cells (such as phagocytes) simply destroy any cells without any specific recognition.
The modern concept developed by scientists Ch. Janeway (Ch. Janeway) and R. Medzhitov radically changed this view. It is based on the idea of interaction between innate and adaptive immunity through the mechanism of pattern recognition. The English term pattern in this context is translated as "image" [obraz]. Innate immunity cells recognize not unique molecules, but typical chemical groups characteristic of foreign and dangerous microorganisms. These universal structures have been named pathogen-associated patterns, or pathogen-associated molecular patterns (PAMPs).
Key features of PAMPs
For a molecule to serve as a reliable marker for the immune system, it must possess three key characteristics:
- Foreignness. The molecular pattern is characteristic of an entire species of microorganisms, rather than a specific individual.
- Association with pathogenicity. The presence of these structures directly indicates the potential danger and pathogenic properties of the microbe.
- Conservatism. These are stable elements that are critically important for the survival of bacteria or viruses, which is why they very rarely and slightly change during evolution.
It is this combination of properties that gives the immune system a huge advantage: using a very limited set of receptors, it is able to flawlessly detect a threat at the earliest stages.
Classification of pattern recognition receptors
Innate immunity receptors that interact with PAMPs are classified by their localization. Such division allows the organism to monitor all possible pathways of infection entry.
1. Membrane receptors
They are located on the cell surface, ensuring the detection of PAMPs in the extracellular environment and the instantaneous transmission of a signal ("alert") inward.
- Toll-like receptors (TLRs 1–11): bind pathogen-associated molecular patterns and activate innate immune cells.
- C-type lectins: recognize carbohydrate residues, their main function being internalization (uptake) of the target.
- Scavenger receptors: bind lipoproteins, lipopolysaccharide, lipoteichoic acid, and own apoptotic cells for subsequent internalization.
- Integrins: react with immunoglobulin superfamily receptors and extracellular matrix proteins, being responsible for adhesion and mobility.
2. Intracellular (cytosolic) receptors
They are located in the cytosol or on the membranes of intracellular granules. They are vital for combating intracellular pathogens whose patterns are not visible from the outside.
- NOD-like receptors (NLRs): detect peptidoglycans.
- RIG-like receptors (RLRs): recognize foreign RNA.
- DAI: react with DNA fragments.
All intracellular receptors perform the function of activating innate immune cells.
3. Soluble (secreted) receptors
These include long-known humoral factors circulating in body fluids.
- Pentraxins: bind PAMPs, immunoglobulins, matrix proteins, histones, etc. They mediate chemotaxis and complement activation.
- Collectins: recognize carbohydrate residues and immunoglobulin Fc fragments (complement activation).
- Complement components: react with proteins and polysaccharides, triggering opsonization, cytolysis, and chemotaxis.
- Ficolins: bind polysaccharides, TGF-β, and membrane proteins, promoting opsonization.
Discovery of Toll-like receptors
The discovery of TLRs (Toll-like receptors) was a turning point in immunology. Initially, the Toll gene (named after a German interjection expressing surprise) was first described in Drosophila fruit flies as a gene responsible for the correct dorso-ventral orientation of the embryo body.
Later, researchers discovered its immense pathogenetic significance: mutations in Toll genes in Drosophila were found to lead to a complete loss of resistance to fungal infections. Based on these findings, R. Medzhitov and co-authors discovered homologs of Toll genes and their protein products in mammals. They were named Toll-like receptors and are recognized today as a crucial component of the innate immune system.
Briefly: answers to topical questions
Which specific ligands are recognized by various types of Toll-like receptors (TLR1–TLR11)?
Various types of Toll-like receptors recognize specific structural components of microorganisms and endogenous molecules.
- Toll-like receptors 1 and 2 (TLR1, TLR2) — triacylated lipopeptide.
- Toll-like receptors 2 and 6 (TLR2, TLR6) — mycoplasma diacylated lipopeptide.
- Toll-like receptor 4 (TLR4) — Gram-negative bacterial lipopolysaccharide, heat shock protein 60 (HSP60), fibronectin, fibrinogen, hyaluronic acid.
- Toll-like receptor 5 (TLR5) — flagellin.
- Toll-like receptor 11 (TLR11) — uropathogenic bacterial patterns.
Intracellular receptors (TLR3, TLR7, TLR8, TLR9) specialize in recognizing nucleic acids. Specific ligands for TLR10 have not been identified.
Which intracellular signaling pathways and transcription factors are activated when PAMPs bind to TLRs?
When PAMPs bind to TLRs, two main signal transduction pathways and their associated transcription factors are activated.
- MyD88-dependent pathway — signal transduction via MyD88 and Mal adapter proteins, followed by activation of the IRAK/IRAK4 → TRAF6 → TAK1 cascade.
- MyD88-independent pathway — characteristic of TLR3 and TLR4; utilizes the TRIF adapter, and for TLR4 also TRAM. NF-κB is activated via RIP1, and IRF3 via TRAF3, TBK1, and IKKε.
- MAP kinase cascade: TAK1 activates JNK and p38, which are involved in the formation of the AP-1 transcription factor.
- NF-κB — activates pro-inflammatory cytokine genes.
- AP-1 — participates in the activation of immunologically relevant genes.
- IRF3 — activates interferon genes, predominantly IFN-β.
- IRF7 — activates the IFN-α gene; sources also note its involvement in turning on IFN-α and IFN-β genes.
Which specific cells of the body express pattern recognition receptors?
Pattern recognition receptors are expressed by a wide range of cells of the immune system and barrier tissues.
- Innate immune cells — monocytes, macrophages, neutrophils, eosinophils, mast cells, natural killer cells, dendritic cells.
- Adaptive immune cells — B cells, T cells, and natural regulatory T cells.
- "Non-professional" cells — vascular endothelium and epithelial cells of barrier tissues.
C-type lectin receptors are predominantly expressed on actively pinocytosing (immature dendritic cells) and phagocytosing cells (monocytes, macrophages).
To memorize the localization of receptors, imagine a fortress: membrane-bound ones are the sentinels on the walls (TLRs, C-type lectins), intracellular ones are the inner guard in the rooms (NLRs, RLRs), and soluble ones are patrols roaming the surrounding area (pentraxins, complement).
Class and exam questions
What is the key difference between pattern recognition and antigen recognition?
Pattern recognition is evolutionarily more ancient, simpler in design, and functions reliably without the risk of autoimmune aggression. However, unlike the response to antigens, it does not generate immunological memory.
What is the purpose of scavenger receptors?
These are scavenger receptors that bind bacterial lipopolysaccharides and lipoteichoic acids, as well as endogenous lipoproteins and apoptotic cells, ensuring their uptake (internalization).
Which receptors respond to intracellular pathogens?
This task is performed by cytosolic receptors: NOD-like receptors (NLRs) bind peptidoglycans, RIG-I-like receptors (RLRs) bind RNA, and DAI receptors respond to DNA. All of them activate immune cells.
What else to study on this topic
- Mechanisms of interaction between innate and adaptive immunity
- Detailed characteristics of Toll-like receptor ligands (TLR 1–11)
- Humoral factors of innate immunity: acute-phase proteins and complement
- Pathogen internalization: the role of C-type lectins and scavenger receptors
- Intracellular signal transduction upon pattern recognition receptor activation
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