Stages of the primary response
The process of immune formation in mucous membranes closely connects barrier tissues and regional lymph nodes. It includes three functional links:
- Afferent link: Dendritic cells (DCs) engulf the antigen in the mucous membrane and migrate with it to the nearest regional lymph node.
- Central link: Antigen presentation to naive T lymphocytes takes place. Their differentiation is triggered: CD4+ cells turn into T helpers (Th1, Th2), CD8+ into cytotoxic lymphocytes, and B lymphocytes into plasma cells. As a result, effector cells and memory cells are formed.
- Efferent link: Activated lymphocytes leave the lymph node, enter the systemic circulation, and migrate back to the mucous membranes to carry out defense functions.
Homing and imprinting mechanisms
The return of effector cells to tissues is called homing. It is strictly determined and depends on the expression of specific adhesion molecules and chemokine receptors on the lymphocyte surface. The direction of movement is set by dendritic cells during antigen presentation — this phenomenon is termed imprinting.
For example, if a DC captures an antigen in the small intestine, it begins to produce retinoic acid. This induces the activated T lymphocyte to express integrin α₄β₇ and the CCR9 receptor. Entering the bloodstream, such a lymphocyte "recognizes" intestinal vessels via the MadCAM ligand and the CCL25 chemokine, after which it exits specifically into this tissue. In the respiratory tract, migration is less specific, but the chemokine CCL5 and its receptor CCR5 play an important role.
Secretory IgA and its functions
The main effector factor of mucosal immunity is secretory IgA (sIgA). Initially, local plasmacytes secrete the molecule as a dimer. To enter the lumen of an organ (e.g., the intestine), IgA binds to the polymeric immunoglobulin receptor (pIgR) on the epithelial basal membrane.
Next, the complex is transported to the apical membrane. There, the receptor is cleaved, but its fragment remains on the antibody molecule as the secretory component (SC). It is this component that protects sIgA from cleavage by local proteases.
Functions of sIgA in mucosa:
- Immobilization (depriving microorganisms of mobility).
- Blockade of pathogen adhesion to the epithelium.
- Facilitation of antigen uptake by M cells for subsequent presentation.
Important: sIgA does not activate the complement system.
Secondary immune response in mucosa
Upon re-exposure to a pathogen, the mucosal response develops much faster and more powerfully, and is executed by "local" cells.
Previously formed memory cells are already localized in barrier tissues: CD8+ in the epithelial layer, and CD4+ and B cells in the submucosa. In the zone of the so-called M-cell "pocket", memory B lymphocytes themselves are capable of acting as antigen-presenting cells. They activate memory T cells on site. Thus, the regional lymph node ceases to be the main site for triggering immune reactions.
Briefly: answers to topical questions
Which adhesion molecules and chemokines ensure the homing of effector lymphocytes to the respiratory tract mucosa?
The homing of effector lymphocytes to the respiratory tract mucosa is ensured by a complex of specific receptors and integrins. There is no single specific "guide" for this tract.
- Adhesion molecules — migration is mediated by integrin α₄β₁.
- Chemokine receptors — CCR5 and CCR10 receptors are expressed on the lymphocyte surface.
- Chemokines — a key role is played by the chemokine CCL5 (RANTES), which is spontaneously produced by lung stromal cells and recognized by the CCR5 receptor.
What cytokines do Th1 and Th2 lymphocytes secrete in the lamina propria of mucous membranes?
Effector Th1 and Th2 lymphocytes secrete specific sets of cytokines that determine the type of immune response in mucous membranes.
- Th1 lymphocytes — produce IFNγ, IL-2, TNFα, TNFβ, IL-3, and GM-CSF. The key cytokine is IFNγ.
- Th2 lymphocytes — secrete IL-4, IL-13, IL-5, IL-6, IL-9, IL-11, IL-21, IL-25, IL-10, IL-3, and GM-CSF. The key cytokine is IL-4.
Common cytokines for both subpopulations are GM-CSF and IL-3 (in humans, also IL-10).
Which classes of immunoglobulins, besides IgA, can be transported across the epithelium via the polymeric immunoglobulin receptor (pIgR)?
In addition to dimeric IgA molecules, IgM class antibodies can be transported across the epithelial layer via the polymeric immunoglobulin receptor (pIgR).
- Immunoglobulin M (IgM) — binds to the pIgR receptor in the form of a pentamer, although this process occurs to a lesser extent compared to IgA.
The receptor-immunoglobulin complex is internalized by the epithelial cell and transported in a vesicle from the basal to the apical pole for subsequent secretion into the organ lumen.
What are the main functions of M cells (microfold cells) in the follicle-associated epithelium?
The main functions of specialized M cells include binding and presentation of antigens without prior stimulation, transport of antigens across the epithelial barrier, and cytokine secretion. Secretory IgA prevents microorganisms from penetrating through the epithelium bypassing M cells.
To remember migration receptors more easily, use a number association: the intestine loves "nines" and "sevens" (chemokine receptor CCR9 and integrin α₄β₇), while the respiratory tract is associated with "fives" (chemokine CCL5 and receptor CCR5).
Class and exam questions
Why is secretory IgA not degraded by enzymes in the intestine?
During passage through the epithelial cell, a part of the transport receptor — the secretory component (SC) — attaches to the IgA molecule. It shields the antibody and makes it resistant to digestive tract proteases.
How does a lymphocyte "understand" which specific mucosa it needs to return to from the bloodstream?
The imprinting mechanism operates. During education in the lymph node, a local dendritic cell programs the T lymphocyte to express on its surface a unique set of integrins and receptors that match only the vascular endothelium of the tissue from which this dendritic cell came.
Is a lymph node necessary to trigger a secondary immune response in mucosal tissues?
No, it is not obligatory. In a secondary response, antigen presentation is facilitated and occurs directly in the barrier tissue. The role of antigen-presenting cells is often assumed by local memory B lymphocytes.
What else to study on this topic
- Regulation and tolerance mechanisms: the role of Tr1 (IL-10) and Th3 (TGFβ)
- Influence of the microenvironment on T helper differentiation (shift towards Th2)
- Antibody synthesis dynamics: switching from IgM to IgA
- Migration of intraepithelial lymphocytes and their life cycle
- Factors enhancing lymphocyte migration during an inflammatory reaction
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