Mechanism of immunological tolerance development
When molecules lacking PAMPs (such as dietary proteins or harmless aeroantigens) enter the intestinal lumen or respiratory tract, a cascade of reactions is triggered, leading to T-lymphocyte anergy.
The process begins with the capture of antigens by epithelial M cells. Since there are no danger markers, innate immune cells are not activated. Instead, they secrete suppressive factors: macrophages secrete PGE2, and epithelial cells secrete TGFβ and TSLP.
In this microenvironment, a special tolerogenic phenotype of dendritic cells is formed — DC2. During migration to lymph nodes, they:
- Weakly express MHC molecules and costimulatory molecules (CD80, CD86).
- Secrete IL-10 (suppresses cellular immunity).
- Do not synthesize IL-12 at all.
Interacting with CD4+ T cells via the co-inhibitory molecule CTLA-4, tolerogenic dendritic cells block their activation. As a result, anergy or accelerated apoptosis of effector T lymphocytes is induced, while regulatory subpopulations (Tr1 and Th3) develop instead, secreting IL-10 and TGFβ, thereby reinforcing the state of non-responsiveness.
Triggering an active immune response
If an antigen carries PAMPs (is a pathogen), events unfold according to a different scenario. The reaction takes place against the background of a potent pro-inflammatory response by innate immune cells.
Having recognized the pathogen, macrophages and epithelial cells sharply reduce the production of suppressive factors and begin secreting pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-1β) and chemokines. This attracts leukocytes from the bloodstream and predetermines the formation of immunogenic dendritic cells — DC1.
Cells of the DC1 phenotype are distinguished by enhanced expression of costimulatory molecules and active secretion of IL-12. Migrating to lymph nodes, they bind to CD4+ T lymphocytes via the CD28 receptor. This leads to the differentiation of effector cells:
- Th1 cells trigger a robust cellular immune response.
- Th2 cells secrete IL-4 and IL-5, stimulating enhanced synthesis of secretory IgA.
Consequences of tolerance breakdown
Normally, tolerance protects us from reactions to food and commensal microflora (which, although having PAMPs, possess a set of them that predominantly induces tolerogenic effects). Disruption of these mechanisms leads to severe pathologies:
- Food allergy — hyperreactivity of Th2 lymphocytes and IgE+ B cells. It can manifest as severe forms of intolerance, such as to gluten.
- Respiratory allergy — occurs when tolerance to aerogenic antigens is impaired (it is much more common than food allergy).
- Inflammatory bowel disease (IBD) — the result of a breakdown in tolerance to own microflora:
- Crohn's disease: a Th1 response predominates with an excess of IFNγ and TNFα.
- Ulcerative colitis: hyperactivation of Th2 cells with hypersecretion of IL-4 and IL-13.
Immunologically privileged organs
The concept of avoiding an immune response applies not only to mucosal surfaces. There are organs (the brain, internal chambers of the eye, testes, pregnant uterus) whose damage by an inflammatory process is unacceptable from an evolutionary standpoint — inflammation will harm them more than the pathogen itself. Immunological privileges are formed within them.
Protection of such zones is ensured by three echelons:
- Isolation (local, passive): the presence of tight tissue barriers (e.g., blood-ocular barrier) and the absence of lymphatic drainage.
- Immunosuppression (local, active): a deficiency of antigen-presenting cells and the presence of local suppressive factors.
- Immunoregulation (systemic, active): the action of regulatory T cells.
Clinically important: organ isolation is never absolute. T lymphocytes capable of recognizing antigens of isolated tissues always circulate in the body if the barrier is damaged.
Briefly: answers to topical questions
What markers do dendritic cells express upon contact with pathogens in mucosal surfaces?
Upon entry of antigens bearing PAMPs, an immunogenic phenotype of dendritic cells (DC1) is formed: the expression of costimulatory molecules CD80 and CD86 increases. Mature myeloid dendritic cells are also characterized by significant expression of MHC-II, the presence of CD11c, and the mature DC marker CD83. Activation of DCs in the presence of pathogens can occur via TLR-2 and TLR-4.
What is the precise receptor sequence during antigen presentation to T helpers by tolerogenic DCs?
The sources do not specify a step-by-step interaction sequence, but they describe the following profile of tolerogenic dendritic cells: weak expression of MHC and costimulatory molecules CD80 and CD86; interaction with CD4+ T cells occurs with the participation of the co-inhibitory molecule CTLA-4. Such interaction does not lead to the activation, proliferation, and differentiation of CD4+ T cells into T helpers, but induces T lymphocyte anergy and promotes the development of regulatory T cells.
To avoid confusing cytokines and cells, use the mnemonic: DC0 (DC2) secrete IL-10 (zero inflammation), generating regulatory cells. DC1 secrete IL-12 (one-two — alarm signal), triggering inflammation via Th1 and Th2.
Class and exam questions
Why doesn't normal intestinal microflora cause inflammation if bacteria have PAMPs?
Symbiotic microorganisms do express PAMPs, yet their qualitative pattern differs from the patterns of true pathogens. When commensals interact with mucosal immune cells, tolerogenic signals predominate.
What is the role of Peyer's patches in the development of food tolerance?
Peyer's patches are the primary site where dendritic cells first encounter dietary antigens entering via M cells. If these structures are absent, the development of oral tolerance is impossible.
Does antibody synthesis cease during the formation of immunological anergy in the intestine?
No, the synthesis of secretory IgA is preserved. This is the only component of the immune response that is active in both cases: during the inflammatory response to a pathogen and during tolerance to food.
What else to study on this topic
- Molecular mechanisms of the co-inhibitory molecule CTLA-4
- Structural features and functions of intestinal epithelial M cells
- Cytokine profiles in inflammatory bowel disease (IBD)
- Active mechanisms of immunosuppression in immunologically privileged organs
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