Local defense mechanisms
Complex sets of factors operate in special areas of the body to restrain the aggression of the immune system:
- Soluble mediators: suppressive cytokines (TGFβ, IL-10), as well as neuropeptides and hormones (somatostatin, calcitonin, ACTH) are released.
- Complement regulation: control proteins rapidly inactivate components of the complement system.
- Cellular composition: such tissues contain few antigen-presenting cells (APCs) expressing MHC-II molecules, but are rich in regulatory T cells (Tregs).
In addition to passive barriers, active isolation operates. Tissue barrier cells express molecules that trigger apoptosis. For example, FasL binds to CD95 on activated effector T cells, and the TRAIL molecule transmits a death signal via the DR5 receptor. Thus, cytotoxic lymphocytes that overcome the barrier are eliminated.
Systemic defense level
Since local barriers do not provide an absolute guarantee, a systemic response is engaged, which is referred to as "truncated". If a foreign antigen enters, for example, the anterior chamber of the eye, the body reacts differently than usual:
- Regulatory T cells are formed.
- Delayed-type hypersensitivity (DTH) is significantly attenuated.
- Antibodies of the IgG2, IgG4, and IgA isotypes that do not fix complement are synthesized.
Risk of tolerance breakdown
The body has no systemic tolerance to the antigens of privileged zones because they were hidden during the period of immune system formation. Compromising the integrity of the barrier threatens the development of an autoimmune disease—a sort of "price for privilege".
The breakdown process is triggered if trauma is accompanied by inflammation. PAMP molecules activate innate immunity, enhancing the expression of MHC-II and costimulatory molecules on APCs. The secreted cytokines direct the response along destructive Th1 and Th17 pathways.
Modern view on privileged zones
Today, these organs include not only traditional barrier structures, but also the developing fetus, the intestinal mucosa (where a response is mounted only against pathogens while ignoring food and normal flora), and tumors that use similar mechanisms of evasion from the immune system.
The fetus is a genetically foreign allograft. Its protection is ensured not by immunological immaturity, but by the specific structure of the placenta. The main role is played by the trophoblast — its cells lack MHC-II molecules and are uniquely devoid of MHC-I molecules, which are normally present on all nucleated cells. Interestingly, the greater the genetic differences between mother and fetus, the larger the placenta forms and the more favorable the pregnancy course.
Briefly: answers to topical questions
Which human organs are classified as classic immune-privileged?
Classic immune-privileged organs include:
- Inner chambers of the eye.
- Brain (CNS).
- Testes.
- Ovaries.
- Hair follicles.
- Pregnant uterus.
The biological significance of immune privilege lies in preventing the inflammatory reaction that accompanies the immune response, since inflammation can damage the organ more severely than the pathogen.
Which specific autoimmune diseases develop when the barriers of immune-privileged organs are disrupted?
When the blood-tissue barriers of immune-privileged organs are disrupted, specific autoimmune diseases develop, affecting previously isolated tissues. Specific clinical forms of such pathology include:
- Thyroiditis — an autoimmune condition of the thyroid gland (occurring when the blood-thyroid barrier is compromised).
- Sympathetic ophthalmia — damage to a healthy eye following trauma to the contralateral eye.
- Orchitis — autoimmune inflammation of the testis (e.g., non-infectious granulomatous orchitis).
- Encephalitis — autoimmune involvement of the brain.
These conditions arise because the antigens of these organs do not normally come into contact with lymphocytes, and when the barrier is breached, the immune system triggers autoaggression.
Through which mechanisms, aside from the absence of classic MHC molecules, does the trophoblast protect the fetus from rejection?
In addition to the absence of classic MHC molecules, the trophoblast and placenta protect the fetus through a complex of mechanisms:
- Physical barrier.
- Complement-regulating proteins.
- Immunoregulatory cells: Treg, Th3, and Th2 cells.
- Antibody trap antigens.
- Indoleamine 2,3-dioxygenase of antigen-presenting cells, creating a tryptophan-depleted microenvironment.
- Non-classical MHC-I molecules: HLA-G and HLA-E, which block NK cell activity and other lymphocyte functions. HLA-G also suppresses the ability of cytotoxic lymphocytes to secrete IFNγ.
Which non-classical major histocompatibility complex molecules are expressed on trophoblast cells?
Trophoblast cells, especially villous cytotrophoblast cells, express non-classical class Ib MHC-I molecules:
- HLA-G — binds to LILRB1 receptors and blocks lymphocyte activity, primarily NK cells; membrane-bound and soluble isoforms exist, notably G5.
- HLA-E — participates in blocking the cytolytic activity of lymphocytes.
- HLA-F — expressed to a lesser extent.
These molecules are characterized by limited polymorphism and presumably do not participate in antigen presentation.
Class and exam questions
Why doesn't the mother's immune system reject the fetus?
The fetus is a unique immune-privileged organ. It is protected by the trophoblast, whose cells physiologically do not express histocompatibility antigens (class I and II MHC), rendering the fetus "invisible" to maternal T lymphocytes.
What is the "price of privilege"?
This carries a high risk of developing autoimmune inflammation. Since the antigens of isolated organs are unknown to the immune system, a barrier breach in the setting of infection or trauma triggers an aggressive immune response against them.
How does active isolation work in such organs?
Special molecules (FasL, TRAIL) are present on barrier cells. When aggressive activated T cells attempt to penetrate the organ, these molecules bind to lymphocyte receptors and trigger apoptosis (programmed cell death) within them.
What else to study on this topic
- The role of suppressive cytokines (TGFβ, IL-10) in the microenvironment
- Specifics of the "truncated" immune response (using the eye as an example)
- Pathogenesis of Th1- and Th17-mediated autoimmune reactions
- Mechanisms of tumor immune evasion
- Features of intestinal mucosal immunity
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Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
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