Phases of DTH Development
The pathogenesis of type IV hypersensitivity is strictly divided into two stages, separated by the time required for the restructuring of the immune system.
1. Sensitization phase (primary contact) The process begins when an antigen enters the body. If it is a low-molecular-weight substance (hapten), it first binds to the body's own proteins, transforming into a full-fledged antigen. Dendritic cells then come into play: they capture the foreign agent, process it, and present it to naive T helper cells (Th0). As a result of this interaction, a specific clone of inflammatory T lymphocytes—Th1—is formed.
2. Effector phase (re-exposure) Upon re-exposure to the same antigen, it is presented to pre-formed Th1 lymphocytes. Activated cells begin actively producing cytokines:
- Chemokines act as "beacons," attracting numerous macrophages to the site of inflammation.
- Interferon-gamma (IFN-γ) powerfully activates the arriving macrophages, shifting them into a state of high aggressiveness.
Mechanisms of tissue damage
The primary damage to own tissues in DTH is caused by the secretory products of activated macrophages. Morphologically, this manifests as tissue induration and inflammation.
Factors of tissue destruction include:
- Hydrolytic enzymes that destroy structural elements of cells.
- Reactive oxygen species (ROS) and nitric oxide, causing potent oxidative stress.
- Pro-inflammatory cytokines.
- TNF-α (tumor necrosis factor-alpha), which is secreted by macrophages and is a key link in granuloma formation.
In addition to macrophages, cytotoxic T cells (CD8+) may operate at the site. They secrete their own cytokines and are capable of directly destroying target cells if the «MHC I + allergen» complex is presented on their surface.
Vascular reaction The vascular endothelium in the affected area is also involved in the process. Endothelial cells begin to actively express adhesion molecules (for the "sticking" of new leukocytes from the bloodstream) and class MHC II molecules.
If DTH transitions into a chronic form, the continuous secretion of growth factors by macrophages inevitably leads to fibrosis—the excessive proliferation of connective (scar) tissue.
Clinical Forms and Autoimmune Pathology
In medical practice, type IV hypersensitivity most commonly occurs in two variants:
- Contact DTH. The triggers are haptens that are part of medications or cosmetics. By binding to tissue proteins, they trigger an immune response.
- Infectious DTH. It accompanies diseases with a chronic course or intracellular localization of the pathogen. These include tuberculosis, leprosy, brucellosis, tularemia, toxoplasmosis, and deep mycoses.
Role in autoimmune diseases DTH underlies many organ-specific autoimmune pathologies, where aggression is directed against one's own tissues by autoreactive T lymphocytes. A classic example is insulin-dependent diabetes mellitus (type 1). In this disease, the islets of Langerhans in the pancreas are infiltrated by lymphocytes and macrophages. The result is the complete destruction of β-cells and critical insulin deficiency.
Laboratory Allergy Diagnostics
Since the immune system "remembers" the antigen in infectious DTH, this property is used for diagnostics. The presence of reactivity indicates that the body has previously encountered the pathogen.
Principles of skin allergy tests:
- Preparations: Specific microbial allergens are used. For tuberculosis, it is tuberculin; for leprosy, lepromin; for brucellosis, brucellin; for tularemia, tularin; for toxoplasmosis, toxoplasmin.
- Administration: The preparation is administered strictly intradermally.
- Evaluation: The result is checked after 24–48 hours. The delay is necessary for the cells to migrate to the site.
- Positive reaction: Manifests as the formation of a papule (induration, cellular infiltrate) consisting of macrophages, monocytes, and lymphocytes.
In complex cases, to confirm the cellular composition of the infiltrate, a histological examination of a skin biopsy may additionally be performed.
Briefly: answers to topical questions
What cytokines do Th1 lymphocytes secrete during the effector phase of DTH?
During the effector phase of DTH, Th1 lymphocytes secrete cytokines and factors that ensure the recruitment and activation of macrophages:
- Interferon-gamma (IFN-γ) activates macrophages.
- Macrophage chemotactic factor (MCF) and macrophage migration inhibitory factor (MIF) are involved in recruiting macrophages to the site.
- Chemokines attract macrophages to the site.
Th1 cells also secrete IL-2, TNF, and GM-CSF.
Which autoimmune diseases develop via the type IV hypersensitivity mechanism?
Autoimmune diseases caused by autoreactive T lymphocytes develop via the type IV hypersensitivity mechanism.
- Insulin-dependent type 1 diabetes mellitus — infiltration of the islets of Langerhans by lymphocytes and macrophages leads to the destruction of β-cells and insulin deficiency.
- Multiple sclerosis is an example of T cell-mediated immune tissue damage.
How does type IV hypersensitivity differ from immediate-type reactions (types I-III)?
The main difference between type IV hypersensitivity (DTH) and immediate-type hypersensitivity (ITH) lies in the cell-mediated mechanism and delayed development.
| Sign | ITH (types I–III) | DTH (type IV) |
|---|---|---|
| Basis of the reaction | Interaction of antigen with antibodies | Interaction of antigen with cells (macrophages and Th1 lymphocytes) |
| Time of development | Acute immune inflammation | Develops 24–72 hours after re-exposure |
| Morphology | Destructive and exudative changes (edema, plasmarrhagia, fibrinoid necrosis) | Cellular (proliferative) nature (lymphohistiocytic infiltrates, granulomas) |
| Vascular damage | Destructive-exudative vasculitis | Productive vasculitis |
What cytokines stimulate the differentiation of naive T helper cells (Th0) into Th1?
The differentiation of naive T helper cells (Th0) into the Th1 subpopulation is stimulated by specific cytokine signals from antigen-presenting cells and the microenvironment.
- Interleukin-12 (IL-12) is the primary inducer and signal from the antigen-presenting cell that triggers the differentiation of CD4+ Th0 lymphocytes.
- Interferon-gamma (IFN-γ) also stimulates the differentiation of naive T-helper cells into Th1 and, together with antagonists, maintains the Th1/Th2 balance in the body.
Class and exam questions
Why is type IV hypersensitivity called "delayed"?
Unlike immediate-type allergies (antibody-mediated), DTH requires time to develop—usually 24–72 hours. This period is necessary for macrophages and T lymphocytes to migrate to the site of antigen entry and mount the cellular response.
Which cell controls the entire process in DTH?
The primary regulator is the Type 1 T-helper cell (Th1). Upon recognizing an antigen, it releases interferon-gamma and chemokines, which recruit macrophages and dramatically increase their aggressiveness.
What does the induration represent in a positive Manttu (tuberculin skin) test?
The papule (induration) that appears after intradermal tuberculin administration is a typical cellular infiltrate. Pathomorphologically, it consists of an accumulation of immunocompetent cells: lymphocytes, monocytes, and macrophages.
What else to study on this topic
- Mechanism of antigen processing and presentation to a naive T-helper cell (Th0)
- Molecular effects of interferon-gamma (IFN-γ) on macrophages
- The process of granuloma formation under the influence of TNF-α
- Pathogenesis of fibrosis in the chronic course of DTH
- Features of CD8+ T-killer cell action in tissues
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