Phases of DTH Development
The pathogenesis of type IV hypersensitivity is strictly divided into two phases, separated by the time required for the immune system to mount a secondary response.
1. Sensitization Phase (Primary Contact) The process begins when an antigen enters the body. If the substance is a low-molecular-weight compound (hapten), it first binds to host proteins, converting into a complete antigen. Next, dendritic cells capture the foreign agent, process it, and present it to naive T helper cells (Th0). This interaction generates a specific clone of inflammatory T lymphocytes, known as Th1 cells.
2. Effector Phase (Secondary Contact) Upon re-exposure to the same antigen, it is presented to pre-sensitized Th1 lymphocytes. These activated cells rapidly produce cytokines:
- Chemokines — act as chemotactic signals, recruiting numerous macrophages to the site of inflammation.
- Interferon-gamma (IFN-γ) — powerfully activates recruited macrophages, shifting them into a highly aggressive state.
Mechanisms of Tissue Damage
The primary tissue injury in DTH is caused by secretory products of activated macrophages. Morphologically, this presents as tissue induration and inflammation.
Factors contributing to tissue destruction include:
- Hydrolytic enzymes, which degrade structural cellular elements.
- Reactive oxygen species (ROS) and nitric oxide, causing severe oxidative stress.
- Pro-inflammatory cytokines.
- TNF-α (tumor necrosis factor-alpha), secreted by macrophages and playing a pivotal role in granuloma formation.
In addition to macrophages, cytotoxic T cells (CD8+) may operate at the site. They secrete their own cytokines and can directly destroy target cells presenting the MHC I + antigen complex.
Vascular Response Blood vessel endothelium in the affected area is also involved. Endothelial cells upregulate adhesion molecules (to capture passing leukocytes from the bloodstream) and MHC class II molecules.
If DTH transitions into a chronic form, continuous secretion of growth factors by macrophages inevitably leads to fibrosis — excessive proliferation of connective (scar) tissue.
Clinical Forms and Autoimmune Pathology
In medical practice, type IV hypersensitivity most commonly manifests in two forms:
- Contact DTH. Triggers include haptens found in medications or cosmetics. By binding to tissue proteins, they trigger an immune response.
- Infectious DTH. Associated with chronic infections or intracellular pathogens. Examples include tuberculosis, leprosy, brucellosis, tularemia, toxoplasmosis, and deep mycoses.
Role in Autoimmune Diseases Type IV hypersensitivity underlies many organ-specific autoimmune pathologies, where tissue injury is driven by autoreactive T lymphocytes.
A classic example is insulin-dependent diabetes mellitus (type 1). In this condition, the islets of Langerhans in the pancreas are infiltrated by lymphocytes and macrophages, resulting in the complete destruction of β-cells and a critical insulin deficiency.
Laboratory Allergy Diagnostics
Because the immune system "remembers" the antigen in infectious DTH, this property is utilized for diagnostic testing. Positive reactivity indicates previous exposure to the pathogen.
Principles of Skin-Allergy Tests:
- Agents: Specific microbial antigens are used. Examples include tuberculin for tuberculosis, lepromin for leprosy, brucellin for brucellosis, tularin for tularemia, and toxoplasmin for toxoplasmosis.
- Administration: The agent is injected strictly intradermally.
- Evaluation: Results are read after 24–48 hours, allowing sufficient time for cells to migrate to the site.
- Positive Reaction: Manifests as a papule (induration, cellular infiltrate) composed of macrophages, monocytes, and lymphocytes.
In complex cases, histological examination of a skin biopsy may be performed to confirm the cellular composition of the infiltrate.