Stages of DTH development
The pathogenesis of type IV hypersensitivity has a pronounced "biphasic" character: the inductive and effector phases are clearly separated in time.
1. Sensitization phase
The initial exposure to the antigen is macroscopically asymptomatic. Antigen-presenting cells (APCs), such as Langerhans cells in the skin, capture the antigen and migrate to regional lymph nodes. There, they present it to naive CD4+ T-lymphocytes, leading to clonal expansion and the formation of effector Th1 cells. Due to the expression of chemokine receptors (CXCR3, CCR5, CCR2), Th1 cells acquire the ability to migrate into tissues. Sensitization lasts 20–30 days.
2. Effector phase
Develops upon repeated exposure to the antigen. Sensitized Th1 cells migrate to the lesion and are activated by local APCs. Activated T-helper cells release factors that attract and retain macrophages. Th1 interaction with macrophages occurs via contact (through CD40) and humorally (via IFNγ). Macrophages become hyperactivated, releasing aggressive substances (oxidative burst products, hydrolases), which causes inflammation and tissue damage.
Variants of sensitization
Antigen capture mechanisms differ depending on its nature.
- Microbial sensitization (tuberculin-type reaction). Caused by intracellular bacteria. Dendritic cells capture and process bacterial antigens directly, after which they present them to T-lymphocytes.
- Contact sensitization. Triggered by haptens (drugs, dyes, metals like nickel). A hapten is a low-molecular-weight substance that is not immunogenic on its own. To be recognized by Langerhans cells, it must first penetrate the skin and bind to the body's endogenous protein. Only such a complex is able to trigger Th1 differentiation.
Clinical significance and pathogenesis
Type IV reactions play a dual role. On the one hand, DTH accompanies immune defense in severe chronic infections (tuberculosis, leprosy). On the other hand, an excessive reaction leads to significant damage to the body's own tissues.
Clinical manifestations of DTH include:
- Formation of granulomas due to macrophage hyperactivation and lymphoid cell proliferation.
- Development of contact dermatitis upon chronic exposure to haptens (manifested by epidermal edema, mononuclear infiltration, and microvesicles).
- Participation in the pathogenesis of autoimmune diseases (e.g., psoriasis).
A distinct variant is the Jones–Mote reaction (cutaneous basophil hypersensitivity), occurring in response to low doses of protein, where the infiltrate is dominated not by macrophages, but by basophils.
Briefly: answers to topical questions
Which cytokines, besides interferon-gamma, do Th1 lymphocytes secrete during the effector phase of DTH?
In addition to IFNγ, Th1 cells during the effector phase of DTH release MCF and MIF factors.
- MCF (macrophage chemotactic factor) — attracts macrophages to the lesion site
- MIF (macrophage migration inhibitory factor) — promotes the accumulation of macrophages in the lesion site
Which intracellular pathogens cause microbial sensitization in DTH?
Microbial sensitization in the tuberculin-type reaction is caused by intracellular bacteria, in particular the causative agents of tuberculosis and leprosy, as well as Gram-negative bacteria that persist intracellularly.
- Mycobacterium tuberculosis and leprae — chronic granulomatous infections with DTH
- Rhinoscleroma agent — intracellular localization causes DTH in the chronic form
- Brucella, Legionella, Francisella tularensis, and Coxiella burnetii — multiply inside phagocytes, form granulomas with the development of DTH
What in vivo diagnostic skin tests exist to detect type IV hypersensitivity?
Intradermal allergic tests with evaluation of results after 24–48 hours are used to detect DTH.
What are the differences between the Jones–Mote reaction and the classic tuberculin-type reaction?
The Jones–Mote reaction (cutaneous basophil hypersensitivity) differs from classic DTH by the predominance of basophils in the cellular infiltrate.
Which substances act as haptens in contact sensitization?
Low-molecular-weight chemical compounds applied to the skin serve as haptens in contact sensitization.
- Dinitrochlorobenzene — a typical inducer of contact dermatitis
- Dinitrophenol — a chemical sensitizer
- Paraphenylenediamine — a component of dyes
- Antibiotics (neomycin) — a drug hapten
- Metals (nickel) — causes contact hypersensitivity
Class and exam questions
What is the main difference between DTH and other types of hypersensitivity?
The fact that it is a cell-mediated (T-cell) response rather than antibody-dependent, and the reaction does not occur immediately, but with a delay after re-exposure.
What is a hapten and what is its role?
It is a low-molecular-weight substance that becomes a full-fledged antigen (and causes contact DTH) only after binding to the body's own proteins.
What causes tissue damage in DTH?
Tissues are damaged due to the excessive activity of macrophages, which, under the influence of cytokines from Th1 cells, massively release aggressive enzymes and radicals.
What else to study on this topic
- The role of complete Freund's adjuvant in creating pro-inflammatory conditions
- The mechanism of action of cell-free transfer factor from lymph nodes
- Participation of the CD1 molecule in antigen presentation during contact hypersensitivity
- Differences in the effects of sensitized Th1 cells vs. memory T cells at late stages
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