IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 26. Hypersensitivity - Type IV

TUBERCULIN-TYPE HYPERSENSITIVITY

This form of hypersensitivity was first described by Koch. Subcutaneous injection of a culture filtrate from tuberculosis-causing mycobacteria (which contains tuberculin, an antigenic complex of these Bacteria) induces fever and a general malaise in tuberculosis patients. Induration and edema develop at the injection site. Similar reactions are elicited in sensitized individuals by soluble Antigens from many microorganisms, including Mycobacterium tuberculosis, M. leprae, and Leishmania tropica. Skin testing is frequently used to assess sensitization to specific microorganisms (Fig. 26.8). This type of hypersensitivity can also be induced by non-microbial antigens, such as beryllium and zirconium.

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Fig. 26.8. Clinical manifestation and histological Features of the tuberculin-type reaction. The reaction of sensitized individuals to an injection of the leprosy bacillus is known as the Fernandez reaction. It is characterized by erythema and Swelling of the skin site, reaching a maximum 48–72 hours after antigen administration (1). Histologically (2), the dermis reveals a dense infiltrate composed of leukocytes and macrophages. Hematoxylin and eosin stain, x 80.

Monocytes are the predominant Cells involved in the tuberculin skin test

The tuberculin skin test detects reactions to soluble antigens in previously infected individuals. Following intradermal injection of tuberculin into sensitized subjects, antigen-specific T cells become activated and begin secreting cytokines that mediate the hypersensitivity reaction. The T-Cell-derived TNFα and lymphotoxin (TNFβ) act on the endothelium of cutaneous Blood Vessels, inducing the sequential expression of adhesion molecules — E-selectin, ICAM-1, and VCAM-1. These molecules bind to surface receptors on leukocytes and recruit them to the reaction site. Neutrophils accumulate During the first 4 hours, but are replaced by monocytes and T cells by 12 hours. The infiltrate expands, disrupting Collagen bundles in the dermis, and reaches its maximum size at 48 hours. CD4⁺ T cells outnumber CD8⁺ cells in the infiltrate by approximately two to one. At 24 and 48 hours, CD1⁺ cells (resembling Langerhans cells but lacking Birbeck granules) are also present in the dermal infiltrate; between 24 and 48 hours, some CD4⁺ cells also penetrate the epidermis.

Monocytes account for roughly 80–90% of all infiltrating cells. Both lymphocytes and macrophages present in the infiltrate express MHC class II molecules, which enhances the antigen-presenting capacity of activated macrophages. Between 48 and 96 hours after the appearance of the lymphocytic infiltrate, the overlying keratinocytes begin to express HLA-DR molecules. These processes are illustrated in Fig. 26.9.

Fig. 26.9. Cell migration following intradermal injection of tuberculin. During the first 1–2 hours, E-selectin is expressed on capillary endothelium, causing a transient influx of neutrophil leukocytes. By 12 hours, endothelial ICAM-1 and VCAM-1 bind to LFA-1 and VLA-4 Integrins expressed on monocytes and lymphocytes, resulting in the accumulation of these cells within the dermis. The reaction peaks at 48 hours, accompanied by the induction of HLA class II molecules on keratinocytes. Epidermal edema is absent.

Macrophages are likely the primary APCs in tuberculin-type hypersensitivity reactions. However, the presence of CD1⁺ cells in the dermal infiltrate suggests the potential involvement of Langerhans cells or other dendritic cells. The trafficking of immunocytes into and out of regional Lymph Nodes in this Setting appears to parallel that seen in contact hypersensitivity.

Tuberculin-induced lesions typically resolve within 5–7 days, but persistent tissue antigen can drive progression into a granulomatous reaction. Subepidermal basophil infiltration is not characteristic of this reaction, though it may occur in certain contact hypersensitivity reactions and skin tests utilizing heterologous Proteins, such as the Jones-Mote reaction.