IMMUNOLOGY - Roit I. - Mir 2000

Chapter 10. Cell-Mediated Immune Responses

T-CELL-INDEPENDENT DEFENSE MECHANISMS

Phagocytosis is a vital component of antimicrobial defense

The initial defense response to any infection relies heavily on the recognition of common microbial components by specialized cellular receptors that differ from the antigen-specific receptors of T AND B Cells.

Numerous components of microbial cells are capable of inducing phagocyte chemotaxis toward the site of infection (Fig. 10.8). Some of these substances, such as bacterial endotoxin, attract phagocytes by inducing the alternative Complement pathway activation with the release of C5a and C3a. Others possess direct intrinsic chemotactic activity. For instance, formyl Peptides inherent to all Bacteria induce chemotaxis and, moreover, directly stimulate phagocytes, which invariably express receptors for them.

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Fig. 10.8. Most microorganisms release substances that induce phagocyte chemotaxis and are subsequently engulfed by these cells. The subsequent destruction of phagocytosed microbes does not require additional phagocyte activation. Antibody-independent alternative complement activation facilitates these processes.

The initial stage of phagocytosis is the binding of the microbe to The surface of the phagocytic Cell. This binding is facilitated by complement activation and the deposition of C3b on the microbial cell surface, which then interacts with CR3 receptors on phagocytes. Similarly, if Antibodies have previously bound to the microbial cell, the Fc receptors of phagocytes participate in its engulfment, thereby promoting phagocytosis.

Microorganisms characterized by intracellular localization within the host Organism possess specific mechanisms for binding to the phagocyte surface: although engulfment occurs via the usual pathway, subsequent activation of bactericidal mechanisms does not take place. This situation, along with the bactericidal mechanisms themselves, is discussed in detail in Chapter 17.

Microbial cell components can induce cytokine release

Another T- and antibody-independent mechanism of antimicrobial defense, highly crucial in the Cytology/cytology/16.html">Early stages of infection, is the release of cytokines and chemokines from macrophages and other cells. Apparently, all invasive microbes contain or release molecules capable of eliciting this effect (see Chapter 17). Among microbial triggers of cytokine release, endotoxin, or lipopolysaccharide (LPS), exerts the most potent effect. LPS interacts in a complex manner with membrane-bound receptors On the surface of leukocytes and, likely, endothelial cells, resulting in the activation of the respective EFFECTOR Functions OF these cells (see Fig. 17.3). A number of other conserved microbial structures can be recognized and act in a similar fashion.

Among the cytokines released by macrophages in response to microbial components, TNFα and IL-12 play a pivotal role. Released during the early phase of the Immune Response, these and other mediators perform three fundamental functions (Fig. 10.9):

✵ they serve as signals for endothelial cells, which consequently begin to recruit leukocytes from the bloodstream;

✵ they activate phagocytic cells in Tissues, thereby providing "innate resistance" during the period when T-cell Immunity is still developing;

✵ they act as one of the signals determining the polarization of the T-cell immune response toward the Th1 or Th2 pathway.

Fig. 10.9. TNFα and IL-1, released by macrophages and tissue cells, are essential during the early phase of the immune response. They act on the vascular endothelium, which subsequently begins to recruit circulating leukocytes. The ensuing migration of leukocytes into tissues, as well as the activation of cells arriving there, is mediated by chemokines (CKs). Additionally, TNFα directly activates macrophages and neutrophils. Upon stimulation by TNFα and IL-12, NK cells release IFNγ, which further enhances the bactericidal activity of phagocytes. Finally, cytokines released by macrophages and other cells, including mast cells, direct The Development of the immune response toward a Th1 or Th2 phenotype. All these events can occur even before T lymphocytes are recruited into the immune response.

Cytokines are essential for recruiting leukocytes from the bloodstream

The Sequential Stages of leukocyte recruitment from the bloodstream are illustrated in Fig. 10.10. Initially, cytokines induce the expression of adhesion molecules on endothelial cells, causing leukocytes to loosely tether to the endothelial surface and begin rolling along it in the direction of Blood flow. In the next stage, tissue cells release chemokines, which bind to endothelial cells and upregulate their integrin expression, thereby triggering a mechanism that strengthens leukocyte adhesion. As a result, leukocytes firmly adhere to the endothelium and arrest their movement. The final stage of leukocyte recruitment is their migration through the vascular endothelium into the tissue.

The existence of these stages of leukocyte recruitment is exemplified by two human immunodeficiency syndromes. In leukocyte adhesion deficiency type II, leukocytes lack the sialylated Lewis X blood group antigen, which serves as a Ligand for E-selectin, and are therefore unable to roll along the endothelium. In contrast, in leukocyte adhesion deficiency type I, the β-chain of integrin molecules is absent; consequently, neutrophils rolling along the endothelium cannot firmly adhere or migrate from the vessel lumen into the tissue. Both leukocyte adhesion deficiency syndromes are accompanied by recurrent bacterial infections.

Fig. 10.10. Stimulated by TNFα, IL-1, and lipopolysaccharide (LPS), endothelial cells express E-selectin and P-selectin, which bind to oligosaccharide chains on the surface of circulating leukocytes. As a result, leukocytes decelerate against the blood flow and begin rolling along the endothelial surface. Cytokines also upregulate the expression of ICAM-1. Chemokines, including MCP-1, RANTES, and MIP-1α—secreted by macrophages, tissue cells, and the endothelium, respectively—immobilize on the surface of endothelial cells and, by activating adjacently localized leukocytes, enhance the functional affinity of leukocyte Integrins. Integrins interact with their ligand (ICAM-1), further reinforcing leukocyte adhesion to the endothelium. Ultimately, leukocytes migrate across the endothelium and navigate along chemotactic mediator gradients. The Mechanism of leukocyte recruitment, as well as the repertoire of adhesion molecules expressed, has distinct features for each leukocyte subpopulation.