21.3Immunity and Biophylaxis


Danger signals to the immune system

Microorganisms like parasites invade the body through epithelia such as those lining the skin, respiratory tract, and digestive tract. Such threats are recognized and processed by macrophages and dendritic cells normally present in the space between epithelial cells and connective tissues. These cells determine from the molecular characteristics of the non-self substances whether they are evolutionarily distant organisms and transmit danger signals if they are judged to be dangerous. This phase is the initial part of the innate immune response. Recognition molecules called toll-like receptors, which are found in macrophages and dendritic cells, play an important role in this response. These cells also seem to monitor whether self cells are in a normal state or not, and when they receive danger signals, they secrete cytokines that induce the activation and differentiation of themselves and other immune cells as well as molecules called chemokine that trigger migration of other cells (see Column the bottom).

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Immune cell lineage and differentiation phase

When macrophages recognize foreign molecules or altered “self” components, they secrete various cytokines, among which the most representative is tumor necrosis factor-α (TNF-α). TNF-α activates endothelial cells, which line the inner surface of blood vessels. This increases the adhesiveness of the inner surface of the blood vessel, causing leukocytes (e.g., neutrophils) and monocytes in the blood flow to attach to the walls of the blood vessels. They are then induced by the secreted chemokine to move into the tissues. Inside the tissues, these cells ingest and eliminate invading microorganisms. The physiological changes in the tissue that accompany neutrophil infiltration are referred to as inflammation. Cytokines that induce inflammation are called inflammatory cytokines, and macrophages that secrete such cytokines are considered cells responsible for causing inflammation.


Cytokines, chemokines, and receptors

Cytokines and chemokines are soluble proteins required for immune cells to communicate with each other. To date, over 30 human cytokines have been identified. In most cases, binding of cytokines to receptors and subsequent intracellular signal transduction of cytokines involve phosphorylation and translocation of proteins of the JAK-STAT pathway (not introduced in Chapters 14 and 15). Over 30 types of chemokines are also known. The molecular weights of chemokines are slightly lower than those of cytokines. Chemokines bind to seven transmembrane receptors and signals are transduced via trimeric G-proteins. Chemokines are chemotactic factors that induce directed chemotaxis for guiding and sustaining the migration of cells.

Both cytokines and chemokines have extremely high physiological activity even at low concentrations. As they are closely involved in pathogenesis, these molecules and their antagonists have high potential as medicine. Many biomedicines used today have been developed through research on these molecules.

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Initiation of acquired immune responses and involvement of MHC gene products

Responses that do not involve T or B cells are innate immune responses by definition. However, the role of dendritic cells, which are closely related to macrophages and are widely distributed in the body, is to initiate acquired immune responses. When dendritic cells recognize the invasion of microorganisms or altered “self” cells, they become activated via toll-like receptors. Furthermore, dendritic cells ingest these etiologic factors and proteins originating from foreign cells, break them down to peptides, and migrate to secondary lymphoid organs, where the fragments of peptides are presented to T cells (Figure 21-2). T cells are then activated by the signals transduced from dendritic cells via T cell receptors.

Why are dendritic cells indispensable for the activation of T cells? This is because only fragments of protein are capable of binding to T cell receptors as antigens and thereby triggering an immune response, and also because T cell receptors can only recognize peptide fragments directly bound to the products of major histocompatibility complex (MHC) genes on the surface of antigen-presenting cells. In particular, only dendritic cells can activate naive T cells (i.e., those that have never encountered antigens) and trigger antigen-specific clone proliferation. This is because dendritic cells are the only cells expressing, at a high level, products (essential for the activation of helper T cells, see Column the bottom) of MHC Class II genes when the T cells are not activated. When dendritic cells are stimulated by toll-like receptors, the expression of Class II MHC increases, and the cells initiate the expression of co-stimulatory molecules on their surface. The mutual recognition between co-stimulatory molecules and T cell surface molecules is critical for T cell activation. Without this interaction, anergy of antigen-specific clones occurs. The immune tolerance acquired before T cells meet foreign antigens in the thymus is called central tolerance, while immune tolerance caused by such anergy is called peripheral tolerance. Once T cells are activated in secondary lymphoid organs, they produce cytokines, which induce the expression of Class II MHCs in B cells and macrophages. These cells then function as antigen-presenting cells to support activation of the T cell populations.

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Activation of T cells

When T cell receptors recognize antigen peptides binding to Class II MHC gene products, helper T cells become activated, which are the type of T cells that play a leading role in the acquired immune response. The intracellular signal transduction that induces T cell activation is a complex pathway involving multiple second messengers. During this process, the association of membrane molecules and intracellular molecules, which attach to T cell receptors, changes and activates protein phosphorylation. This phosphorylation further activates other phosphoenzymes, thereby activating phospholipase C and G protein. The activation of phospholipase C frees intracellular calcium through the production of inositol triphosphate and activates calcium-dependent protein kinase through the production of diacylglycerol. The consequent intracellular events are diverse. The particularly important events include the activation and nuclear translocation of transcription factors such as NF-κB and NFAT. As a result of the activation of G protein, the phosphorylation and nuclear translocation of transcription factors can occur directly or via MAP kinase activation. The transcriptional changes that occur as a result are also complex, and one of the most important changes is the initiation of transcription of the interleukin-2 (IL-2) cytokine and its receptor. IL-2 has strong proliferation-promoting effects on lymphocytes.

The immunosuppressive drugs cyclosporin A and FK506, which are widely used to prevent graft rejection, are known to inhibit the activation of NFAT.

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Cellular immune and humoral immune responses

The main function of helper T cells that have undergone antigen-specific activation and proliferation is to activate and control cellular and humoral immune responses. Cellular immune responses are based on the activities of killer T cells, macrophages, and NK cells. In contrast, humoral immune responses are based on the activation of B cells and the activities of the immunoglobulins or antibodies that they produce. From the T helper cell populations, the T helper cell type 1 cells (Th1 cells) promote cellular immune responses and T helper cell type 2 cells (Th2 cells) promote humoral immune responses. By secreting different types of cytokines, these two types of T helper cells activate multiple immune cell types described above. Although cellular and humoral responses occur concomitantly, there are many cases in which either of the two responses becomes dominant due to influence factors such as the type of antigen, the route of invasion, a stimulant that entered the body together with the antigen, and the genetic background of the host. For example, allergies such as pollinosis are caused by the production of immunoglobulin E, as part of humoral immune responses promoted by Th2 cells (see Column Selection 4 of Chapter 21). It is known that people prone to allergies have a higher predisposition to trigger the Th2 cell-mediated immune responses.


MHC and graft rejection

Class I MHC gene products are antigen-presenting molecules required for T cells to sense infectious parasites inside the cell, whereas class II MHC gene products are required for T cells to sense extracellular parasites. Both are important transplantation antigens when transplanted organs or cells are being sensed. The human MHC gene product is called human leukocyte antigen (HLA). Class I genes contain three loci (A, B, C) on chromosome 6, whereas class II genes contain three loci (DP, DQ, and DR) on chromosome 6. Both are polymorphic, based on the differences in the amino acid sequence. This polymorphism of human MHC genes is the most diverse among human genes, demonstrating that diversity in this region was advantageous for human populations during evolution.

The diversity of MHC has two major significances. First, this polymorphism is located in peptide*1 -binding sites for antigen presentation. In the peptide sequence of the same protein antigen, epitopes that can be presented to T cells thus differs according to the individual. In other words, the diversity of MHC corresponds directly to the diversity of immune responses. Second, this diversity of MHC makes it extremely difficult to find a transplant donor with an HLA pattern that won’t be rejected. As both chromosomes of a pair are expressed dominantly, assuming that the main variation of the three loci is five types each, there will be 56 types of individual differences. In bone marrow transplants, lymphocytes and their precursor cells present in the transplanted bone marrow cells may cause a graft-versus-host (GVH) reaction, in which the donor’s cells attack the recipient’s cells, resulting in serious consequences. This diversity of MHC is profoundly connected to the likeliness to develop certain diseases, in particular autoimmune diseases.

*1 Class I genes are made up of nine amino acids while class II are made up of twelve. Normally for both classes, two amino acids and the distance between them will determine whether peptide binding can occur.

Column Figure 21-1 Interactions between Class II MHC and antigen peptide

AResults of X-ray crystal structure analysis show that MHC gene products have grooves enclosed by two α helices on the β sheet, implying that when antigen peptides are trapped into these grooves, the resulting complex is recognized by T cell receptors. If the sequence of the part of the MHC marked with “*” has mutated, it will be recognized as a non-self structure.

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