Principles of the Immune System

The immune system is the organ that fights infection by pathogenic organisms such as bacteria, viruses, protozoa, or even worms. It also protects against toxins, for instance those from bacteria. The defense system of invertebrates against pathogens is simple, relying mostly on macrophages and bactericidal substances. In vertebrates, however, highly specialized cells have evolved, capable of producing cells with receptors of high binding specifity against literally billions of molecules, be they peptides, lipids, sugars, metal salts, or other chemical classes. The vertebrate immune system is a unique organ in that it is composed of a multitude of cells, molecules, and organized tissue structures, found distributed over the entire body as its field of action (Table 1). Immune cells are mobile and capable of communicating directly with each other by cell surface structures, or over considerable distances via lymphokines and chemokines. Close cell-cell contact is often necessary to orchestrate an effective immune response. Lymphoid organs are found at many sites in the body and can provide the relevant spatial structures for this contact. The number of lymphocytes (T and B cells) in the human body is approx. 1012, i.e., about the same as the number of cells of the brain or the liver.

Several features of the immune system must be considered when looking at the possible impact of chemical substances on the immune system: (1) the continuous differentiation and de novo generation of immune cells, (2) the capacity of the specific immune system to distinguish between structures of the own body and foreign structures (called 'self' and 'nonself') and between harmless and harmful molecules, (3) the high mobility of immune cells, (4) the sequestration of certain cell types within the body, (5) immunologic memory, and (6) communication with the environment via specialized signal transduction and cell surface receptors (Table 2).

All cells of the immune system, lymphoid and myeloid, are generated throughout life from the common hematopoietic stem cell, and have individual lifespans ranging from a few days (e.g., granulocytes) to many years. For instance, memory Tand B cells can live several years.1-3 Differentiating immune cells pass many checkpoints, which

Table 1 Some components making up the immune systema

Component

Target foT

Organs

Primary lymphoid organs Secondary lymphoid organs

Lymph vessels

Bone marrow Thymus Lymph nodes

Gut-associated lymphoid tissue (GALT) Bronchus-associated lymphoid tissue (BALT) Thoracic duct

Benzene

Cells

Innate immune response

Antigen presentation specialists

Adaptive immune response

Migration

Macrophages, monocytes

Granulocytes

Natural killer (NK) cells

Dendritic cells (myeloid, lymphoid, plasmacytoid) Langerhans cells

Kupffer cells

B cells (CD5+ B cells, other B cells) Tcells (Thi, Th2, Tc, TReg) NKT cells

High endothelial venules

Dioxin

Penicillin, procainamid, urishiol, dioxin

Nickel

Molecules

Destruction of bacteria Cell migration

Lymphocyte function, differentiation, and communication

Adhesion and trafficking

Cell destruction and apoptosis

Recognition of antigen

Direct and indirect neutralization of antigen

Antigen presentation

Second signal in antigen presentation

Communication and opsonization

Intracellular signaling and special features of immune cells

Effector molecules

Complement

Chemokines, chemokine receptors, leukotrienes Lymphokines/interleukins, lymphokine receptors

ICAM-1, integrins, selectins, CD44 Dioxin

Perforin

Fas, FasL

T cell receptors, B cell receptors, Toll-like receptors, NK receptors Antibodies

MHC class I, MHC class II, CD1

CD28, ICOS, CD80, CD86, CTLA-4 Nickel

Fc receptors Organotin

NFkB, RAG-1, RAG-2, STAT molecules, Arsenic suppressors of cytokine signaling (SOCS)

Histamine, myeloperoxidase, reactive oxygen species a Note that the list is not exhaustive, but highlights only the most important categories of immune system components. bSome examples of substances, which are known to adversely affect the indicated component of the immune system.

Table 2 Important features of the immune system which can be targeted by toxic substances

Feature

Immunotoxic effect

Differentiation, .signaling, and cell interactions

Continuous de novo cell generation, differentiation, and cell death

Cell mobility within the body

Forming and dissolving functional cell contacts

Immunosuppression

Response to exogenous stimuli by special signaling cascasdes

Antigen presentation and recognition

Specific recognition via T cell or B cell receptors of billions of antigens

Tolerance toward self antigens

Tolerance against harmless nonself antigens

Defense against harmful nonself antigens

Autoimmunity, allergy, immunosuppression

Sequestration of specific cells Eye chamber, brain

Systemic versus local effects

Bone marrow

Gut-associated lymphoid tissue Skin mucosal surfaces are either intrinsically programmed or triggered exogenously, e.g., by antigen. Most checkpoints are at the same time 'points of no return,' and there appears to be very limited transdifferentiation. Immunotoxic substances can interfere with cell differentiation, cell homeostasis, or immune functions of cells. Various differentiation stages and cell lineages can become targets of chemical substances, e.g., by affecting intrinsic cell programming or interfering with the quality of the necessary exogenous stimuli such as antigen presentation (Figure 1). Thus, it is important to think of the immune system as a continuously dynamic spatial and temporal organ in order to understand any toxic interference by chemicals and to evaluate risks.

The immune system can be divided into the nonadaptive (or innate) part and the adaptive immune system. The adaptive immune system has 'memory,' i.e., it can react faster and better on a renewed contact with the chemical, even after years of not having had any exposure. The cells of the innate immune system use surface receptors to recognize bacterial structures, and initiate defense reactions against them directly. Moreover, the innate defense reaction may include recruitment and instruction of cells of the adaptive immune response, for instance via secretion of cytokines or chemokines. Adaptive immune responses by T cells and B cells can in principle respond to any given structure, i.e., any protein (Tcells and B cells), lipid (some specialized Tcells, B cells), sugar chain, or chemical substance (B cells only), and mount a humoral or cellular response. Antibody producing B cells, cytokine producing helper Tcells, and killer Tcells capable of directly killing infected cells recognize pathogenic insult in a uniquely specific way, by virtue of their receptors. These receptors are generated by a genetic process involving stochastic rearrangement of gene segments to finally give rise to coding genes for the millions of different B cell or T cell receptors. B cell receptors in soluble form are also known as antibodies. Every single B cell or T cell has a receptor specificity different from any other B cell or T cell. Because the process of genetic rearrangement is stochastic it will also generate receptors with undesired specificities, i.e., with specificities against molecules of one's own body. Destruction of self - autoimmunity - can be the consequence. The status of not mounting an immune response against self antigens is called tolerance. Not being tolerant against self would pose a strong risk for the body, thus many mechanisms exist to ensure tolerance. The most prominent mechanism is the elimination of autoreactive Tcells, which react with good affinity against self proteins; this happens directly after Tcells are generated in the thymus.4 The process has its limits where self proteins are not present in the thymus to begin with,5 or where self proteins are modified outside of the thymus, e.g., by xenobiotic substances, and thus 'look' foreign. The latter phenomenon is important in immunotoxic effects of many chemical molecules, as will be discussed in detail below.

The immune system also must ignore or not recognize, let alone fight, harmless structures such as food constituents, inhaled pollen, proteins from animal hair, or many xenobiotic chemicals of the environment whether inhaled, ingested, or

Possible chemical interference

Intrinsically driven proliferation and differentiation

Antigen driven

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