10 IMMUNE-LYMPHATIC SYSTEM

Organization of the immune-lymphatic system

The lymphatic system includes primary and secondary lymphoid organs.

The primary lymphoid organs produce the cell components of the immune system. They are (1) the bone marrow and (2) the thymus. The main cell type is the lymphocyte originated from a lymphoid stem cell in bone marrow (Figure 10-1).

Figure 10-1 Lineage origin of the lymphoid progeny within the context of hematopoiesis

The secondary lymphoid organs are the sites where immune responses occur. They include (1) the lymph nodes, (2) the spleen, (3) the tonsils, and (4) aggregates of lymphocytes and antigen-presenting cells in the lung (bronchial-associated lymphoid tissue [BALT] and the mucosa of the digestive tract (gut-associated lymphoid tissue [GALT] including Peyer’s patches). The lymphatic system is widely distributed because pathogens can enter the body at any point.

The main function of the lymphoid organs, as components of the immune system, is to protect the body against invading pathogens or antigens (bacteria, viruses, and parasites). The basis for this defense mechanism, or immune response, is the ability to distinguish self from nonself.

The two key cell components of the immune system are lymphocytes and accessory cells (Figure 10-2). Lymphocytes include two major cell groups: (1) B cells, responding to cell-free and cell-bound antigens; and (2) T cells, subdivided into two categories: helper T cells and cytolytic or cytotoxic T cells. T cells respond to cell-bound antigens presented by specific molecules.

Figure 10-2 Major cells participating in immune reactions

After leaving the two primary organs (bone marrow and thymus), mature B and T cells circulate in the blood until they reach one of the various secondary lymphoid organs (lymph nodes, spleen, and tonsils).

B and T cells can leave the bloodstream through specialized venules called high endothelial venules, so called because they are lined by tall endothelial cells instead of the typical squamous endothelial cell type.

The accessory cells include two monocyte-derived cell types: macrophages and dendritic cells. An example of a dendritic cell is the Langerhans cell found in the epidermis of the skin. A third type, the follicular dendritic cell, is present in lymphatic nodules of the lymph nodes. Follicular dendritic cells differ from ordinary dendritic cells in that they do not derive from a bone marrow precursor.

Before we start our discussion of the origin, differentiation, and interaction of lymphocytes and accessory cells, we will define the characteristics of the immune system. Then, we will be able to integrate the structural aspects of each major lymphatic organ with the specific characteristics of the immune responses.

INNATE (NATURAL) AND ADAPTIVE (ACQUIRED) IMMUNITY

Immunity in general is the reaction of cells and tissues to foreign (nonself) substances or pathogens including bacterial, viral, and parasite antigens. Two types of immunity are distinguished: (1) innate or natural immunity and (2) adaptive or acquired immunity (Figure 10-3).

Figure 10-3 Types and acquisition of immunity

Innate or natural immunity of the newborn is the simplest mechanism of protection. It does not require previous exposure to a pathogen and elicits rapid responses by macrophages and dendritic cells. Toll-like receptors (see Box 10-A) initiate innate immunity against components of invading pathogens (such as nucleic acids, proteins, lipids and polysaccharides). Stimulation of macrophages and dendritic cells by their ligand-bound Toll-like receptors leads to the production and secretion of proinflammatory cytokines, thereby initiating an inflammatory response.

Box 10-A Toll-like receptors

• Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs). The term PAMPs designates proteins associated with a wide spectrum of pathogens recognized by cells of the innate or natural immune system.

• Activated TLR activate in turn the NF-κB transcription factor pathway (see Chapter 3, Cell Signaling), which regulates cytokine expression. Activation of the NF-κB pathway links innate and acquired immune responses by stimulating the production of inflammatory cytokines, such as interleukines and tumor necrosis factor-α, and chemokines, as well as triggering the expression of costimulatory molecules (CD40, CD80, and CD86).

• The intracellular domain of the TLR has structural homology with the cytoplasmic region of interleukin-1 receptors. It is known as Toll-interleukin-1 receptor domain, or TIR domain, and participates in signaling by recruiting downstream proteins.

• The extracellular region of the TLR contains leucine-rich repeat (LLR) motifs, whereas the extracellular domain of interleukin receptors contains three immunoglobulin-like domains. LLR is involved in the recognition of PAMPs facilitated by accessory proteins (for example, lipopolysac-charides).

Adaptive or acquired immunity develops when an individual is exposed to a pathogen with the aims of eliminating the pathogen as well as the generation of immunologic memory. To achieve adaptive or acquired immunity, it is necessary to select lymphocytes (clonal selection) from a vast repertoire of cells bearing antigen-specific receptors generated by a mechanism known as gene rearrangement. Essentially, adaptive immunity is the perfection of innate or natural immunity that recognizes vital components of the microorganism utilizing a limited number of pattern-recognition receptors expressed on all cells of a given type (nonclonal) and independent of immunologic memory.

Adaptive immunity involves two types of responses to an antigen (pathogen): The first response is mediated by antibodies produced by plasma cells, the final differentiation product of B cells as we have seen in Chapter 4, Connective Tissue. This response is known as humoral immunity and operates against antigens located outside a cell or bound to its surface. When antibodies bind to an antigen or toxins produced by a pathogen, they can facilitate the phagocytic action of macrophages or recruit leukocytes and mast cells to take advantage of their cytokines and mediators, respectively, and strengthen a response. Humoral immunity results in persistent antibody production and production of memory cells.

The second type of response requires the uptake of a pathogen by a phagocyte. An intracellular pathogen is not accessible to antibodies and requires a cell-mediated response, or cell-mediated immunity. T cells, B cells, and antigen-presenting cells are the key players in cell-mediated immunity.

A consequence of adaptive or acquired immunity is the protection of the individual when a second encounter with the pathogen occurs. This protection is specific against the same pathogen and, therefore, adaptive or acquired immunity is also called specific immunity.

Passive immunity is a temporary form of immunity conferred by serum or lymphocytes transferred from an immunized individual to another individual who has not been exposed or cannot respond to a pathogen. The transfer of maternal antibodies to the fetus is a form of passive immunity that protects newborns from infections until they can develop active immunity. Active immunity is the form of immunity resulting from exposure to a pathogen.

Properties of adaptive or acquired immunity

Both humoral and cell-mediated immunity developed against foreign pathogens have the following characteristics:

1. Specificity: Specific domains of an antigen are recognized by individual lymphocytes. We will see later how cell membrane receptors on lymphocytes can distinguish and respond to subtle variations in the structure of antigens offered by an antigen-presenting cell. This molecular interaction is known as the immunologic synapse.

2. Diversity: Lymphocytes utilize a gene rearrangement mechanism to modify their antigen receptors in such a way that they can recognize and respond to a large number and types of antigenic domains.

3. Memory: The exposure of lymphocytes to an antigen results in two events: their antigen-specific clonal expansion by mitosis, as well as the generation of reserve memory cells. Memory cells can react more rapidly and efficiently when exposed again to the same antigen.

4. Self-limitation: An immune response is stimulated by a specific antigen. When the antigen is neutralized or disappears, the response ceases.

5. Tolerance: An immune response pursues the removal of a non-self antigen while being “tolerant” to self-antigens. Tolerance is achieved by a selection mechanism that eliminates lymphocytes expressing receptors specific for self-antigens. A failure of self-tolerance (and specificity) leads to a group of disorders called autoimmune diseases.

B CELLS

The bone marrow is the site of origin of B and T cells from a lymphoid stem cell. In Chapter 6, Blood and Hematopoiesis, we discussed developmental aspects of the myeloid and erythroid lineages from a hematopoietic stem cell. The same hematopoietic stem cell gives rise to a lymphoid stem cell that generates precursors for B cells and T cells (see Figure 10-1). B cells mature in the bone marrow, whereas the thymus is the site of maturation of T cells.

Stem B cells in the bone marrow proliferate and mature in a microenviron-mental niche provided by bone marrow stromal cells producing interleukin-7 (IL-7) (Figure 10-4). During maturation, B cells express on their surface immunoglobulins M (IgM) or D (IgD) interacting with two additional proteins linked to each other, immunoglobulins α (Igα) and β (Igβ). The cell surface IgM or IgD, together with the conjoined Igα and Igβ, form the B cell antigen receptor complex. The intracellular domains of Igα and Igβ contain a tyrosine-rich domain called immunoreceptor tyrosine-based activation motif (ITAM).

Figure 10-4 Development of B cells in bone marrow

Binding of an antigen to the B cell antigen receptor complex induces the phosphorylation of tyrosine in the ITAM, which, in turn, activates transcription factors that drive the expression of genes required for further development of B cells.

Self-antigens present in the bone marrow test the antigen-binding specificity of IgM or IgD on B cell surfaces. This is a required testing step before B cells can continue their maturation, enter peripheral lymphoid tissues, and interact with foreign (non-self) antigens. Self-antigens binding strongly to two or more IgM or IgD receptor molecules on B cells induce apoptosis. Self-antigens with a weaker binding affinity for the B cell antigen receptor complex enable the survival and maturation of these B cells when ITAMs of IgM- or IgD-associated Igα and Igβ transduce signaling events, resulting in further differentiation of B cells and the entrance of mature B cells into the circulation.

T CELLS

Major histocompatibility complex and human leukocyte antigens

The presentation of antigens to T cells is carried out by specialized proteins encoded by genes in the major histocompatibility locus and present on the surface of antigen-presenting cells. Antigen-presenting cells survey the body, find and internalize antigens by phagocytosis, break them down into antigenic peptide fragments, and bind them to major histocompatibility complex (MHC) molecules (Figure 10-5) so that the antigen peptide fragment–MHC complex can be exposed later on the surface of the cells. The MHC gene locus expresses gene products responsible for the rejection of grafted tissue between two genetically incompatible hosts.

Figure 10-5 Structure of the T cell receptor and class I and II major histocompatibility complex (MHC)

There are two types of mouse MHC gene products: class I MHC and class II MHC. The class I MHC molecule consists of two polypeptide chains: an α chain, consisting of three domains (α₁, α₂, and α₃) encoded by the MHC gene locus, and β₂-microglobulin, not encoded by the MHC gene locus. Antigens are housed in a cleft formed by the α₁ and α₂ domains. CD8, a coreceptor on the surface of cytolytic T cells, binds to the α₃ domain of class I MHC.

Class II MHC consists of two polypeptide chains, an α chain and a β chain. Both chains are encoded by the MHC gene locus. The α₁ and β₁ domains form an antigen-binding cleft. CD4, a coreceptor on the surface of helper T cells, binds to the β domain of class II MHC. CD4 and CD8 are cell surface identifiers, members of the cluster of differentiation or designation (abbreviated as CD). See Box 10-B.

Box 10-B CD antigens

• Cell surface molecules recognized by monoclonal antibodies are called antigens. These antigens are markers that enable the identification and characterization of cell populations. A surface marker that identifies a member of a group of cells, has a defined structure, and is also recognized in other members of the group by a monoclonal antibody is called a cluster of differentiation or designation (CD).

• A helper T cell, which expresses the CD4 marker, can be differentiated from a cytolytic T cell, which does not contain CD4 but expresses the CD8 marker.

• CD markers permit the classification of T cells that participate in inflammatory and immune reactions. CD antigens promote cell-cell interaction and adhesion as well as signaling leading to T cell activation.

All nucleated cells express class I MHC molecules. Class II MHC molecules are restricted mainly to antigen-presenting cells (macrophages, dendritic cells, and B cells), stromal epithelial cells of the thymus, and endothelial cells.

The MHC-equivalent molecules in the human are designated human leukocyte antigens (HLAs). HLA molecules are structurally and functionally homologous to mouse MHC molecules and the gene locus is present on human chromosome 5 (β₂-microglobulin is encoded by a gene on chromosome 15).

The class I MHC locus encodes three major proteins in the human: HLA-A, HLA-B, and HLA-C. The class II MHC locus encodes HLA-DR (R for antigenically related), HLA-DQ, and HLA-DP (Q and P preceding R in the alphabet).

T cell receptor complex

In addition to MHC molecules, subsets of T cells have cell surface receptors that enable each of them to recognize a different antigen peptide–MHC combination. Antigen recognition involves an immunologic synapse mechanism consisting in the formation of stable antigen-presenting cell–T cell adhesiveness followed by an activating signaling cascade by T cells (see Box 10-C).

Box 10-C The Immunologic synapse

• The initiation and regulation of a specific immune response depends on the communication between T cells and antigen-presenting cells (APCs). The immunologic response results from molecular interactions at the site of T-cell and APC contact also known as the immunologic synapse. Essentially, the immunologic synapse can be regarded as a combined cell-cell adhesion and signaling device.

• The diversity of cell surface molecules of APCs (class I MHC and class II MHC) and T cells (T cell receptor and coreceptors) provides a framework for the molecular regulation and activity of the immunologic synapse. The immunologic synapse has a significant role in T cell maturation, activation and differentiation taking place in the cortex of the thymus. The immunologic synapse concept also applies to B cell maturation in bone marrow.

The receptor that recognizes specific antigenic peptides presented by class I and class II MHC molecules is the T cell receptor (TCR). TCR acts together with accessory cell surface molecules, called coreceptors, to stabilize the binding of antigen-presenting cells to T cells.

The TCR consists of two disulfide-linked transmembrane polypeptide chains: the α chain and the β chain (see Figure 10-5). A limited number of T cells have a TCR composed of γ and δ chains. Each α and β chain consists of a variable (Vα and Vβ) domain and a constant (Cα and Cβ) domain. When compared with the immunoglobulin molecule, the Vα and Vβ domains are structurally and functionally similar to the antigen-binding fragment (Fab) of immunoglobulins.

The TCR molecule is associated with two proteins, CD3 and ζ (not shown in Figure 10-5), forming the TCR complex. CD3 and ζ have a signaling role and are present in all T cells. CD3 contains the ITAM cytoplasmic domain previously mentioned as part of the B cell antigen receptor complex and involved in signaling functions.

CD4 and CD8 coreceptors

CD4 and CD8 are T cell surface proteins interacting selectively with class II MHC and class I MHC molecules, respectively. When the TCR recognizes an antigen bound to the cleft of MHC, CD4 or CD8 coreceptors cooperate in the activation of T cell function (see Figure 10-5).

CD4 and CD8 are members of the immunoglobulin (Ig) superfamily. In Chapter 1, Epithelium, we discussed the function and structure of cell adhesion molecules belonging to the Ig superfamily.

Members of the Ig superfamily have a variable number of extracellular Ig-like domains. The two terminal Ig-like domains of CD4 bind to the β₂ domain of the class II MHC (see Figure 10-5). The single Ig-like domain of CD8 binds to the α₃, domain of the class I MHC.

Thus, CD4⁺ helper T cells recognize antigens associated with class II MHC, and CD8⁺ cytolytic T cells (cytolytic thymus-derived lymphocytes [CTL]) respond to antigens presented by class I MHC (Figure 10-6).

Figure 10-6 General features of helper and cytolytic T cells

MHC molecules and adaptive immune responses

T cells are MHC-restricted. T cells are able to react against a foreign antigen fragment bound to their own (self-) MCH molecules and contribute to adaptive immune responses. T cells should not respond to self-antigen peptide fragments bound to self-MHC molecules. This lack of response is called self-tolerance. Developing T cells express unique TCRs generated by random rearrangement of a variety of gene segments. These randomly produced TCRs provide the diversity required to identify numerous foreign peptides.

During their maturation in the cortex of the thymus, T cells are selected to be self-MHC–restricted and self-tolerant. This selective process, known as positive selection, occurs only when self-MCH–restricted T cells are selected (see Figure 10-7). Negative selection takes place when T cells do not bind to any MHC or bind to the body’s tissue-specific antigens (self-molecules). We discuss later how a portfolio of self-antigens expressed in the thymus permits the elimination of autoreactive T cells by apoptosis. Only those T cells that can recognize foreign peptides and self-MHC survive, leave the thymus, and migrate into the secondary lymphoid organs.