IMMUNE-LYMPHATIC SYSTEM

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).



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.



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).



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.



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.




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).



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.



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.



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).



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.




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.



The cortex of the thymus contains branching and interconnected thymic cortical epithelial cells involved in the positive selection of T cells. The medulla of the thymus houses thymic medullary epithelial cells involved in the negative selection of potentially autoreactive T cells. Contact between MHC molecules on the thymic epithelial cell surfaces and TCRs of developing T cells is an important feature in positive selection. This is another example of the importance of the immunological synapse (see Box 10-C).




T cell-mediated immunity


When T cells complete their development in the thymus, they enter the bloodstream and migrate to the peripheral lymphoid organs in search of an antigen on the surface of an antigen-presenting cell.


Helper T cells contain both the TCR and CD4 coreceptor. Helper T cells recognize class II MHC on antigen-presenting cells.


There are two distinct subtypes of helper T cells derived from the same CD4+ T cell precursor: Th1 and Th2 cells.


Th1 cells participate in the regulation of immune responses caused by intracellular pathogens (viruses causing infections, certain bacteria, or single-cell parasites) with the significant participation of macrophages. Th1 cells produce interferon-γ, which can suppress the activity of Th2 cells.


Immune responses controlled by TH2 cells are observed in patients with helminthic (Greek helmins, worm) intestinal parasites. Th2 cells produce interleukin-4 (IL-4) and interleukin-13 (IL-13), among other cytokines, and determine the production of immunoglobulin E by plasma cells to activate the responses of mast cells, basophils, and eosinophils. The activation of macrophage responses is minimal in Th2-driven immune responses.


Cytolytic (or killer) T cells display both the TCR and CD8 coreceptor. Cytolytic T cells recognize class I MHC on antigen-presenting cells. We will return to the clinical significance of helper and cytolytic T cells when we discuss their involvement in the pathology of human immunodeficiency virus-type 1 (HIV-1) infection, allergy, and cancer immunotherapy.



How do helper T cells help?


Helper T cells are activated when they recognize the antigen peptide–class II MHC complex (Figure 10-8).



In the presence of cells with antigen peptide bound to class II MHC, helper T cells proliferate by mitosis and secrete cytokines, also called interleukins. These chemical signals, in turn, attract B cells, which also have receptor molecules of single specificity on their surface (immunoglobulin receptor). Unlike helper T cells, B cells can recognize free antigen peptides without MHC molecules.


When activated by interleukins produced by the proliferating helper T cells, B cells also divide and differentiate into plasma cells secreting immunoglobulins, a soluble form of their receptors. Secreted immunoglobulins diffuse freely, bind to antigen peptides to neutralize them, or trigger their destruction by enzymes or macrophages.


Plasma cells synthesize only one class of immunoglobulin (several thousand immunoglobulin molecules per second; lifetime of a plasma cell is from 10 to 20 days). Five classes of immunoglobulins are recognized in humans: IgG, IgA, IgM, IgE, and IgD (see Box 10-D). Abnormal plasma cells may accumulate in bones and bone marrow, causing bone destruction and affecting the production of normal blood cells. This pathologic condition is called multiple myeloma (see Box 10-E).



Jun 18, 2016 | Posted by in HISTOLOGY | Comments Off on IMMUNE-LYMPHATIC SYSTEM

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