CHAPTER 5 As stated previously, the function of the immune system is to protect against infectious pathogens and the development of cancer. There are two categories of immune responses that are based in part on their specificity for the antigen: (1) innate immunity and (2) adaptive immunity (Fig. 5-1). Innate immune responses are considered the first-line defense mechanisms, are not specific to the antigen, and lack memory. These defense mechanisms are the result of anatomic (e.g., skin, mucosal epithelia, cilia) and physiologic (e.g., stomach pH, body temperature) properties, and phagocytic and inflammatory responses. Major components of innate immunity are intact epithelial barriers, phagocytic cells, natural killer (NK) cells, and a number of plasma proteins, the most important of which are the proteins of the complement system. Phagocytic cells are recruited to sites of infection during an inflammatory response where they have a number of functions, two of which are to ingest and destroy pathogenic organisms and neutralize toxins. Neutrophils, monocytes, and tissue macrophages are the major cells involved in phagocytosis. These cells recognize components of microbial pathogens through the expression of several membrane receptors, including receptors for mannose residues and N-formyl-methionine containing peptides and a family of pattern recognition receptors (PRRs) that, when activated by microbial components, signal the activation of transcription factors that facilitate the microbicidal mechanisms of the phagocytic cell and are discussed later. NK cells are the cytotoxic cells of innate immunity and are also discussed later. The complement system, discussed in Chapter 3, is a complex cascade of proteins that has a number of biologic functions, including the formation of the membrane attack complex that efficiently lyses plasma membranes of microbial pathogens. The complement system can be activated by either the innate immune system (alternative and mannose/lectin pathways) or the adaptive immune system (classical pathway). Other important plasma proteins of the innate immune system include mannose-binding protein and C-reactive protein; two of the functions of these proteins are to facilitate phagocytosis through opsonization of pathogens and complement activation. Inflammatory responses comprise vascular, permeability, and cellular phases that act in response to damage to vascularized tissue. The features of the inflammatory response are also presented in Chapter 3. Fig. 5-1 Innate (nonspecific) and adaptive (specific) immunity are depicted in relation to the time course of an infection. TLRs are the mammalian homologue of the Toll receptor originally identified in Drosophila. It has not only an embryologic function but also an immunologic function. In mammals, TLRs are membrane molecules that function in cellular activation by a wide range of microbial pathogens. TLRs are classified as PRRs because they recognize PAMPs and signal to the host the presence of an infection. Pathogen associated molecules include lipopolysaccharide (LPS) from Gram-negative bacteria, peptidoglycan from Gram-positive bacteria, double-stranded RNA from viruses, or α-glucans from fungi (Table 5-1). In general, TLRs 1, 2, 4, and 6 recognize unique bacterial products that are found on the cell surface, and TLRs 3, 7, 8, and 9 are involved in viral detection and nucleic acid recognition within endosomes. The specificity of TLRs for microbial products depends on interactions between TLRs and non-TLR adapter molecules. All TLRs contain an extracellular domain characterized by a leucine-rich repeat motif flanked by a cysteine-rich motif (Fig. 5-2). They also contain a conserved intracellular signaling domain, Toll/IL-1 receptor (TIR), that is identical to the cytoplasmic domain of the IL-1 and IL-18 receptors. Fig. 5-2 illustrates how TLRs function in the recognition of LPS. In the blood or extracellular fluid, the binding of LPS to LPS-binding protein (LBP) facilitates the binding of LPS to CD14, a plasma protein and glycophosphatidylinositol-linked membrane protein present on most cells. The binding of LPS to CD14 results in the dissociation of LBP and the association of the LPS-CD14 complex with TLR4. An accessory protein, MD2, complexes with the LPS-CD14-TLR4 molecule and results in LPS-induced cell signaling. TABLE 5-1 Toll-Like Receptors (TLRs) and TLR Ligands and Their Microbial Source Modified from Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders. Fig. 5-2 Signaling pathway for Toll-like receptor 4 (TLR4) in response to bacterial lipopolysaccharide (LPS). Fig. 5-3 Overview of humoral and cell-mediated arms of adaptive immunity. Although all T lymphocytes express the TCR-CD3 complex, they are further classified according to accessory CD4 and CD8 molecules. These nonpolymorphic accessory molecules include CD4, CD8, CD2, integrins, and CD28. CD4 and CD8 functionally subdivide T lymphocytes into CD8+ cytotoxic T lymphocytes (CTL [TC]) and CD4+ helper T lymphocytes (TH). During antigen presentation, CD4+ lymphocytes only recognize antigen bound to MHC class II molecules (Fig. 5-4), whereas CD8+ lymphocytes only recognize antigen bound to MHC class I molecules. This coreceptor requirement is commonly referred to as MHC class I and MHC class II restriction, the basis for positive selection in the thymus. Although there have been reports in some species of CD4 lymphocytes that are functionally cytotoxic and CD8 lymphocytes that are functionally “helper”-like, these appear to be anomalies and for the purposes of this text are excluded. In most species, peripheral blood T lymphocytes express either CD4 or CD8. Except for ruminants and swine, lymphocytes negative for both CD4 and CD8—“double negative” lymphocytes—are rare in the peripheral blood. So-called “double positive” lymphocytes, positive for both CD4 and CD8, are rare, except in swine, where they can approach 25% of the T lymphocytes in the peripheral circulation. T lymphocytes require two signals for activation. Signal 1 is provided by the TCR and the MHC-antigen complex and the CD4 or CD8 MHC complex. Signal 2 is provided by another accessory molecule expressed by T lymphocytes, the CD28 molecule. The ligands for CD28 are B7-1 (CD80) and B7-2 (CD81) expressed on activated dendritic cells, B lymphocytes, and macrophages (see Fig. 5-4). An inability to deliver the second signal results in an unresponsive T lymphocyte that either undergoes apoptosis or remains anergic. These molecules provide an important co-stimulatory signal for T lymphocyte activation, and are discussed in more detail later in the chapter regarding anergy and the development of tolerance with regard to autoimmunity. When T lymphocytes are activated by antigen and receive the appropriate co-stimulatory signals, they clonally expand as a result of their secretion of IL-2. This clonally expanded population of T lymphocytes, of the same antigen specificity, differentiates into populations of effector lymphocytes and memory lymphocytes. Fig. 5-4 The T lymphocyte receptor complex (T lymphocyte receptor [TCR]). TH lymphocytes can be classified based on their functional capacity and ability to elicit primarily an antibody response or a cell-mediated immune response. After activation of TH lymphocytes, by recognition of antigen bound to MHC class II molecules on the surface of an antigen-presenting cell, there is clonal expansion of TH lymphocytes of the same antigen specificity. These clonally expanded lymphocytes are important in directing the immune response as either primarily an antibody response or a cellular response. The type of response is dictated by a restricted cytokine profile that primarily activates B lymphocytes in the case of an antibody response or activates CTL (Tc) and macrophages in a cellular response. The restricted cytokine profile for TH lymphocytes allows for their classification as either TH1 or TH2 lymphocytes (Web Table 5-1). TH1 lymphocytes synthesize and secrete IL-2 and interferon-γ (IFN-γ), stimulating CTL (Tc) and macrophages, and induce a cell-mediated immune response. TH2 lymphocytes synthesize and secrete IL-4, IL-5, IL-6, and IL-13 that stimulate B lymphocytes to develop into antibody-secreting plasma cells and inhibit macrophage functions, and induce an antibody response. The type of immune response (antibody versus cell-mediated) can have a profound influence on the outcome of a disease. In the instance of an intracellular protozoal infection, a TH2 type response results in rapid proliferation of the organism and death of the host, whereas a TH1 type response results in elimination of the organism and survival of the host. Similarly, a TH2 response to an allergen results in the elaboration of immunoglobulin (Ig) E, through IL-4 production, stimulation of eosinophils, through IL-5 production, and the development of an allergic reaction. The exact regulation of the TH1 versus the TH2 lymphocyte response is unknown, but studies suggest that IL-12 produced by activated macrophages stimulates the TH1 response, whereas IL-4 inhibits the TH1 response, allowing the TH2 response to dominate. TH lymphocytes predominately drive the immune response to microbial pathogens by activating macrophages or B lymphocytes. Another functionally distinct subpopulation of CD4+ T lymphocytes is the regulatory T lymphocyte (T reg). T reg lymphocytes function to suppress the response of self-reactive CD4 lymphocytes that have escaped the negative selection process in the thymus. They are distinguished from other CD4 T lymphocytes by the expresson of CD25 on the cell surface. Like TH1 and TH2 lymphocytes, T reg lymphocyte differentiation is driven by cytokine environments; however, where TH1 and TH2 lymphocyte activation occurs through transcripional activators T-bet and GATA-3, respectively, T reg lymphocytes are activated through the transcriptional repressor FoxP3 (Fig. 5-5). This subpopulation of T reg lymphocytes are often referred to as Fox3P lymphocytes and produce the immunosuppressive and antiinflammatory cytokines IL-4, IL-10 and TGF-β. FoxP3 lymphocytes are an intense area of investigation for their role as suppressor lymphocytes of immunity and inflammation. T reg lymphocytes have been shown to have a role in the prevention of organ-specific autoimmune diseases and in modulation of immune responses to microbial pathogens to prevent overwhelming inflammatory reactions. Finally, a subpopulation of CD4 lymphocytes characterized by the ability to produce IL-17 is designated as TH17 lymphocytes. TH17 lymphocyte differentiation is driven by TGF-β, IL-6, IL-1, and IL-23. TH17 lymphocytes, through production of chemokines IL-17 and IL-22, induce the recruitment of monocytes and neutrophils to sites of inflammation. Again, one must recognize that this is an oversimplification of a complex regulatory mechanism and that as additional knowledge is gained about TH1, TH2, T reg, and TH17 lymphocyte responses, we will be able to understand pathogenic mechanisms of diseases, which will lead to the development of more specific therapeutic targets. Fig. 5-5 Differentiation and expression of CD4 T lymphocytes. WEB TABLE 5-1 Basic Cytokine and Functional Profiles of TH1 and TH2 Lymphocytes B lymphocytes constitute 5% to 20% of the peripheral blood mononuclear cells. B lymphocyte development occurs in two phases, an antigen-independent phase in the primary lymphoid tissues, followed by an antigen-dependent phase in secondary lymphoid tissues. B lymphocytes can be found in primary lymphoid tissues, such as the bone marrow and ileal Peyer’s patches (a primary lymphoid tissue in some species because it is the site of B lymphocyte development, rather than the bone marrow), and in secondary lymphoid tissues, such as the spleen, lymph nodes, tonsils, and Peyer’s patches. Within secondary lymphoid tissues, B lymphocytes are aggregated in the form of distinct lymphoid follicles, which on activation expand to form prominent pale regions called germinal centers (Fig. 5-6). This anatomic localization, similar to T lymphocytes in the PALS and paracortex, is the result of elaboration of chemokines for which the B lymphocyte has receptors. The antigen receptor of the B lymphocyte is the membrane bound immunoglobulin. After the antigen-independent phase of development, B lymphocytes express IgM and IgD on their surface that signifies a mature B lymphocyte. In the antigen-dependent phase, antigen-activated mature B lymphocytes differentiate into IgM-secreting plasma cells or switch to another antibody isotype. Immunoglobulins can be generated against an almost unlimited number of antigenic determinants through the rearrangement of genes encoding the light chain and heavy chain components. As in the case of the TCR, an evaluation of the rearranged genes of a B lymphocyte can be used to molecularly phenotype B lymphocyte neoplasms (see Chapter 6). Fig. 5-6 Histology of a hyperplastic lymph node. Fig. 5-7 The B lymphocyte antigen receptor complex. In general, a circulating MPS cell in the blood is designated as a monocyte, whereas the tissue-based cell is designated as a macrophage. The blood monocyte-to-tissue macrophage is well recognized, although the mechanisms that allow for differentiation of the circulating monocyte pool into the tissue-based pool are still largely unknown. The monocyte is a bone marrow–derived cell of the myeloid lineage that is the precursor cell to the terminally differentiated macrophage that has limited recirculation and replication capacity. The myeloid dendritic cell represents a specific type of mononuclear cell present in nonlymphoid tissues with unique migratory properties and is discussed separately. As opposed to granulocytic myeloid cells, macrophages are long-lived (days to months) and can exist as quiescent “resident” cells widely distributed throughout the body. It is becoming increasingly clear that there is heterogeneity in the circulating monocyte pool that corresponds with the ultimate tissue localization of resident macrophages. The phenotypic characterization of the cells the MPS contains is often used in an attempt to identify specific populations of MPS (Fig. 5-8). Morphologically, monocytes are variably sized with an irregular shape, oval or kidney-shaped nucleus, prominent cytoplasmic vesicles, and a high cytoplasm to nucleus ratio. These features are not unique to monocytes, and as a result, they are difficult to distinguish from circulating dendritic cells, activated lymphocytes, and NK cells based on morphology or by light scatter (flow cytometry). This section covers basic concepts attributable to monocytes, tissue macrophages, and myeloid dendritic cells and refers to specific organ systems. See additional chapters in the section on pathology of organ systems for details on organ-specific cells of the MPS. Certain organ systems have specific names for their resident macrophages, whereas other organ systems only refer to them as macrophages (Table 5-2). TABLE 5-2 Nomenclature and Location of Nonlymphoid Monocyte-Macrophage Cell Types Growth and differentiation of monocytes is regulated by specific growth factors, such as IL-3, colony-stimulating-factor-1 (CSF-1), granulocyte-macrophage CSF (GM-CSF), IL-4, and IL-13, and inhibitors such as type I interferons and transforming growth factor-β (TGF-β). CSF-1 is the most important because it controls the proliferation, differentiation, and survival of the monocyte. Monocytes represent approximately 4% to 10% of blood leukocytes and are identified in mammals, birds, amphibians, and fish. They are largely viewed as accessory cells that importantly link inflammation and innate immune responses to adaptive immunity. Hematopoietic stem cells (HSC) give rise to the common myeloid progenitor (CMP), the precursor cell to the granulocyte/macrophage progenitor (GMP) and macrophage/dendritic cell progenitor (MDP). The MDP is the common progenitor cell for monocytes, macrophages, and conventional dendritic cells. Monocytes express the CSF-1 receptor (CD115) and the chemokine receptor CX3CR1, are differentiated from polymorphonuclear cells (PMNs), NK cells, and lymphoid cells, and do not express CD3, CD19, or CD15. Monocyte heterogeneity based on surface marker expression and function has identified subsets that are an area of intense investigation and are best characterized in humans and rodents. Subpopulations of blood monocytes can be phenotyped based on the expression of surface markers CD14 and CD 16 (FcγR-III). Two additional subpopulations of blood monocytic cells are the myeloid blood dendritic cells, which are negative for CD14 and CD16. In the mouse, the main subset of CD115+ monocytes are characterized as large cells expressing Ly6C, the chemokine receptor CCR2 and the adhesion molecule L-selectin (CD62L), and CX3CR1 (Fig. 5-9). These are referred to as inflammatory monocytes or inflammatory-monocyte-derived macrophages that are preferentially recruited to inflamed tissues and lymph nodes where they produce high levels of TNF-α and IL-1. The emigration of Ly6C+ monocytes from the bone marrow to the periphery depends on the chemokine receptor CCR2 and its ligands CCL7 and CCL2. Ly6C negative monocytes have less of an influence on inflammatory reactions and appear to function more importantly as tissue resident cells and as cells involved in healing and regeneration associated with vascular injury. In those species characterized to date, there appear to be two major functional subpopulations of monocytes, one that is recruited and differentiated into macrophages at the site of inflammation and expresses higher levels of MHC class II and adhesion molecules and one that is responsible for repopulating resident tissue macrophages. Both populations can give rise to dendritic cells (see Fig. 5-8). Classification schemes are forever evolving, and there are definite species differences that may explain species differences in rates of infection and types of clinical disease associated with specific microbial agents. Similar phenotypic and functional heterogeneity exists with tissue-based macrophages. Mononuclear phagocytic cells include circulating monocytes and tissue-based macrophages. In the spleen, macrophages are located in the marginal zone, white pulp, and red pulp, where they function primarily as phagocytic cells. In the lymph node, macrophages are located in the subcapsular sinus, which is analogous to the marginal zone of the spleen, and the medulla. These physical locations, the subcapsular sinus of lymph nodes and marginal zone of the spleen, facilitate their exposure to potential antigens. Nonlymphoid tissue-based macrophages have different functions and are named according to the tissue in which they reside (see Table 5-2). One primary function of these cells is phagocytosis, as discussed in Chapter 3. Macrophages express Fc receptors (FcR) for antibody and can phagocytose antigens opsonized by antibody or complement components. Another primary function is their involvement in the immune response as antigen-presenting cells. In this instance, they phagocytose antigen and process it into peptide fragments, which are then presented to T lymphocytes, and the induction of cell-mediated immune responses. Although all nucleated cells express MHC class I molecules and could be considered antigen-presenting cells, only three cell types normally express MHC class II molecules and are regarded as the major antigen-presenting cells. They are the macrophage, dendritic cell, and B lymphocyte. Whereas B lymphocytes and dendritic cells constitutively express MHC class II molecules, macrophages express MHC class molecules on activation. Dendritic cells comprise a distinct population of cells that are characterized by elongate cell processes. Most dendritic cells are antigen-presenting cells, which process antigens and present fragments to T lymphocytes. They are more efficient than macrophages and B lymphocytes at antigen presentation. Antigen-presenting dendritic cells are nonphagocytic, bone marrow–derived cells. They are the most important antigen-presenting cell for initiating primary immune responses to protein antigens (Fig. 5-10). Antigen-presenting dendritic cells express a number of molecules, such as TLRs and mannose receptors, that make them efficient at capturing and responding to antigens. They also express high concentrations of MHC class II molecules and B7 co-stimulatory molecules. By expressing chemokine receptors similar to T lymphocytes, they have the ability to localize in T lymphocyte regions of lymphoid tissue. By colocalizing to these areas, they are uniquely positioned to present antigens to recirculating T lymphocytes. Antigen-presenting dendritic cells function to capture antigen and then migrate to T lymphocyte areas of secondary lymphoid organs, where they present fragments of the antigen on their surface and increase their expression of co-stimulatory molecules that activate T lymphocytes. Specifically, migrating dendritic cells, derived from Langerhans’ cells that have captured antigen, enter the lymph node through efferent lymphatics and localize in lymphoid organs, where they present antigenic peptides to T lymphocytes that facilitate B lymphocyte activation and the production of antibody-secreting plasma cells. In addition to their function as antigen-presenting cells, they are also important in the process of negative selection in the thymus and in the maintenance of peripheral tolerance. The four types of antigen-presenting dendritic cells and their locations are listed in Table 5-3. Circulating dendritic cells, also known as veiled cells, make up less than 1% of peripheral blood mononuclear cells. The second type of dendritic cell, the follicular dendritic cell, is primarily located in lymphoid follicles. These cells are not derived from the bone marrow, do not express MHC class II molecules, and do not function as an antigen-presenting cell. Follicular dendritic cells have FcR and receptors for C3b. They store antigen-antibody and antigen-C3b complexes and are thought to be involved in the development and maintenance of memory B lymphocytes. TABLE 5-3 Antigen-Presenting Dendritic Cells and Their Primary Location Fig. 5-10 Dendritic cell functions. General Properties of Cytokines Cytokines that broadly influence innate and adaptive immune responses include IL-1, interferons (type 1), IL-6, and TNF-α. These cytokines are produced and influence a wide array of cell types. Cytokines that are involved in hematopoiesis and lymphocyte development include IL-2, IL-3, IL-4, IL-5, IL-12, IL-15, TGF-β, and GM-CSF to mention a few. Chemokines are a large group of cytokines that influence leukocyte development, trafficking, and function. They are organized into subfamilies, with distinct functions, based on the position of cysteine residues. The C-X-C subfamily of chemokines is primarily produced by activated macrophages and tissue cells (e.g., endothelium), and the C-C subfamily is largely produced by activated T lymphocytes. Chemokines are responsible for the anatomic localization (“homing”) of lymphocytes within lymphoid and nonlymphoid tissue. Chemokines and the other proinflammatory cytokines are more thoroughly covered in Chapter 3. The most important functional group of cytokines related to the pathogenesis of a number of diseases of immunity are those involved in the regulation of TH lymphocytes. As discussed previously, TH lymphocytes are classified based on their functional capacity and ability to elicit primarily an antibody response or a cell-mediated immune response rather than on their expression of specific cell markers (Fig. 5-13). TH1 lymphocytes are activated by IL-12 and IL-18 and produce primarily IL-2, IFN-γ, and TNF-β to direct a cell-mediated immune response. TH2 lymphocytes are activated by IL-4 and produce primarily IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13 to direct a humoral immune response. As discussed later in the chapter, the type of response (TH1 versus TH2 type) may determine if a diseased state will occur. IL-15 regulates the growth and activity of NK cells. As indicated in Fig. 5-13, some cytokines, such as IL-10 and TGF-β, downregulate immune responses. In summary, cytokines produced by the TH1 or TH2 subset of lymphocytes not only promote the activation and functional capacities of the subset that produces them (autocrine effect) but also inhibit the development and activity of the other subset. This is known as cross-regulation and has important implications with regard to protective immune responses and adverse immune responses, as is discussed later. Fig. 5-13 Cross-regulation of immunity. Fig. 5-14 Antigen processing and presentation by an antigen-presenting cell, and antigen recognition by T lymphocytes.
Diseases of Immunity
Innate Immunity (Nonspecific Immunity)
NK, Natural killer. (From Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)
Toll-Like Receptors
The binding of LPS to TLR4 results in activation of a signal transduction pathway, leading to gene transcription and the elicitation of an inflammatory response. AP-1, Activating protein 1; NF-κB, nuclear factor-kappa B; TIR, Toll/interleukin-1 receptor. (From Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)
Adaptive Immunity (Specific Immunity)
CTL, Cytotoxic T lymphocyte. (Adapted from Goldsby RA, Kindt TJ, Osborne BA: Kuby immunology, ed 4, New York, 2000, WH Freeman.)
Cells and Tissues of the Immune System
A, TCR-α and TCR-β chains complexed with CD3 γ-, δ-, and ε-chains and the invariant, ζ-chains. B, Illustrating how the TCR recognizes antigen in the context of major histocompatibility complex on the antigen-presenting cell (top) and how the ζ-chains and CD3 γ-, δ-, and ζ-chains deliver one of the two required signals for activation of the T lymphocyte. The second required signal is delivered by the co-stimulator molecules CD28 on the T lymphocyte and B7 on the antigen-presenting cell. MHC, Major histocompatibility complex. (A from Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders. B from Kumar V, Abbas AK, Fausto N, et al: Robbins & Cotran pathologic basis of disease, ed 8, Philadelphia, 2009, Saunders.)
Cytokines in the extracellular tissue fluids direct the differentiation of CD4 T lymphocytes to specific secretory types, such that they secrete specific cytokines that have specific functions on other lymphocytes in the environment. (Adapted from Parham P: The immune system, ed 3, 2009, Garland Science.)
Cytokine
TH1
TH2
IL-2
+
IFN-γ
++
TNF-β
++
GM-CSF
++
+
IL-3
++
++
IL-4
++
IL-5
++
IL-13
++
Function
Antibody*
+
++
IgE
++
Eosinophils, mast cells
++
Macrophages
++
Type IV hypersensitivity
++
Cytotoxic T lymphocytes
++
B Lymphocytes
A, Outer cortex, containing numerous secondary lymphoid follicles with characteristic pale centers, and inner medulla are easily identifiable. B, Localization of B lymphocytes (labeled with a B lymphocyte marker conjugated with a green fluorochrome) and T lymphocytes (labeled with a T lymphocyte marker conjugated with a red fluorochrome). Immunofluorescence photomicrograph. C, Higher magnification of a secondary lymphoid follicle illustrating the central pale, germinal center, which contains primarily proliferating B lymphocytes, CD4+ lymphocytes and dendritic cells, surrounded by densely packed small B lymphocytes. H&E stain. (A, B, and C from Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)
Membrane IgM (or IgD, not shown) and the signaling molecules Igα and Igβ. CD21, also known as complement receptor-2, binds complement components and activates B lymphocytes. Ig, Immunoglobulin. (Courtesy Dr. Alex McPherson, University of California, Irvine.)
Mononuclear Phagocytic System (Monocyte-Macrophage System)
Organ/Tissue
Name
Location
Lung
Alveolar macrophages
Pulmonary intravascular macrophages
Alveolar spaces
Capillaries of the lung
Connective tissues
Histiocytes
Interstitium
Kidney
Mesangial cells
Glomerular tuft
Brain
Microglial cells
Neuroparenchyma and perivascular areas
Bone
Osteoclasts
Bone marrow
Blood
Monocytes
Circulation
Liver
Kupffer cells
Hepatic sinusoids
Macrophages
Dendritic Cells
Dendritic Cells
Location
Langerhans’ cells
Skin, mucous membranes, iris, ciliary body
Interstitial dendritic cells
Most major organs
Interdigitating dendritic cells
T lymphocyte area of secondary lymphoid tissue and thymic medulla
Circulating dendritic cells
Peripheral blood
Specialized dendritic cells in the epidermis (Langerhans’ dendritic cells) capture antigen via phagocytosis or endocytosis and migrate to regional lymph nodes, where they present peptide fragments of the antigen to naïve T lymphocytes. (From Kumar V, Abbas AK, Fausto N, et al: Robbins & Cotran pathologic basis of disease, ed 8, Philadelphia, 2009, Saunders.)
Cytokines: Messenger Molecules of the Immune System
Cross-regulation of TH1 and TH2 lymphocytes in part determines if an immunity is primarily a cell-mediated response or a humoral response. TH1 lymphocytes, activated primarily by IL-12 and IL-18, promote cell-mediated immunity (CMI) by activating macrophages and cytotoxic T lymphocytes. TH2 lymphocytes, activated primarily by IL-4, promote humoral immunity by producing cytokines that activate B lymphocytes to develop into antibody-secreting plasma cells. TH2 lymphocytes also produce cytokines that activate mast cells and eosinophils in the pathogenesis of allergic diseases. The cross-regulation of TH1 and TH2 lymphocytes provides an inverse relationship between cell-mediated and humoral immunity. IFN-γ, Interferon-γ; Ig, immunoglobulin; IL, interleukin; NK, natural killer; TNF-β, tumor necrosis factor-β. (Adapted from Goldsby RA, Kindt TJ, Osborne BA: Kuby immunology, ed 4, New York, 2000, WH Freeman.)
Structure and Function of Histocompatibility Antigens
A class I major histocompatibility complex (MHC)–restricted CD8+ lymphocyte is depicted. ER, Endoplasmic reticulum; TCR, T lymphocyte receptor. (From Kumar V, Abbas AK, Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)
Disorders of the Immune System
Diseases of Immunity
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