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- Antigen-Presenting Cells
- Polymorphonuclear Leukocytes
- Cytotoxic Leukocytes
- Acute Phase Reactants
- Resources In This Article
- Drugs Mentioned In This Article
Components of the Immune System
The immune system consists of cellular and molecular components that work together to destroy antigens (Ags).
Although some Ags can stimulate the immune response directly, T cell–dependent acquired immune responses typically require antigen-presenting cells (APCs) to present Ag-derived peptides within major histocompatibility complex (MHC) molecules.
Intracellular Ag (eg, viruses) can be processed and presented to CD8 cytotoxic T cells by any nucleated cell because all nucleated cells express class I MHC molecules. By encoding proteins that interfere with this process, some viruses (eg, cytomegalovirus) can evade elimination.
Extracellular Ag must be processed into peptides and complexed with surface class II MHC molecules on professional APCs to be recognized by CD4 helper T (T H ) cells. The following cells constitutively express class II MHC molecules and therefore act as professional APCs:
Monocytes in the circulation are precursors to tissue macrophages. Monocytes migrate into tissues, where over about 8 h, they develop into macrophages under the influence of macrophage colony-stimulating factor (M-CSF), secreted by various cell types (eg, endothelial cells, fibroblasts). At infection sites, activated T cells secrete cytokines (eg, interferon-γ [IFN-γ]) that induce production of macrophage migration inhibitory factor, preventing macrophages from leaving.
Macrophages are activated by IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). Activated macrophages kill intracellular organisms and secrete IL-1 and tumor necrosis factor-α (TNF-α). These cytokines potentiate the secretion of IFN-γ and GM-CSF and increase the expression of adhesion molecules on endothelial cells, facilitating leukocyte influx and destruction of pathogens. Based on different gene expression profiles, subtypes of macrophages (eg, M1, M2) have been identified.
Dendritic cells are present in the skin (as Langerhans cells), lymph nodes, and tissues throughout the body. Dendritic cells in the skin act as sentinel APCs, taking up Ag, then traveling to local lymph nodes where they can activate T cells. Follicular dendritic cells are a distinct lineage, do not express class II MHC molecules, and therefore do not present Ag to T H cells. They are not phagocytic; they have receptors for the crystallizable fragment (Fc) region of IgG and for complement, which enable them to bind with immune complexes and present the complex to B cells in germinal centers of secondary lymphoid organs.
Polymorphonuclear (PMN) leukocytes, also called granulocytes because their cytoplasm contains granules, include
All, except for mast cells, occur in the circulation, and all have multilobed nuclei. Mast cells are tissue-based and functionally similar to circulating blood basophils.
Neutrophils constitute 40 to 70% of total WBCs; they are a first line of defense against infection. Mature neutrophils have a half-life of about 2 to 3 days.
During acute inflammatory responses (eg, to infection), neutrophils, drawn by chemotactic factors and alerted by the expression of adhesion molecules on blood vessel endothelium, leave the circulation and enter tissues. Their purpose is to phagocytose and digest pathogens. Microorganisms are killed when phagocytosis generates lytic enzymes and reactive O 2 compounds (eg, superoxide, hypochlorous acid) and triggers release of granule contents (eg, defensins, proteases, bactericidal permeability-increasing protein, lactoferrin, lysozymes). DNA and histones are also released, and they, with granule contents such as elastase, generate fibrous structures called neutrophil extracellular traps (NETs) in the surrounding tissues; these structures facilitate killing by trapping bacteria and focusing enzyme activity.
Patients with immunodeficiencies that affect the phagocytes' ability to kill pathogens (eg, chronic granulomatous disease) are especially susceptible to chronic bacterial and fungal infections.
Eosinophils constitute up to 5% of WBCs.
They target organisms too large to be engulfed; they kill by secreting toxic substances (eg, reactive O 2 compounds similar to those produced in neutrophils), major basic protein (which is toxic to parasites), eosinophil cationic protein, and several enzymes. Eosinophils are also a major source of inflammatory mediators (eg, prostaglandins, leukotrienes, platelet-activating factor, many cytokines).
Basophils constitute < 5% of WBCs and share several characteristics with mast cells, although the 2 cell types have distinct lineages. Both have high-affinity receptors for IgE called FcεRI. When these cells encounter certain Ags, the bivalent IgE molecules bound to the receptors become cross-linked, triggering cell degranulation with release of preformed inflammatory mediators (eg, histamine, platelet-activating factor) and generation of newly synthesized mediators (eg, leukotrienes, prostaglandins, thromboxanes).
Mast cells occur in different tissues of the body. Mucosal mast cell granules contain tryptase and chondroitin sulfate; connective tissue mast cell granules contain tryptase, chymase, and heparin . By releasing these mediators, mast cells play a key role in generating protective acute inflammatory responses; basophils and mast cells are the source of type I hypersensitivity reactions associated with atopic allergy (see Atopic and Allergic Disorders). Degranulation can be triggered by cross-linking of IgE receptors or by the anaphylatoxin complement fragments C3a and C5a.
Cytotoxic leukocytes include
Typical NK cells constitute 5 to 15% of peripheral blood mononuclear cells. They have a round nucleus and granular cytoplasm and induce apoptosis in infected or abnormal cells by a number of pathways. As cells of the innate response, they lack antigen-specific receptors and immunologic memory. NK cells are best characterized by CD2+, CD3-, CD4-, CD8+, CD16+ (a receptor for IgG-Fc), and CD56+ surface markers.
Typical NK cells are thought to be important for tumor surveillance. NK cells express both activating and inhibitory receptors. The activating receptors on NK cells can recognize numerous ligands on target cells (eg, MHC class I–related chain A [MICA] and chain B [MICB]); the inhibitory receptors on NK cells recognize MHC class I molecules. NK cells can kill their target only when there is no strong signal from inhibitory receptors. The presence of MHC class I molecules (normally expressed on nucleated cells) on cells therefore prevents destruction of cells; their absence indicates that the cell is infected with certain viruses that inhibit MHC expression or has lost MHC expression because cancer has changed the cell.
NK cells can also secrete several cytokines (eg, IFN-γ, IL-1, TNF-α); they are a major source of IFN-γ. By secreting IFN-γ, NK cells can influence the acquired immune system by promoting differentiation of type 1 helper T (T H 1) cells and inhibiting that of type 2 (T H 2) cells.
Patients with NK-cell deficiencies (eg, some types of severe combined immunodeficiency) are especially susceptible to herpes and human papillomavirus infections.
Some leukocytes develop into potent lymphokine-activated killers, capable of killing a wide spectrum of tumor target cells and abnormal lymphocytes (eg, infected with certain viruses). These cells are a phenomenon rather than a unique subset of cells. LAK precursors are heterogeneous but can be classified as primarily NK-like (most common) or T-cell–like.
The 2 main types of lymphocytes are
They are morphologically indistinguishable but have different immune functions. They can be distinguished by Ag-specific surface receptors and molecules called clusters of differentiation (CDs), whose presence and absence define some subsets. More than 300 CDs have been identified (for further information on CD Ags, see the Human Cell Differentiation Molecules web site). Each lymphocyte recognizes a specific Ag via surface receptors.
About 5 to 15% of lymphocytes in the blood are B cells; they are also present in the bone marrow, spleen, lymph nodes, and mucosa-associated lymphoid tissues.
B cells can present Ag to T cells and release cytokines, but their primary function is to develop into plasma cells, which manufacture and secrete antibodies (Abs—see Components of the Immune System : Antibodies).
Patients with B-cell immunodeficiencies (eg, X-linked agammaglobulinemia) are especially susceptible to recurrent bacterial infections.
After random rearrangement of the genes that encode immunoglobulin (Ig), B cells have the potential to recognize an almost limitless number of unique Ags. Gene rearrangement occurs in programmed steps in the bone marrow during B-cell development. The process starts with a committed stem cell, continues through pro‒B and pre‒B cell stages, and results in an immature B cell. At this point, any cells that interact with self Ag (autoimmune cells) are removed from the immature B cell population via inactivation or apoptosis (immune tolerance). Cells that are not removed (ie, those that recognize nonself Ag) continue to develop into mature naive B cells, leave the marrow, and enter peripheral lymphoid organs, where they may encounter Ag.
Their response to Ag has 2 stages:
Primary immune response: When mature naive B cells first encounter Ag, they become lymphoblasts, undergo clonal proliferation, and differentiate into memory cells, which can respond to the same Ag in the future, or into mature Ab-secreting plasma cells. After first exposure, there is a latent period of days before Ab is produced. Then, only IgM is produced. After that, with the help of T cells, B cells can further rearrange their Ig genes and switch to production of IgG, IgA, or IgE. Thus, after first exposure, the response is slow and provides limited protective immunity.
Secondary (anamnestic or booster) immune response: When memory B and T H cells are reexposed to the Ag, the memory B cells rapidly proliferate, differentiate into mature plasma cells, and promptly produce large amounts of Ab (chiefly IgG because of a T cell–induced isotype switch). The Ab is released into the blood and other tissues, where it can react with Ag. Thus, after reexposure, the immune response is faster and more effective.
T cells develop from bone marrow stem cells that travel to the thymus, where they go through rigorous selection. There are 3 main types of T cell:
In selection, T cells that react to self Ag presented by self MHC molecules or to self MHC molecules (regardless of the Ag presented) are eliminated by apoptosis. Only T cells that can recognize nonself Ag complexed to self MHC molecules survive; they leave the thymus for peripheral blood and lymphoid tissues.
Most mature T cells express either CD4 or CD8 and have an Ag-binding, Ig-like surface receptor called the T-cell receptor (TCR). There are 2 types of TCR:
Genes that encode the TCR, like Ig genes, are rearranged, resulting in defined specificity and affinity for the Ag-derived peptide displayed in the MHC molecule of an APC. As for B cells, the number of T-cell specificities is almost limitless.
For T cells to be activated, the TCR must engage with Ag-MHC (see Figure: Two-signal model for T-cell activation.). Costimulatory accessory molecules must also interact; otherwise, the T cell becomes anergic or dies by apoptosis. Some accessory molecules (eg, CTLA-4) inhibit previously activated T cells and thus dampen the immune response. Polymorphisms in the CTLA-4 gene are associated with certain autoimmune disorders, including Graves disease and type I diabetes.
Two-signal model for T-cell activation.
Helper T (T H ) cells are usually CD4 but may be CD8. They differentiate from T H 0 cells into one of the following:
T H 1 cells: In general, T H 1 cells promote cell-mediated immunity via cytotoxic T cells and macrophages and are thus particularly involved in defense against intracellular pathogens (eg, viruses). They can also promote the production of some Ab classes.
T H 2 cells: T H 2 cells are particularly adept at promoting Ab production by B cells (humoral immunity) and thus are particularly involved in directing responses aimed at extracellular pathogens (eg, bacteria, parasites).
T H 17 cells: T H 17 cells promote tissue inflammation.
Each cell type secretes several cytokines (see Table: Functions of T Cells). Different patterns of cytokine production identify other T H -cell functional phenotypes. Depending on the stimulating pathogen, T H 1 and T H 2 cells can, to a certain extent, downregulate each other's activity, leading to dominance of a T H 1 or a T H 2 response.
Functions of T Cells
The distinction between the different T H cells is clinically relevant. For example, a T H 1 response dominates in tuberculoid leprosy, and a T H 2 response dominates in lepromatous leprosy. A T H 1 response is characteristic of certain autoimmune disorders (eg, type 1 diabetes, multiple sclerosis), and a T H 2 response promotes IgE production and development of allergic disorders, as well as helps B cells produce autoantibodies in some autoimmune disorders (eg, Graves disease, myasthenia gravis). T H 17 cells, via their role in inflammation, may also contribute to autoimmune disorders such as psoriasis and RA. Patients with immunodeficiencies characterized by defective T H 17 cells (eg, hyper-IgE [Job] syndrome) are especially susceptible to infection with Candida albicans and Staphylococcus aureus.
Regulatory T cells mediate suppression of immune responses and usually express the Foxp3 transcription factor. The process involves functional subsets of CD4 or CD8 T cells that either secrete cytokines with immunosuppressive properties or suppress the immune response by poorly defined mechanisms that require cell-to-cell contact. Patients with functional mutations in Foxp3 develop the autoimmune disorder IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome.
Cytotoxic T (T C ) cells are usually CD8 but may be CD4; they are vital for eliminating intracellular pathogens, especially viruses. T C cells play a role in organ transplant rejection.
T C -cell development involves 3 phases:
A precursor cell that, when appropriately stimulated, can differentiate into a T C cell
An effector cell that has differentiated and can kill its appropriate target
A memory cell that is quiescent (no longer stimulated) but is ready to become an effector when restimulated by the original Ag-MHC combination
Fully activated T C cells, like NK cells, can kill an infected target cell by inducing apoptosis.
T C cells can secrete cytokines and, like T H cells, have been divided into types T C 1 and T C 2 based on their patterns of cytokine production.
T C cells may be
Some T C cells can directly recognize foreign MHC (direct pathway); others may recognize fragments of foreign MHC presented by self MHC molecules of the transplant recipient (indirect pathway).
NKT cells are a distinct subset of T cells. Activated NKT cells secrete IL-4 and IFN-γ and may help regulate immune responses.
Abs act as the Ag receptor on the surface of B cells and, in response to Ag, are subsequently secreted by plasma cells. Abs recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of Ags (eg, proteins, polysaccharides, nucleic acids). Abs and Ags fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same Ab molecule can cross-react with related Ags if their epitopes are similar enough to those of the original Ag.
Abs consist of 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) joined by disulfide bonds to produce a Y configuration (see Figure: B-cell receptor.). The heavy and light chains are divided into a variable (V) region and a constant (C) region.
V regions are located at the amino-terminal ends of the Y arms; they are called variable because the amino acids they contain are different in different Abs. Within the V regions, hypervariable regions determine the specificity of the Ig. They also function as antigens (idiotypic determinants) to which certain natural (anti-idiotype) Abs can bind; this binding may help regulate B-cell responses.
The C region of the heavy chains contains a relatively constant sequence of amino acids (isotype) that is distinctive for each Ig class. A B cell can change the isotype it produces and thus switch the class of Ig it produces. Because the Ig retains the variable part of the heavy chain V region and the entire light chain, it retains its antigenic specificity.
The amino-terminal (variable) end of the Ab binds to Ag to form an Ab-Ag complex. The Ag-binding (Fab) portion of Ig consists of a light chain and a fragment of a heavy chain and contains the V region of the Ig molecule (ie, the combining sites). The crystallizable fragment (Fc) contains most of the C region of the heavy chains; Fc is responsible for complement activation and binds to Fc receptors on cells.
Antibodies are divided into 5 classes:
The classes are defined by their type of heavy chain (μ for IgM, γ for IgG, α for IgA, ε for IgE, and δ for IgD); there are also 2 types of light chains (κ and λ). Each of the 5 Ig classes can bear either κ or λ light chains.
IgM is the first Ab formed after exposure to new Ag. It has 5 Y-shaped molecules (10 heavy chains and 10 light chains), linked by a single joining (J) chain. IgM circulates primarily in the intravascular space; it complexes with and agglutinates Ag and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins and many Abs to gram-negative bacteria are IgM. Monomeric IgM acts as a surface Ag receptor on B cells. Patients with hyper-IgM syndrome have a defect in the genes involved in antibody class switching (eg, genes that encode CD40, CD154, or NEMO [nuclear factor–κB essential modulator]); therefore, IgA, IgG, and IgE levels are low or absent, and levels of circulating IgM are often high.
IgG is the most prevalent Ig isotype in serum and is also present in intravascular and extravascular spaces. It coats Ag to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to Ag (secondary immune response) and is the predominant isotype contained in commercial γ-globulin products. IgG protects against bacteria, viruses, and toxins; it is the only Ig isotype that crosses the placenta. Therefore, this class of antibody is important for protecting neonates, but pathogenic IgG antibodies (eg, anti-Rh 0 [D] antibodies, stimulatory anti-TSH receptor autoantibodies), if present in the mother, can potentially cause significant disease in the fetus.
There are 4 subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. They are numbered in descending order of serum concentration. IgG subclasses differ functionally mainly in their ability to activate complement; IgG1 and IgG3 are most efficient, IgG2 is less efficient, and IgG4 is inefficient. IgG1 and IgG3 are efficient mediators of Ab-dependent cellular cytotoxicity; IgG4 and IgG2 are less so.
IgA occurs at mucosal surfaces, in serum, and in secretions (saliva; tears; respiratory, GU, and GI tract secretions; colostrum), where it provides an early antibacterial and antiviral defense. J chain links IgA into a dimer to form secretory IgA. Secretory IgA is synthesized by plasma cells in the subepithelial regions of the GI and respiratory tracts. Selective IgA deficiency is relatively common but often has little clinical impact because there is cross-functionality with other classes of antibody.
IgD is coexpressed with IgM on the surface of naive B cells. Whether these 2 classes function differently on the surface of the B cell and, if so, how differently are unclear. They may simply be an example of molecular degeneracy. Serum IgD levels are very low, and the function of circulating IgD is unknown.
IgE is present in low levels in serum and in respiratory and GI mucous secretions. IgE binds with high affinity to receptors present in high levels on mast cells and basophils and to a lesser extent on several other hematopoietic cells, including dendritic cells. If Ag bridges 2 IgE molecules bound to the mast cell or basophil surface, the cells degranulate, releasing chemical mediators that cause an inflammatory response. IgE levels are elevated in atopic disorders (eg, allergic or extrinsic asthma, hay fever, atopic dermatitis) and parasitic infections.
Acute phase reactants are plasma proteins whose levels dramatically increase (called positive acute phase reactants) or, in some cases, decrease (called negative acute phase reactants) in response to the elevated circulating levels of IL-1 and IL-6 that occur when infection or tissue damage occurs. Most dramatically increased are C-reactive protein (CRP) and mannose-binding lectin (which fix complement and act as opsonins), the transport protein α 1 -acid glycoprotein, and serum amyloid P component. CRP and ESR are often measured; elevated levels are a nonspecific indicator suggesting infection or inflammation. Increased fibrinogen is the main reason ESR is elevated.
Many acute phase reactants are made in the liver. Collectively, they may help limit tissue injury, enhance host resistance to infection, and promote tissue repair and resolution of inflammation.
Cytokines are polypeptides secreted by immune and other cells when the cell interacts with a specific Ag, with pathogen-associated molecules such as endotoxin, or with other cytokines (see Table: Selected Cytokines). Main categories include
Although lymphocyte interaction with a specific Ag triggers cytokine secretion, cytokines themselves are not Ag-specific; thus, they bridge innate and acquired immunity and generally influence the magnitude of inflammatory or immune responses. They act sequentially, synergistically, or antagonistically. They may act in an autocrine or paracrine manner.
Cytokines deliver their signals via cell surface receptors. For example, the IL-2 receptor consists of 3 chains: α, β, and γ. The receptor’s affinity for IL-2 is
Mutations or deletion of the γ chain is the basis for X-linked severe combined immunodeficiency (see Severe Combined Immunodeficiency (SCID)).
Chemokines induce chemotaxis and migration of leukocytes. There are 4 subsets, defined by the number of intervening amino acids between the first 2 cysteine residues in the molecule. Chemokine receptors (CCR5 on memory T cells, monocytes/macrophages, and dendritic cells; CXCR4 on resting T cells) act as coreceptors for entry of HIV into cells.
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