The complement system consists of a group of glycoproteins in the extracellular space that can be stimulated in a cascading fashion to produce biologically active fragments that either directly attack foreign substances or enhance the functions of certain types of inflammatory leukocytes. The complement system consists of two recognition-stimulation pathways that are designated as the classical and alternative pathways, either of which may lead to the formation of a cell membrane attack complex (Fig. 1-20).
Figure 1-20. The complement system. Activation of either wing of the system leads to the formation of peptide fragments that function on leukocytes and forms the membrane attack complex.
The classical pathway of the complement system may be activated by antigen-antibody complexes of the IgG, IgG3, or IgM isotypes by their binding to the C1q subunit of the first component of complement (Fig. 1-20). Consequently, the C1qrs subunits of C1 form an esterase that cleaves the next component, C4, to two fragments, the larger of which, C4b, binds covalently to hydroxyl or amino groups on cellular membranes. The next component, C2, after binding to C4b is partially digested by C1s esterase to form C2b. The resultant membrane-bound complex, C4b2a, is an enzyme (C3 convertase) that cleaves C3 into two biologically active fragments, C3a and C3b.
The alternative pathway of the complement system is activated independently of antigen-antibody complexes (Fig. 1-20). The major exogenous activators of the pathway are microbial agents and their products. The major components of the pathway are the serum protein factors B, D, and P (properdin). A small amount of C3 in the fluid phase, which normally is spontaneously activated, interacts with factor B to form C3Bb, which cleaves other C3 molecules to form C3b. C3b in turn attaches to surfaces and binds factor B. The resultant C3bB is then cleaved by factor D to form C3bBb, the C3 convertase of the alternative pathway. That enzyme is distinct from the one generated from the classical pathway but serves the same purpose. This complex then is stabilized by factor P.
The binding of C3 to factor B is prevented, particularly in the fluid phase, by a regulatory molecule, factor H. The more vigorous activation of this pathway occurs when the host is exposed to microorganisms that are poor in sialic acid. In those circumstances, the binding of factor B to C3 is favored, and the activation of the alternative pathway is not readily inhibited by factor H. Therefore, more C3b is generated and a positive amplification loop that generates more C3bBb (C3 convertase) is created. In contrast, sialic acid-rich encapsulated microorganisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Niesseria meningitides are incapable of activating the alternative pathway and require binding to specific IgG or IgM antibodies to activate the classical pathway and generate the C3b for phagocytosis and the formation of the membrane attack complex. The receptors for activated complement fragments are 1) CR1, principally on phagocytic cells for C3b; 2) CR2, principally on B cells for a fragment called C3d (receptor for EBV); and CR3 (Mac-1), on phagocytic and NK cells for inactivated C3b (C3bi) and C3d-g fragments.
The activation of the complement system eventually leads to the formation of the membrane attack complex that consequently lyses cells. The membrane attack complex is formed in the following manner. As a result of the formation of C3b, C5 is cleaved into two fragment, C5b and C5a. The larger fragment, C5b, combines with C6 and the complex attaches to the cell surface, where it forms the foundation for the sequential binding of C7, 8 and 9, e.g., the membrane attack complex (Fig. 1-20). C3b and its degradation product, C3bi, are opsonins. C3a and C5a are chemotaxins and anaphylotoxins; C5a is the more potent of the two factors.
Once the membrane attack complex is formed, discrete holes are created in the surface membranes of the target cells. Consequently, extracellular fluid accumulates in the target cell, eventually leading to its lysis.
The first line of defense against most potential pathogens is the skin and mucous membranes. In addition to anatomic barriers, certain protective biochemical agents are produced at mucosal sites. These include simple chemicals such as acids and bases, and macromolecular proteins, including lysozyme, lactoferrin, secretory IgA antibodies, and interferons.
The genesis of secretory IgA antibodies is as follows. Under the influence of IL-5, IL-6, and IL-10, B cells bearing surface IgM in Peyer's patches and in the submucosa of the tracheo-bronchial tree switch to IgA-bearing cells. When the surface antibodies of these altered cells combine with a specific antigen, the cells are stimulated to migrate through afferent lymphatics to the regional lymph nodes and then through efferent lymphatic channels into the vascular circulation. They then home to submucosal sites in the upper small intestine, or to the respiratory system, where they differentiate into plasma cells that secrete large amounts of specific dimeric IgA antibodies and are transported across epithelial cells to the lumen by secretory component, as previously described. The resultant secretory IgA is particularly well suited to mucosal sites since it is more resistant than other types of immunoglobulins to the digestive processes of the alimentary tract. These antibodies protect by complexing adherence structures and toxins from microbial pathogens.
The second line of defense consists of local factors and leukocytes that are activated or recruited to the site of microbial invasion. These local elements of defense include the coagulation system, the fibrinolytic system, kallikrein, the complement system, resident macrophages, and elicited inflammatory cells.
If the pathogen is able to overcome the first two lines of defense, systemic acquired responses are marshalled to prevent further invasion and damage. This third line of defense includes intracellular killing by circulating phagocytes, stimulation of monokine production, interleukin production by T cells, production of circulating antibodies by plasma cells in regional lymph nodes and the spleen, intravascular activation of the complement system, and phagocytosis of opsonized pathogens by cells of the RES. Cytotoxic mechanisms directed against ingested microbes or infected cells play a major role in defense.
Unless the microbial inoculum is overwhelming, unusually virulent, or the host defenses are compromised, the infection should be contained and finally obliterated via a combination of local and systemic responses. At the same time local fibroblasts and epithelial cells proliferate, the tissue becomes more vascularized, and debris is removed by local tissue phagocytes. The inflammatory reaction abates and the tissue heals.
Five major types of immune responses to infecting agents may lead to disease. 1) Circulating immune complexes formed from microbial antigens such as hepatitis B virus bound to IgM or IgG antibodies, may deposit in skin, synovia, or glomeruli and elicit inflammation by activating the classical pathway of complement. 2) Invading microorganisms may give rise to antibodies that cross-react with autoantigens. For example, antibodies produced against Group A, beta-hemolytic streptococci in patients with rheumatic fever often react against sarcolemmal antigens in cardiac muscle. 3) Vasoactive compounds may be released into local tissues or the systemic circulation because of activation of the alternative pathway of complement by certain bacteria deficient in sialic acid such as Salmonella. 4) Cytokines such as TNF-alpha, IL-1, and IFN-gamma released during infection from stimulated macrophages and T lymphocytes, may lead to fever, dysregulate nutritional pathways, and contribute to the vascular instability seen in sepsis. 5) Finally, delayed hypersensitivity reactions that damage surrounding tissues occur in indolent infections such as tuberculosis by the formation of granulomas consisting of activated macrophages and cytotoxic T cells.
There is an orderly development of the immune system during the intrauterine period. Pluripotent stem cells appear first in the yolk sac, then in the fetal liver, and finally the bone marrow (Fig. 1-2). Neutrophils, monocytes, and macrophages are produced during fetal life, but the mononuclear phagocytes do not mature until after birth. An epithelial thymus appears during the first few fetal weeks and then becomes populated with lymphocytes. Mature T and B cells appear in the blood soon thereafter, but they are largely not activated. Furthermore, IgG antibodies are usually not produced until after birth, and IgG antibodies to polysaccharide antigens do not appear until ~ 2 years of age. In addition, there are developmental delays in the production of certain cytokines, including GM-CSF, IL-10, TNF-alpha and IFN-gamma.
Neonates have as many B and T cells in the peripheral blood as do adults, these cells in the peripheral lymphoid organs are not as well developed because of the paucity of prenatal antigenic stimuli. As antigen stimulation occurs, the T and B cell zones of the peripheral lymphoid organs are progressively populated and the products of these stimulated cells, such as antibodies, begin to appear. The sequence of immunoglobulin production is as follows: IgM production occurs first and is then followed by IgG and IgA. Systemic IgG antibodies to polysaccharides are not produced, however, until the child is 2 to 2.5 years old. The secretory component is produced at birth, but the main immunoglobulin in external secretions in the first few weeks of postnatal life is IgM. Subsequently, secretory IgA becomes the dominant immunoglobulin at mucosal sites.
The mother transmits immune factors to the offspring both through the placenta and milk. Large quantities of IgG are transmitted via the placenta, whereas other immunoglobulin isotypes are not. Consequently, virtually all IgG in neonatal blood is of maternal origin, the concentration of IgG in umbilical cord blood is somewhat higher than in adults, and the levels of other immunoglobulin isotypes are exceptionally low. Low concentrations of some factors such as IgG and secretory IgA antibodies are also transmitted via amniotic fluid, but little is known about their in vivo effects upon the fetal mucosal immune system.
An array of host resistance factors are transmitted to the infant in human milk, including leukocytes, secretory IgA, lactoferrin, lysozyme, and oligosaccharides and glycoconjugates that are receptor analogs for microbial adhesins and toxins. In addition to those antimicrobial factors, anti-inflammatory agents, and immunomodulating agents including TNF-alpha, TGF-beta, IL-1beta, IL-6, IL-8, IL-10, G-CSF, and M-CSF. These factors are designed to act at mucosal sites and to protect by noninflammatory mechanisms. Since the endogenous production of these agents is incompletely developed in early infancy and they are scarce in cow's milk or other substitute feedings, it is not surprising that breastfeeding increases resistance to gastrointestinal and respiratory infections, allergic diseases, and certain inflammatory diseases that occur much later in childhood.
Immune deficiencies may be due to genetic or acquired defects, and these defects lead to increased risks to certain infectious diseases depending upon the specific immune defects. Much of the basic information concerning the development and function of the immune system has been learned from investigations of inherited, congenital, and acquired defects of the system. Examples of the principal defects that have lead to an elucidation of the immune system are as follows.
The principal genetic defects in the immune system are summarized in Table 1-4. They are as follows.
X-Linked Agammaglobulinemia: In this immunoglobulin deficiency disease, there is a genetic defect in the development of B cells from pre-B cells in the bone marrow. The defect is due to mutations in the gene that encodes for B cell tyrosine kinase. Consequently, the B cells are not produced. Because of the block in the development of B cells, germinal centers, plasma cells, and specific antibodies are profoundly reduced. The rest of the immune system is normal. Affected individuals are unusually susceptible to infection by virulent encapsulated respiratory bacteria and enteroviruses. These patients benefit greatly from intravenous infusions of human IgG.
Hyper-IGM Antibody Deficiency: A second X-linked defect in antibody formation, the hyper-IgM antibody deficiency, is characterized by a block in immunoglobulin class switching. Consequently, IgM (and IgD) antibodies are produced, but IgA and IgG antibodies are not. These patients are also unusually susceptible to infection by virulent encapsulated respiratory bacteria. The disease is due to mutation in the gene that encodes for CD40 ligand (CD39) on T cells. Because of the defect, T and B cell interactions are insufficient for immunoglobulin class switching. These patients also benefit greatly from intravenous infusions of human IgG.
Severe Combined Immunodeficiency (SCID): The most common type of SCID is due to stop codon defects in the X-chromosome gene that encodes for the gamma-chain that is common to IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. A more moderate combined immunodeficiency disease has been reported and is due to a missense point mutation in a part of the gene that encodes for the cytoplasmic region of that gene. In addition, other defects reported to cause SCID involve an autosomal recessive defect in the formation of adenosine deaminase, a defect in the formation of CD3, a defect in the post TcR-CD3 receptors' signalling, and deficiency in the formation of IL-2.
Patients with these diseases display few T lymphocytes, decreased T cell functions, poor antibody formation, and variable numbers of B cells and serum concentrations of immunoglobulins. As a consequence of the deficiencies in T cells, these patients are very susceptible to opportunistic pathogens, including Candida albicans, Salmonellae, Pneumocystis carinii, Cytomegalovirus, and Varicella zoster virus. Patients with SCID usually die before the age of two years, unless definitive immunologic interventions are instituted.
Specific treatments have been devised for patients with SCID. Many patients have been treated successfully with bone marrow transplants to supply normal stem cells. Patients with adenosine deaminase deficiency may also be managed by infusing the enzyme packaged with polyethylene glycol. Recently, some patients with adenosine deaminase deficiency have been successfully treated with gene therapy. Although the beneficial effects have not been permanent, nevertheless, they are encouraging.
Two major intrinsic defects in the function of phagocytic cells have been recognized. The first one is an autosomal recessive defect in the formation of the common beta-subunit of the family of adherence glycoproteins (integrins). The deficiency interferes with the ability of these leukocytes to adhere to the surface of endothelial cells. Consequently, the motility of these cells on two-dimensional surfaces is impaired. Thus, this defect results in bacterial infections in interstitial sites, such as in the skin and periodontium.
The second disorder, chronic granulomatous disease, was the first recognized genetic defect of the function of phagocytic cells. The disease is X-linked in ~ 70% of affected patients. In those cases, the gene for the gp90 protein subunit of cytochrome b558 is abnormal. Consequently, the protein is not produced, the cytochrome does not persist, and intracellular killing is impaired. Less frequently (~ 3% of cases), the disease is due to a defect in the autosomal gene for the lower molecular weight subunit of the heterodimer, p22phox. Autosomal defects in genes for cytoplasmic proteins that stabilize the cytochrome have also been recognized.
In these disorders, phagocytes are unable to mount a respiratory burst and therefore are unable to produce toxic oxygen compounds, such as hydrogen peroxide, which are required for intracellular killing of catalase-positive microorganisms such as Candida albicans, Escherichia coli, and Serratia species. The failure to kill catalase-positive microorganisms occurs because the microbial agents do not supply the oxygen substrates required for intracellular killing. In contrast, these dysfunctional neutrophils kill catalase-negative microorganisms such as the streptococci since those microorganisms bring hydrogen peroxide into the phagolysosome.
Protein-Calorie Malnutrition: Protein-calorie malnutrition is the leading cause of immune deficiency in the world. Protein-calorie malnutrition leads principally to a profound deficiency in the production and function of T cells, rendering the victim susceptible to many of the opportunistic infections that occur in genetic T cell deficiencies. With increasing protein-energy deficiency other parts of the immune system are also affected. Specific nutrient deficits such as iron or vitamin A deficiency also depress certain parts of the immune system.
Certain types of infections temporarily depress parts of the immune system. For example, many acute viral infections suppress cellular immunity for several days to a few weeks, and serious bacterial infections inhibit the ability of neutrophils to respond to chemotactic agents. Furthermore in schistosomiasis, Th1 responses are accentuated and Th2 responses are suppressed. This leads to a decreased ability to form antibodies after antigenic challenges.
Malnutrition and infection interact to inhibit the immune system. As a result of malnutrition, the immune system becomes compromised. That leads to respiratory and gastrointestinal infections. Those infections may in turn further interfere with the immune system. Moreover, some infections further compromise nutritional status by increasing nutrient losses (intestinal malabsorption) and utilization (fever, caloric expenditure during sweating) or by interfering with normal nutrient metabolic pathways (cachectic effect of TNF-alpha). Consequently, immune function is further impaired.
Human Immunodeficiency Virus Infections: A second acquired immunodeficiency is due to human immunodeficiency virus (HIV) infection. This retrovirus infection was first encountered in homosexual males and individuals who were injecting illicit drugs or who received blood products contaminated with the virus. The infection has since spread to heterosexual populations by sexual transmission. The infection has reached epidemic proportions in developed as well as developing countries and continues to increase. The resultant acquired immune deficiency syndrome (AIDS) occurs because the virus infects and destroys CD4+ T cells. The virus binds to the CD4 surface antigen on T cells and to the same or similar moiety on macrophages. Since CD4+ T cells are essential for the genesis of cellular immunity and for orchestrating the function of many other parts of the immune system, a deficiency in these T cells increases the patient's susceptibility to opportunistic infections. The vast majority of such infected patients die after several years. No preventative immunizations or curative treatments are available for the infection at this time.
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