Page 27 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 1 The Human Immune Response 13

of additional proinflammatory molecules. The protective role that this positive response be tightly regulated by mechanisms
of IgE is in host defenses against parasitical infestation, particularly that operate to turn off the response and to eliminate cells no
with helminths (Chapter 31). longer required. 50,51 Under physiological circumstances, once an
immune response fades, commonly as a consequence of antigen
Complement and Immune Complexes depletion, two pathways to terminal lymphocyte differentiation
As noted, the biological functions of IgG and IgM are importantly become available: apoptosis or differentiation into memory cells.
reflections of their capacities to activate the complement system. Memory cells are, of course, a key to the effectiveness of the
Through a cascade of sequential substrate–enzyme interactions, adaptive immune system, since a second activating encounter
the 11 principal components of the antibody-dependent comple- with antigen (e.g., pathogen) is both more rapid and more
ment cascade (C1q, C1r, C1s, and C2–C9) cause many of the productive. Isotype-switched high-affinity antibodies are rapidly
principal consequences of an antigen-antibody interaction produced, and/or clones of CTL effector cells proliferate. But
(Chapter 21). These include the establishment of pores in a the majority of lymphocytes in an active response are not required
target cell membrane by the terminal components (C5–C9) for maintenance of immunological memory, and the necessity
leading to osmotic lysis; the production of factors (principally for homeostasis leads to apoptosis of cells no longer required.
C5a) with chemotactic activity for phagocytic myeloid cells; Apoptosis (or Regulated Cell Death; RCD) is a unique process
opsonization by C3b, promoting phagocytosis; and the ability of cellular death, widely conserved phylogenetically, and distin-
to induce degranulation of mast cells (C3a, C4a, and C5a). There guished from death by necrosis by cellular shrinking, DNA
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are three distinct pathways to complement activation. The fragmentation, and breakdown of cells into “apoptotic bodies”
pathway mediated by the binding of the first component (specifi- containing nuclear fragments and intact organelles that can be
cally C1q) to IgG or IgM has been termed the “classical” pathway eliminated by phagocytosis without release into the extracellular
(CP). The lectin pathway is similar to the CP but is activated space of the majority of intracellular, especially nuclear, compo-
by selected carbohydrate-binding proteins, the mannose (or nents. Necrosis can be genetically determined (Regulated Necrosis;
mannan)-binding lectin (MBL), and ficolins, which recognize RN) or unregulated, reflecting some accidental or otherwise
certain carbohydrate repeating structures on microorganisms. inevitable process (Chapter 13). Apoptosis depends on the
MBL and ficolins are plasma proteins that are homologous to activation of cysteinyl proteases, termed caspases, which cleave
C1q and contribute to innate immunity through their capacity proteins that regulate DNA repair and the establishment/
to induce antibody- and C1q-independent activation of the CP. maintenance of cellular architecture. In the absence of these
Finally, a large number of substances, including certain bacterial, apoptotic mechanisms, massive proliferation of cells in lymphoid
fungal, and viral products, can directly activate the cascade tissues results and is seen clinically as autoimmune lympho-
through a distinct series of proteins also leading to activation proliferative syndrome (ALPS), which is characterized by lym-
of the central C3 component. Although bypassing C1, C4, and phocytosis with lymphadenopathy and splenomegaly as well as
C2, this distinct pathway can achieve all the biological conse- autoimmunity and hypergammaglobulinemia. 52
quences of C3–C9 activation. Non–antibody-induced activation
of C3 is referred to as the “alternative” pathway (AP) or “pro- MECHANISMS OF IMMUNOLOGICAL DISEASES
perdin” pathway. Additionally, the central components of the
cascade (e.g., C5a) can be directly produced by the action of Immunological diseases can be classified on the basis of our
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serine proteases of the coagulation system. Reflecting these understanding of normal immune physiology and its perturba-
separate pathways to activation and the fact that many types of tions in disease states (Table 1.2). One type of immunological
leukocytes express receptors for activated complement compo- disease results from failure or deficiency of a component of the
nents, the complement system is a major contributor to the immune system leading to failure of normal immune function
efferent limbs of both innate and acquired immune systems. (Chapters 32–40). Such disorders are usually identified by
In addition to their roles in pathogen/antigen elimination, increased susceptibility to infection (Chapter 37). Failure of host
constituents of the complement system, together with antigen– defense can be congenital (e.g., X-linked agammaglobulinemia;
antibody (immune) complexes, act at leukocyte surfaces to Chapter 34) or acquired (e.g., acquired immunodeficiency
regulate immune functions. For example, interaction of immune syndrome [AIDS]; Chapter 39). It can be global (e.g., severe
complexes via FcγR on B cells decreases their responsiveness combined immunodeficiency [SCID]; Chapter 35) or, quite
to stimulation. In contrast, complement activation on B-cell specific, involving only a single component of the immune system
surfaces coligates their receptors with B-cell receptors for antigen, (e.g., selective IgA deficiency; Chapter 34).
rendering the cells more readily activated and resistant to A second type of immunological disease is malignant trans-
apoptosis. formation of immunological cells (Chapters 77–80). Manifesta-
Essential for the proper function of the complement system tions of leukocyte malignancies are protean, most commonly
is a series of downregulatory mechanisms that prevent unwanted
activation of the system and that extinguish its activity when
no longer needed. The regulatory pathways are mediated by a TABLE 1.2 Mechanisms of Immunological
combination of both soluble complement-binding and digesting Diseases
molecules and cell surface binding proteins. 1. Functional deficiency of key immune system components
a. Congenital
b. Acquired
APOPTOSIS AND IMMUNE HOMEOSTASIS 2. Malignant transformation of immune system cells
3. Immunological dysregulation
An immune response is commonly first viewed in a “positive” 4. Autoimmunity
sense—that is, lymphocytes are activated, proliferate, differentiate, 5. Untoward consequences of physiological immune function
and carry out effector functions. It is equally important, however,