Page 28 - Clinical Immunology_ Principles and Practice ( PDFDrive )

14 Part one Principles of Immune Response

reflecting the secondary consequences of solid organ or bone Inflammatory lesions in such diseases are the result of the normal
marrow infiltration or replacement of normal cells by tumor function of the immune system. A typical example is contact
cells, with resulting anemia and immunological deficiency. dermatitis to such potent skin sensitizers as urushiol, the causative
The remaining types of immunopathogenesis are more specific agent of poison ivy dermatitis (Chapter 44). These diseases can
to the immune system. Dysregulation of an essentially intact also have an iatrogenic etiology that can range from mild and
immune system constitutes a third general type of immune self-limited (e.g., delayed hypersensitivity skin test reactions) to
disorder. Features of an optimal immune response include antigen life-threatening (e.g., graft-versus-host disease, organ graft
recognition and elimination, with little adverse effect on the rejection).
host. Both initiation and termination of the response, however,
involve regulatory interactions that can go awry when the host HOST IMMUNE DEFENSES SUMMARIZED
is challenged by antigens of a particular structure or presented
in a particular fashion. Diseases of immune dysregulation can The first response upon initial contact with an invading pathogen
result from genetic and environmental factors that act together depends on components of the innate immune system (Chapter
to produce a pathological immune response, such as acute allergic 3). This response begins with recognition of PAMPs expressed
diseases (Chapters 41–49). Some forms of allergic disease are by cells of the pathogen. These include lipoproteins, lipopolysac-
thought to be a consequence of insufficient exposure to non- charide, unmethylated CpG-DNA, and bacterial flagellin, among
pathogenic microbes and other potential allergens in early others. PAMPs bind to PRRs on or within effector cells of the
childhood, resulting in an increased susceptibility to allergy, host’s innate immune system, including DCs, granulocytes, and
3
atopy, and asthma once the immune system has matured. The ILCs. The best characterized PRRs are the TLRs, first recognized
so-called “hygiene hypothesis” suggests that mucosal tissue- as determinants of embryonic patterning in Drosophila and
colonizing organisms play key roles in the initial establishment subsequently appreciated as components of host defenses in both
53
of immune homeostasis. The importance of establishing insects and vertebrates. TLR subfamilies can be distinguished
immune homeostasis early in life is also supported by studies by expression either on the cell surface or in intracellular compart-
demonstrating reduction in the likelihood of food allergy associ- ments. A second major family of PRRs comprises NLRs, which
ated with feeding of the allergenic foods to infants at high risk detect intracellular microbial products. Binding of TLRs or NLRs
for allergy 54-56 (Chapter 45). by PAMP ligands triggers intracellular signaling pathways via
A fourth type of immunological disorder is the result of multiple “adapters,” leading to a vigorous inflammatory response.
failure of a key feature of normal immune recognition, the The innate immune response also includes the capacity of
molecular discrimination between self and nonself. Ambigu- NK lymphocytes to identify and destroy, by direct cytotoxic
ity in this discrimination can lead to autoimmune tissue mechanisms, cells lacking surface expression of MHC class I
4
damage (Chapters 50–76). Although such damage can be molecules, which marks them as potentially pathogenic. Addition-
mediated by either antibodies or T cells, the common asso- ally, an innate immune response involves elements of the humoral
ciation of specific autoimmune diseases with inheritance of immune system that function independently of antibody,
particular HLA alleles (Chapter 5) suggests that the patho- especially the activation of the complement cascade through
genesis of autoimmune diseases usually represents a failure of the lectin pathway and the AP, with consequent opsonization
regulation of the anti-self inflammatory response by T cells. The of particles and microbes to promote their phagocytosis and
immunologic attack on self-tissues can be general, leading to destruction.
systemic autoimmunity, such as systemic lupus erythematosus; The nature of the adaptive immune response to any particular
or it can be localized, as in organ-specific autoimmune diseases. pathogenic agent is determined largely by the context in which
In the latter instances, the immune system attacks specific types the pathogen is encountered. Regardless, effectiveness depends
of cells and usually particular cell surface molecules. In most on the four principal properties of adaptive immunity: (i) a
cases, pathology is a consequence of target tissue destruction (e.g., virtually unlimited capacity to bind macromolecules, particularly
multiple sclerosis, rheumatoid arthritis, or insulin-dependent proteins, with exquisite specificity, reflecting generation of
diabetes mellitus). However, depending on the antigenic specificity antigen-binding receptors by genetic recombination and, in the
of the abnormal immune response, autoimmunity can lead to case of B cells, somatic hypermutation; (ii) the capacity for self/
receptor blockade (e.g., myasthenia gravis or insulin-resistant nonself discrimination, consequences of a rigorous process
diabetes) or hormone receptor stimulation (e.g., Graves disease). It involving positive and negative selection during thymocyte
is thought by many immunologists that ambiguity in self/nonself differentiation, as well as negative selection during B-cell dif-
discrimination is commonly triggered by an unresolved encounter ferentiation; (iii) the property of immunological memory, reflecting
with an infectious organism or other environmental agent that antigen-driven clonal proliferation of T cells and B cells, which
shares some structural features with self-tissue structures, although results in increasingly rapid and effective responses on second
this remains a subject of controversy 57,58 (Chapter 50). Insight and subsequent encounters with a particular antigen or pathogen;
into mechanisms whereby specific HLA alleles predispose to and (iv) mechanisms for pathogen destruction, including direct
development of autoimmunity and others may be protective cellular cytotoxicity, release of inflammatory cytokines, opsoniza-
are suggested by studies in HLA-transgenic mice, which suggest tion with antibody and complement, and neutralization in solution
that alleles that predispose animals to a particular autoimmune by antigen precipitation or conformational alteration plus
disease may reflect a T cell phenotype associated with secretion phagocytosis and intracellular digestion.
of pro-inflammatory cytokines. In contrast protective alleles Although most acquired immune responses include multiple
were associated with elaboration of trolerogenic cytokines by defense mechanisms, several generalizations may be conceptually
regulatory T cells. 59 useful. T cell–mediated (and NK cell–mediated) effector functions
A fifth form of immunological disease occurs as a result are particularly important in defenses against pathogens encoun-
of physiological, rather than pathological, immune functions. tered intracellularly or at cell surfaces, such as intracellular viruses,