Pathologic Basis of Veterinary Disease PDF

CH APT ER 5 Diseases of Immunitya...

CH APT ER 5 Diseases of Immunitya Paul W. Snyder Key Readings Index General Features of the Immune Mononuclear Phagocytic System Cytokine-Related Diseases, 325 System, 295 (Monocyte-Macrophage System), 307 General Features of Autoimmune Innate Immunity (Nonspecific Immunity), Macrophages, 310 Disease, 326 295 Dendritic Cells, 310 Immunologic Tolerance, 326 Recognition Molecules of Innate Immunity Natural Killer Cells, 310 Mechanisms of Autoimmunity, 326 (Pathogen-Associated Molecular Cytokines: Messenger Molecules of the Specific Autoimmune Diseases, 329 Patterns), 296 Immune System, 312 Systemic Lupus Erythematosus, 329 Toll-Like Receptors, 298 Structure and Function of Rheumatoid Arthritis, 332 Adaptive Immunity (Specific Immunity), 299 Histocompatibility Antigens, 312 Sjögren-Like Syndrome, 332 Cells and Tissues of the Immune Major Histocompatibility Complex and Immunodeficiency Syndromes, 333 System, 299 Disease Association, 313 Immune Checkpoints in Immunity and Innate Lymphoid Cells (ILCs), 301 Disorders of the Immune System, 313 Cancer, 338 T Lymphocytes, 301 Mechanisms of Immunologic Tissue Amyloidosis, 338 B Lymphocytes, 306 Injury: Hypersensitivity Reactions, 313 The emphasis of this chapter is on diseases that are the result of General Features of the Immune System inadequate or inappropriate immune responses. Prerequisite to an The immune system is a defensive system whose primary function is understanding of the pathogenic mechanisms of these diseases is an to protect against infectious organisms, such as bacteria, viruses, fungi, understanding of the basic elements of the immune system. The chap- and parasites, and the development of cancer. The complexity by which ter begins with an overview of our current understanding of innate these functions occur is evidenced not only by the cell types, recogni- and adaptive immunity, cells of the immune system, cytokines, and tion molecules, and soluble factors involved and interactions with other major histocompatibility complex (MHC) molecules. This overview systems (e.g., endocrine, nervous) but also by the ability to recognize lays the groundwork for the subsequent discussion of disorders of the virtually any foreign antigen. Immunologic responses result in patho- immune system, which includes hypersensitivity reactions, autoim- logic processes, primarily inflammatory responses, either because of nor- munity, and immunodeficiency. This chapter concludes with a dis- mal immune responses to foreign antigens (e.g., microbial pathogens) or cussion of amyloidosis, a diverse group of conditions characterized from aberrations of the immune system as in the case of hypersensitivity by the deposition of a pathologic extracellular protein. One of these reactions and autoimmune diseases. Finally, the importance of a normal conditions is associated with the deposition of immunoglobulin com- functional immune system cannot be more evident than in instances in ponents. Although the focus of this text is on the pathologic basis of which it is deficient as the result of a genetic defect or as the result of an veterinary diseases with an emphasis on domestic animal species, this acquired immunodeficiency disease. chapter uses the vast knowledge base of human and rodent immu- Immunity is the result of nonspecific (innate) and specific (adap- nology (applicable to most mammalian species studied to date) and tive) responses that together provide effective protection. The incorporates major known relevant species differences as appropriate. immune system’s recognition and response functional capabilities are key components of both innate and adaptive immune responses. The recognition capabilities are highly specific and allow immune Innate Immunity (Nonspecific Immunity) responses to develop against a diverse group of foreign (nonself) As stated previously, the function of the immune system is to protect antigens and prevent the development of immune responses to self- against infectious pathogens and the development of cancer. There Copyright © 2021. Mosby. All rights reserved. antigens. Innate and adaptive immune responses feature effector are two categories of immune responses that are based in part on mechanisms for eliminating or neutralizing the antigen, whereas their specificity for the antigen: (1) innate immunity and (2) adap- adaptive immunity has the additional feature of memory. A common tive (specific) immunity (Fig. 5.1). Innate immune responses are paradigm shared by antigen nonspecific and specific mechanisms of considered the first-line defense mechanisms, are not specific to the immunity is the ability to polarize the responses in the direction of antigen, and lack memory (Essential Concept 5.1). These defense those most efficient in eliminating the pathogen. Unfortunately, mechanisms are the result of anatomic (e.g., skin, mucosal epithelia, this polarization can also be misdirected, resulting in inappropriate cilia) and physiologic (e.g., stomach pH, body temperature) prop- immune responses such as in allergy and autoimmunity. erties and phagocytic and inflammatory responses. Major compo- nents of innate immunity are intact epithelial barriers, phagocytic aFor a glossary of abbreviations and terms used in this chapter, see E-Glossary cells, innate lymphoid cells (ILCs [see later discussion]), and several plasma proteins, the most important of which are the proteins of 5.1. 295 Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  CHAPTER 5 Diseases of Immunity 295.e1 E-Glossary 5.1 GLOSSARY OF ABBREVIATIONS AND TERM AA Amyloid associated IRF Interferon regulatory factor AALT Auditory-associated lymphoid tissues LAD Leukocyte adhesion deficiency ACAID Anterior chamber–associated immune LALT Larynx-associated lymphoid tissues deviation LBP LPS-binding protein ADCC Antibody-dependent cellular cytotoxicity LE Lupus erythematosus AICD Activation-induced cell death LPS Lipopolysaccharide AIRE Autoimmune regulator protein LTi Lymphoid tissue inducer AL Amyloid light chain MALT Mucosal-associated lymphoid tissue ANA Antinuclear antibody MAPK Mitogen-activated protein kinase Anergy Functional inactivation of lymphocytes MDP Macrophage/dendritic cell progenitor that encounter antigen MHC Major histocompatibility complex Antigen sequestration Antigen within “immunologically MPS Mononuclear phagocytic system privileged sites” that cannot be seen NALT Nasal-associated lymphoid tissues by the immune system NF Nuclear factor APC Antigen presenting cell NFAT Nuclear factor of activated T APP Amyloid precursor protein lymphocytes ASC Apoptosis-associated speck-like protein NK Natural killer BLAD Bovine leukocyte adhesion deficiency NLRs NOD-like receptors Central tolerance Tolerance of T lymphocytes to antigens NOD Nucleotide-binding oligomerization attributable to mechanisms in the domain thymus PALS Periarteriolar lymphoid sheath CLAD Canine leukocyte adhesion deficiency PAMPs Pathogen-associated molecular patterns CMP Common myeloid progenitor Peripheral tolerance Tolerance of T lymphocytes attributable COPD Chronic obstructive pulmonary disease to mechanisms within peripheral CSF Colony-stimulating factor tissues CTL Cytotoxic T lymphocyte PMNs Polymorphonuclear cells (neutrophils) DAMPs Danger-associated molecular patterns PRRs Pattern recognition receptors DIC Disseminated intravascular coagulation RLRs Retinoic acid–inducible gene (RIG)-I– DISC Death-inducing signaling complex like receptors DTH Delayed-type hypersensitivity SAA Serum amyloid A ER Endoplasmic reticulum SCID Severe combined immunodeficiency FcR Fc receptor disease GALT Gut-associated lymphoid tissues SLE Systemic lupus erythematosus GMP Granulocyte/macrophage progenitor TAP Adenosine triphosphate–binding HSC Hematopoietic stem cell peptide transporter IAPP Islet amyloid polypeptide TCR T lymphocyte receptor IFN Interferon TLRs Toll-like receptors IgD Immunoglobulin D TNF Tumor necrosis factor IgM Immunoglobulin M TRAF Tumor necrosis factor (TNF) receptor IL Interleukin -associated factor ILCs Innate lymphoid cells XLA X-linked agammaglobulinemia Immunologic tolerance Nonresponsive immune system XSCID X-linked severe combined IRAK IL-1 receptor–associated kinase immunodeficiency disease Copyright © 2021. Mosby. All rights reserved. Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  296 SECTION I General Pathology INNATE IMMUNITY ADAPTIVE IMMUNITY Physiologic Anatomic Phagocytic Inflammatory B lymphocytes T lymphocytes barriers barriers barriers and barriers pH, Intact epithelium Mononuclear Delivery of cells Antibodies Cytotoxic cells temperature, (skin, mucous phagocytic cells and proteins and helper cells etc. membranes) Antibodies Microbes B lymphocytes Epithelial barriers Phagocytes Effector T lymphocytes T lymphocytes NK cells and other ILCs Complement ADAPTIVE IMMUNITY NITY 3 4 TE IMMU 1 2 5 A INN 12 fection Days Time since in 6 s 0 Ho r u Figure 5.1 Innate (Nonspecific) and Adaptive Immunity (Specific Immunity). Innate immunity is the first-line defense against infectious organisms and comprises chemical and physical barriers, proteins such as complement, and non–antigen-specific mononuclear cells such as innate lymphoid cells (ILCs) and phagocytic cells. Adaptive immunity is the antigen-specific defense arm of immunity directed by T and B lymphocytes that have been “primed” by cells of in- nate immunity and result in effector mechanisms for eliminating infectious organisms. NK, Natural killer. the complement system. Phagocytic cells are recruited to sites of permeability, and cellular phases that act in response to damage to infection during an inflammatory response, where they have several vascularized tissue. The features of the inflammatory response are functions, two of which are to ingest and destroy pathogenic organ- also presented in Chapter 3, Inflammation and Healing. isms and neutralize toxins. Neutrophils, monocytes, and tissue mac- rophages are the major cells involved in phagocytosis. These cells Recognition Molecules of Innate Immunity recognize components of microbial pathogens through the expres- (Pathogen-Associated Molecular Patterns) sion of several membrane receptors, including receptors for mannose The recognition molecules of innate immunity provide an opportu- residues, N-formyl-methionine–containing peptides, and a family nity to recognize pathogens by cells other than lymphocytes. These of pattern recognition receptors (PRRs) that, when activated by germline-encoded molecules function to sense molecular structures microbial components, signal the activation of transcription factors shared by microbes and endogenous molecules associated with that facilitate the microbicidal mechanisms of the phagocytic cell inflammation. The recognition molecules associated with microbes Copyright © 2021. Mosby. All rights reserved. (discussed later). ILCs are cells of innate immunity and are discussed are generally referred to as pathogen-associated molecular patterns later. The complement system, discussed in Chapter 3, Inflammation (PAMPs). The function of the innate immune system extends and Healing, is a complex cascade of proteins that has many biologic beyond microbial pathogen recognition to include endogenous functions, including the formation of the membrane attack complex molecules associated with cell damage and inflammation, which that efficiently lyses plasma membranes of microbial pathogens. The are generally referred to as danger- or damage-associated molecular complement system can be activated by either the innate immune patterns (DAMPs). The activation of the innate immune system system (alternative and mannose/lectin pathways) or the adaptive through these invariant PRRs not only precedes lymphocyte activa- immune system (classical pathway). Other important plasma pro- tion but also is required to initiate the adaptive immune responses. teins of the innate immune system include mannose-binding pro- The molecular patterns of PRRs are associated with microbial tein and C-reactive protein; two of the functions of these proteins pathogens and classified as secreted, transmembrane, and cytosolic are to facilitate phagocytosis through opsonization of pathogens and forms. Collectins and pentraxin are examples of secreted PRRs complement activation. Inflammatory responses comprise vascular, that function primarily to bind to microbial surfaces and activate Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  CHAPTER 5 Diseases of Immunity 297 (NOD) and NOD-like receptors (NLRs). These recognition mol- ESSENTIAL CONCEPT 5.1 Innate Immunity ecules provide the host with the ability to sense “danger” either Innate immunity is a group of nonspecific first-line defense mecha- through PAMPs, in the case of microbial infections, or through nisms that occur immediately or within a very short time frame (i.e., DAMPs, in the presence of cellular damage or stress. This allows minutes to hours) following exposure to antigens (from microbes the innate immune system to detect and initiate immune responses [also tumor cells; see Chapter 6, Neoplasia and Tumor Biology]). in response to infectious and noninfectious causes. NLR molecules These defenses and mechanisms include (1) barrier systems (see as immune sensors are not unique to mammals because they have Chapter 4, Mechanisms of Microbial Infections) provided by skin been found in plants and urchins. The molecules are designated or mucosae; (2) physiologic properties of these barriers such as based on the structure of the molecule NLR with a suffix of P pH, mucus layer, and body temperature; and (3) inflammatory and (pyrin domain) or C (caspase activation and recruitment domains phagocytic responses within these barriers. Key structural com- ponents are epithelial cells of intact barriers; phagocytic cells [CARD]), referring to the N-terminal moiety followed by a number such as neutrophils, monocytes, and tissue macrophages within (e.g., NLRP1, NLRP2, or NLRP3). The function of these pattern these barriers; innate lymphoid cells (ILCs) and dendritic cells recognition molecules is also extended beyond the initiation of within these barriers; and plasma proteins, such as those of the adaptive immunity to also include regulation of cell death (apop- complement system. When the epithelium of a barrier system is tosis). As is often the case in immunology, our understanding of penetrated by a microbe, it subsequently encounters well-vascu- immune responses is greatly enhanced through the identification of larized (endothelial cells) extracellular matrix in the lamina propria, genetic immunologic disorders. Deficiencies in components of the submucosa, or dermis/subcutis. NLRs have been described in human beings and are most frequently Microbes express unique patterns of biologic molecules (li- associated with inflammatory disorders (e.g., Crohn’s disease and gands) on or in their membranes called pathogen-associated inflammatory bowel disease). molecular patterns (PAMPs). PAMPs include molecules such as glycans, glycoconjugates, and lipopolysaccharide that are ex- Analogous to the adaptive immune response, which has pressed across large groups of different types of microbes, thus developed the ability to defend the host against a diverse array making the innate immune response nonspecific to a particu- of microbial pathogens (humoral versus cell-mediated responses), lar individual genus of microbe as occurs in adaptive immunity. the innate immune system is now seen as also having an ability to Endothelial cells, phagocytic cells, and ILCs have pattern rec- distinguish specific types of pathogens. Intracellular (e.g., viruses) ognition receptors (PRRs), including Toll-like receptors (TLRs), and extracellular (e.g., bacteria) pathogens require different types that recognize and respond to PAMPs and other cell surface of immune responses to control them. The innate immune system molecules on microbes. These ligand-receptor interactions initi- has developed cell-intrinsic and cell-extrinsic recognition mecha- ate acute inflammation and the recruitment of phagocytic cells nisms dependent on whether it is mediated by an infected cell or from the vasculature and result in phagocytosis, phagosome-lys- an uninfected cell. Cell-extrinsic recognition mechanisms are a osome fusion, neutralization of toxins, and digestion of microbes. TLRs (1) regulate cell recruitment to sites of infection through way in which an uninfected cell can participate in the immune adhesion molecules, chemokines, and chemokine receptors dur- response and are mediated through transmembrane receptors ing an inflammatory response; (2) activate leukocytes (primarily (e.g., TLRs) on specialized cells of the innate immune system such neutrophils and natural killer cells of the innate immune system) as macrophages and dendritic cells. Cell-intrinsic recognition and epithelial, endothelial, and hematopoietic cells; and (3) are mechanisms are essential for recognizing intracellular pathogens essential for linking the innate immune response to the adaptive and involve type I interferon (IFN) gene transcription signaling immune responses (see Essential Concept 5.2). by members of the RLRs. Three members of the RLR family are The innate immune system can also distinguish between intra- RIG-I, melanoma differentiation-associated gene 5 (MDA5), and cellular (e.g., viruses) and extracellular (e.g., extracellular bacteria) laboratory of genetics and physiology gene 2 (LPG2). In viral microbes and initiate different types of responses to control them sensing the RLRs are highly discriminating with regard to the through cell-intrinsic and cell-extrinsic recognition mechanisms in infected cells or uninfected cells, respectively. ILCs are commonly cytoplasmic localization and sensing of specific RNAs. They spe- located within skin or mucosae of barrier systems and act through cifically detect RNA molecular patterns not normally present in PRR-PAMP interactions to initiate acute inflammation and other the cytoplasm. Abnormal RNA patterns include chemical modifi- cytotoxic and noncytotoxic effects on microbes, as well as to ini- cations, secondary or tertiary RNA conformations, specific RNA tiate and sustain adaptive immune responses, primarily against sequences, or double-stranded RNA. Although much of what is microbes. Finally, the innate immune system can activate the com- currently known about RLRs is centered around the sensing of plement system via the alternative or mannose/lectin pathways RNA viruses, there is preliminary evidence that similar intracel- (see Chapter 3, Inflammation and Healing). This mechanism re- lular mechanisms may exist for sensing DNA viruses and some sults in the formation of a membrane attack complex (see Chapter intracellular bacteria. 3, Inflammation and Healing) that kills microbes by perforating Members of the NLR molecule group are central regulators of their cell membranes. immunity and inflammation largely through activation of tran- scription factors such as nuclear factor (NF) κB, interferon regu- Copyright © 2021. Mosby. All rights reserved. the complement system. Collectins, having properties of collagen latory factor (IRF), or nuclear factor of activated T lymphocytes and lectins, include mannose-binding lectins and pulmonary sur- (NFAT). Some members of the NLR family form multiprotein factants A and D. Pentraxin is composed of five identical subunits complexes with the cysteine protease procaspase-1 and the adapter that form a pentamer and include C-reactive protein, an activator molecule ASC (apoptosis-associated speck-like protein [contain- of the classical pathway of complement. Toll-like receptors (TLRs) ing a CARD]) referred to as inflammasomes (also see Fig. 3.13). and C-type lectins are examples of the transmembrane PRRs, and The inflammasome is a multiprotein complex that activates cas- they have limited cellular distribution, including macrophages, pase-1. PAMPs and DAMPs are sensed through activation of the natural killer (NK) cells, and dendritic cells. TLRs are expressed on inflammasome complex, resulting in activation of caspase-1, which the plasma membrane or in endosomal/lysosomal organelles. The elicits effector functions through proteolytic cleavage of cytosolic cytosolic PRRs are more widely distributed, including all nucle- proinflammatory cytokines (e.g., pro-interleukin [IL]-1β and pro- ated cells, and include retinoic acid–inducible gene (RIG)-I–like IL-18), which are then secreted in their active form. The inflam- receptors (RLRs) and nucleotide-binding oligomerization domain masome model is analogous to the model for the activation of the Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  298 SECTION I General Pathology apoptotic caspases by CD95/Fas death-inducing signaling complex Toll-Like Receptors (TLRs), Ligands, and (DISC) and the Apaf-1 apoptosome. IL-1β functions in localized Table 5.1 Microbial Sources and systemic responses to infections and injury to cause fever, acti- vation of lymphocytes, and the extravasation of leukocytes at sites TLR Ligand Microbial Source of injury or infection. IL-18 functions to induce IFN-γ by activated TLR2 Lipoproteins Bacteria T lymphocytes and NK cells during a T helper lymphocyte type 1 Peptidoglycan Gram-positive bacteria (TH1) response and to induce secondary inflammatory cytokines, Zymosan Fungi chemokines, cell adhesion molecules, and nitric oxide (NO) syn- LPS Leptospira spp. thesis. Other members of the NLR family are involved in inflamma- GPI anchor Trypanosomes some-independent (noninflammasome) innate immune responses Lipoarabinomannan Mycobacterium spp. and signal through different multicomponent signalosomes such Phosphatidylinositol Mycobacterium spp. as nodosomes, transcriptomes, and mito-signalosomes. Noninflam- dimannoside masome-mediated innate immune responses occur through NF-κB TLR3 Double-stranded RNA Viruses activation, mitogen-activated protein kinase (MAPK) activation, TLR4 LPS Gram-negative bacteria HSP60 Chlamydia cytokine and chemokine production, antimicrobial reactive oxy- TLR5 Flagellin Various bacteria gen species production, IFN (IFN-α and IFN-β) production, and TLR6 CpG DNA Bacteria, protozoans ribonuclease L activity. TLR7 Single-stranded RNA Viruses TLR8 Single-stranded RNA Viruses Toll-Like Receptors TLR9 CpG DNA Bacteria, viruses TLRs are the mammalian homologue of the Toll receptor origi- TLR10 Unknown Unknown nally identified in Drosophila spp. It has not only an embryologic TLR11 Profilin Toxoplasma spp., function but also an immunologic function. In mammals, TLRs uropathogenic bacteria are membrane molecules that function in cellular activation by TLR12 Profilin Toxoplasma spp. TLR13 rRNA Various bacteria a wide range of microbial pathogens. TLRs are classified as PRRs because they recognize PAMPs and signal to the host the pres- CpG, Cytosine and guanine linked oligonucleotide; GPI, glycosylphosphati- ence of an infection. Pathogen-associated molecules include lipo- dylinositol; HSP60, heat shock protein 60; LPS, lipopolysaccharide. polysaccharide (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 LPS LPS binding surface, and TLRs 3, 7, 8, and 9 are involved in viral detection Leucine-rich protein repeat motifs 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 MD2 CD14 extracellular domain characterized by a leucine-rich repeat motif TLR4 flanked by a cysteine-rich motif (Fig. 5.2). They also contain a conserved intracellular signaling domain, Toll/IL-1 receptor Cystine-rich flanking motif (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 rec- ognition of LPS. In the blood or extracellular fluid, the binding of LPS to LPS-binding protein (LBP) facilitates the binding of LPS TIR domain 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 Adapter protein the LPS-CD14 complex with TLR4. An accessory protein, MD2, complexes with the LPS-CD14-TLR4 molecule and results in Kinase LPS-induced cell signaling. Briefly, TLR signaling through the binding of PAMP to a TLR leads to the activation of TIR, which forms a complex with the cyto- plasmic adapter protein MyD88, an IL-1 receptor–associated kinase (IRAK), and tumor necrosis factor (TNF) receptor–associated factor AP-1 NFκB 6 (TRAF 6). Activated TRAF then activates the MAPK cascade, Copyright © 2021. Mosby. All rights reserved. leading to the activation of NF-κB, a transcription factor. MyD88 is a universal signaling molecule for NF-κB activation, and MyD88- deficient mice are incapable of activation by TLR, IL-1, and IL-18. Gene transcription: There also may be signaling mechanisms unique to individual TLRs. inflammatory response TLRs and their pathogen-associated ligands are important rec- Figure 5.2 Toll-Like Receptor 4 (TLR4) Signaling in Response to Bacte- ognition molecules for the innate immune system and trigger a rial Lipopolysaccharide (LPS). LPS is transferred from the LPS-binding number of antimicrobial and inflammatory responses. Up to 15 dif- protein molecule to the TLR4, resulting in activation of cascade of signal ferent TLR genes have been identified. The importance of these transduction pathways leading to upregulation of genes that regulate inflam- receptors in immunity is further supported by the observation of matory cellular and non-cellular responses. NF-κB, Nuclear factor κ B; TIR, polymorphisms in the genes encoding them. TLR are not only Toll/interleukin 1 receptor. Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  CHAPTER 5 Diseases of Immunity 299 central regulators of innate immunity, but also have been demon- Cells and Tissues of the Immune System strated to have a role in the pathogenesis of immune-mediated and Lymphoid Tissues autoimmune diseases. Lymphoid tissues, present in all vertebrates, are essential to the Although the individual TLRs exhibit ligand specificity, they development of a normal immune system and an adaptive immune differ in their cellular expression patterns and the signal pathways response. A complete review of all the complexities, known and they activate, similar to that described for cytokines, which exhibit unknown, of lymphoid tissues is beyond the scope of this text; how- pleiotropy, redundancy, synergy, and antagonism. There are con- ever, a basic knowledge of the lymphoid tissues based on functional stitutively and inducibly expressed TLRs in different tissues. TLRs criteria is essential to general pathology processes and will facilitate regulate cell recruitment to sites of infection through the upregu- the understanding of the pathogenesis of many diseases of immunity. lation of the expression of adhesion molecules, chemokines, and The simplest functional classifications are primary and second- chemokine receptors during an inflammatory response. TLRs ary lymphoid organs. Primary lymphoid organs include the thymus, activate leukocytes (primarily neutrophils and NK cells of the bursa of Fabricius, bone marrow, ileal Peyer’s patches (ruminants), innate immune system) and epithelial, endothelial, and hemato- and fetal liver and are responsible for the antigen-independent poietic cells. TLRs are also hypothesized to be essential for linking development of T and B lymphocytes. The designation of T lym- the innate immune response to the adaptive immune responses. phocytes was based on their development in the thymus, and the Central to this hypothesis is the TLR-dependent dendritic cell– designation of B lymphocytes was based on their development in mediated control of T lymphocyte activation. Dendritic cells are the bursa of Fabricius. Secondary lymphoid organs are anatomi- important antigen-presenting cells for T lymphocyte activation. cally distinct and include the spleen, tonsil, Peyer’s patches, and Dendritic cells uptake microbial antigens in the peripheral tissues lymph nodes and are the sites for initiation of antigen-dependent and migrate to regional lymph nodes, where they present peptide immune responses and the generation of adaptive immunity effec- fragments, in the context of MHC molecules, to naïve T lympho- tor responses. Lymphoid tissues functionally equivalent to second- cytes. In addition to the expression of the peptide-MHC signal, ary lymphoid organs are located throughout the body or develop dendritic cells are also required to provide a second, costimula- under chronic inflammatory conditions and are generally termed tory signal through the expression of B7, the ligand for the CD28 tertiary lymphoid tissues. Unlike secondary lymphoid organs, ter- molecule on naïve T lymphocytes. The activation and maturation tiary lymphoid tissues are uniquely positioned to filter the body pathway related to the costimulatory signal occurs through TLR fluids (e.g., blood and lymph). They are frequently associated recognition of PAMPs. with epithelial surfaces and include the mucosal-associated lym- There are species differences in the ligand specificity of TLRs and phoid tissues (MALTs), gut-associated lymphoid tissues (GALTs), in the cellular responses elicited. Although sequences for canine, nasal-associated lymphoid tissues (NALTs), larynx-associated feline, and chicken TLR4 have been identified, no functional data lymphoid tissues (LALTs), and auditory-associated lymphoid tis- have been published. With regard to domestic animals, a significant sues (AALTs). Because of the complex and diverse nature of the body of literature exists on TLRs of cattle. secondary and tertiary lymphoid organs and tissues across species, Finally, TLRs have been implicated in “innate autoimmunity,” the reader may find that some immunology texts consider second- with TLRs recognizing fibrinogen, heat shock proteins, or DNA. ary lymphoid organs to include the aforementioned associated TLRs may also bind with DNA as a factor in directing antibody pro- lymphoid tissues. The further subdividing of secondary lymphoid duction by autoreactive B lymphocytes, contributing to the patho- tissues such as the GALTs into isolated lymphoid follicles and genesis of rheumatoid arthritis and systemic lupus erythematosus cryptopatches is only relevant as to the generation of intraepi- (SLE). Further studies are necessary to more fully understand these thelial lymphocytes in the intestinal tract. Complexities of sec- observations and the underlying immunopathogenesis. ondary lymphoid organs across species are further evidenced by the absence of lymph nodes in most birds excepting waterfowl. Another group of tertiary lymphoid tissues are the lymphoid nod- Adaptive Immunity (Specific Immunity) ules found in the genital tract, mammary gland, and urinary blad- Adaptive immunity in general consists of cell-mediated immunity, der mucosa. mediated by T lymphocytes against intracellular pathogens, and The formation and organization of the lymphoid organs and tis- humoral immunity, mediated by B lymphocytes against extracellular sues are highly dependent on structural (stromal) and functional pathogens and toxins (Fig. 5.3; Essential Concept 5.2). The adaptive (cell-to-cell) interactions that generally determine their location immune response is the second-line defense mechanism and is char- and are necessary for the localization, development, maturation, acterized by antigen specificity, diversity, memory, and self-/nonself- differentiation, or activation of immune cells. T lymphocyte devel- recognition. Antigen specificity and self-/nonself-recognition are opment is initiated and completed in the thymus through stromal the result of distinct membrane molecules. Mature B lymphocytes interactions and the influence of IL-7. Although B lymphocyte are activated by a specific antigen-binding molecule on its mem- development is more diverse across species with respect to anatomic brane. The antigen receptor is membrane-bound immunoglobulin. locations, the successive stages of B lymphocyte development are Copyright © 2021. Mosby. All rights reserved. Mature T lymphocytes express a specific antigen-binding molecule, conserved across species and dependent on the chemokine CXC the T lymphocyte receptor (TCR), on their membrane. Unlike ligand 12 and IL-7. In birds, B lymphocytes begin their develop- membrane-bound immunoglobulin on the B lymphocyte, which ment and maturation in the spleen but complete these processes can recognize antigen alone, TCRs can recognize only antigens that in the bursa of Fabricius. In contrast, B lymphocyte development are associated with cell membrane proteins called MHC molecules. and maturation in most mammals begins in the bone marrow and Self-/nonself-recognition is the result of MHC molecules. There are is completed in the spleen. The ruminant is unique as the ileal Pey- two major classes of MHC molecules. Class I molecules are present er’s patch is the site of B lymphocyte development and maturation. on all nucleated cells, and class II molecules are present primarily on Phylogenetically, there is relative conservation of primary lymphoid antigen-presenting cells. T lymphocytes and B lymphocytes are the organs with increasing complexity of secondary and tertiary lym- major cells of adaptive immunity. phoid organs and tissues with respect to organization and function. Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  300 SECTION I General Pathology Antigens Foreign Viruses Bacteria Parasites Fungi proteins Vertebrate host Humoral Cell-mediated response response B lymphocyte T lymphocyte + TH lymphocyte TC lymphocyte Antigen +TH lymphocytes +Ag-class II cytokines MHC molecule +Ag-class I Activated MHC molecule TH lymphocyte Ab-secreting plasma cells CTL Killing of altered self-cells Cytokine secretions Antigen elimination Altered self-cells Virus-infected cell, neoplastic cell Figure 5.3 Overview of Humoral and Cell-Mediated Arms of Adaptive Immunity (Specific Immunity). Ab, Antibody; Ag, antigen; CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex; TC, cytotoxic T lymphocyte; TH, T helper lymphocyte. (Modified from Goldsby RA, Kindt TJ, Osborne BA: Kuby immunology, ed 4, New York, 2000, WH Freeman.) Copyright © 2021. Mosby. All rights reserved. Soluble antigens can be transported to secondary lymphoid infection (beneficial) or in association with an autoimmune dis- organs via lymph or by antigen-presenting dendritic cells. Sec- ease (harmful). ondary lymphoid organs, and to a lesser extent tertiary lymphoid It is appropriate here to discuss the difference between a lymph tissues, provide complex environments for cellular interactions node, lymphoid follicle, and lymphoid nodule. Lymph nodes are necessary for antigen recognition, T and B lymphocyte activa- anatomically distinct secondary lymphoid organs with a capsule, tion, and the development of adaptive immune responses resulting afferent and efferent lymphatic vessels, sinuses, and lymphoid tis- in antibody and memory responses critical to a normal immune sue localized throughout specific regions of the body (e.g., mesen- response. Tertiary lymphoid tissue may develop at sites of chronic teric lymph nodes, axillary lymph nodes, mandibular lymph nodes). inflammation, whether it be associated with a response to an Lymphoid follicles are associated primarily with secondary lymphoid Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  CHAPTER 5 Diseases of Immunity 301 ILCs. A common paradigm of both innate and adaptive immunity is ESSENTIAL CONCEPT 5.2 Adaptive Immunity the ability of exogenous signals (e.g., microbial antigen in the case Adaptive immunity is a group of specific second-line defense re- of adaptive immunity) to polarize (i.e., focus) immune responses in sponses that occur days to weeks after exposure to microbial an- most instances into a highly effective defensive response. It has now tigens during the innate immune response (see Essential Concept been recognized that these responses can also be polarized to unde- 5.1) at barrier systems provided by skin or mucosae (see Chapter 4, sirable responses (dysregulated) in some instances, contributing to Mechanisms of Microbial Infections). Unlike innate immune re- the pathogenesis of certain allergic, inflammatory, and autoimmune sponses, adaptive responses are highly specific to antigens of diseases such as atopy, inflammatory bowel disease, and rheumatoid the particular genera or species of microbe that induce them, and arthritis, respectively. the response is “remembered” by the immune system. Adaptive ILCs are one of three major cell populations that constitute immune responses are designed to destroy microbes and the toxins/enzymes they produce; therefore, such responses must be innate immunity. The other two cell populations include phago- against molecules that are foreign to the animal and not against cytic cells (macrophages and neutrophils) and dendritic cells. structural and/or functional molecules of the animal itself. Through ILCs, like T and B lymphocytes, are derived from a common lym- the MHC system, the adaptive immune system is able to distin- phoid precursor cell lineage. Unlike their adaptive lymphoid cell guish foreign molecules from self-molecules. The defenses and counterparts, ILCs lack recombination activating genes (RAGs) mechanisms of adaptive immunity include (1) cell-mediated immu- and RAG-mediated recombined antigen receptors and thus do not nity, mediated by T lymphocytes against intracellular pathogens, express antigen-specific receptors. Similar to their adaptive lym- and (2) humoral immunity, mediated by B lymphocytes against phoid cell counterparts, ILCs are often not defined by specific cel- extracellular pathogens and toxins. lular markers but rather by cytokine profiles and in some instances Innate immune responses and molecules expressed by in- transcriptional regulators that are involved in their development nate lymphoid cells (ILCs) initiate and sustain responses of the adaptive immune system. Lymphocytes (ILCs and other types), and function. ILCs are broadly classified as two distinct lineages: dendritic cells, and other types of antigen-presenting cells at the cytotoxic ILCs and noncytotoxic ILCs (Fig. 5.6). Cytotoxic ILCs site of injury in affected barrier systems deliver microbial anti- are the conventional NK cells (cNK cells, also known as killer or gens to local lymphoid tissues such as mucosa-associated lym- cytotoxic ILCs), whereas the noncytotoxic ILCs are further sub- phoid tissues and skin equivalents and then via lymphatic ves- divided into three distinct groups: group 1 ILCs, group 2 ILCs, sels to secondary lymphoid organs such as the spleen, lymph and group 3 ILCs. Cytotoxic ILCs are discussed later. Group 1 nodes, and lymph nodules. These tissues are responsible for ILCs are transcriptionally regulated by T-bet and produce IFN-γ immune responses to antigens, such as the production of anti- and TNF. Group 1 ILCs are important defenses against intracel- body and cell-mediated immune reactions (see also Chapter 13, lular bacteria and parasites. Group 2 ILCs are transcriptionally Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic Sys- regulated by GATA-3 and produce IL-4, IL-5, IL-9, and IL-13. tem). Lymphocytes are activated by microbial-specific antigens and undergo clonal selection, proliferation, and differentiation, Group 2 ILCs are important defenses against helminths and con- so they respond specifically to a unique species or genera of tribute to the pathogenesis of certain types of asthma and allergic microbe. This process serves as the basis for immunizations in diseases. Group 3 ILCs are transcriptionally regulated by RORγt domestic animals. and are further subdivided by transcriptional regulator T-bet into lymphoid tissue inducer (LTi) cells that produce IL-17A, IL-22, and granulocyte-macrophage colony-stimulating factor (GM- CSF), and a second population that produces TNF, IFN-γ, IL-22, organs and make up the primary and secondary lymphoid follicles. and GM-CSF. Both populations of group 3 ILCs are involved in Lymphoid nodules are generally not associated with secondary lym- lymphoid tissue development and intestinal homeostasis and are phoid organs and do not have a capsule, sinuses, or lymphatic ves- important defense mechanisms against extracellular bacteria. In sels but generally have similar structural and functional features to short, group 1 and 3 ILCs promote innate immune responses to lymphoid follicles. viruses, intracellular bacteria and parasites, and fungi, whereas group 2 ILCs promote innate immune responses to extracellular Innate Lymphoid Cells (ILCs) helminths. Our understanding of how immune responses are initiated and sustained has been greatly enhanced through the identification of T Lymphocytes ILCs. ILCs are a heterogeneous population of non-B and non-T T lymphocytes are small nongranular cells that constitute 50% lymphocytes that are not antigen specific. ILCs develop in an Id2- to 70% of the peripheral blood mononuclear cells. They origi- dependent pathway and through additional transcriptional fac- nate in the bone marrow and migrate to the thymus (thus the tors differentiate into subpopulations of cells that not only initiate “T” designation), where they undergo differentiation, selection, and sustain immune responses but also are important regulators in and maturation processes before exiting to the periphery as effec- maintaining tissue integrity. The primary functions of ILCs involve tor lymphocytes. In secondary lymphoid tissues, they are located Copyright © 2021. Mosby. All rights reserved. defenses against infectious microbes, lymphoid tissue formation, primarily in the paracortical regions of lymph nodes and the peri- and tissue remodeling following damage. Although first recognized arteriolar lymphoid sheath (PALS) of the spleen. These specific as integral components of lymphoid tissue development, ILCs are anatomic sites elaborate chemoattractant cytokines (chemokines), now also recognized as important initiators of inflammation at for which the T lymphocytes express receptors. The definitive mucosal and epithelial surfaces in response to microbial infection marker for T lymphocytes is the TCR, the polymorphic antigen- or tissue damage (Fig. 5.4). Similar to CD4+ T helper cell subsets, binding molecule. The antigen specificity of individual lympho- ILCs can be polarized toward restricted cytokine profiles, allowing cytes is attributed to their respective TCR, which is genetically for tremendous plasticity (Fig. 5.5). This plasticity is driven by exog- determined. TCRs are classified as either αβ-TCR or γδ-TCR, enous signals that are not fully understood but are in part directed by based on the composition of their disulfide-linked heterodimers. recognition molecules of innate immunity expressed on surfaces of The individual polypeptide chains of the heterodimers contain Zachary, James F.. Pathologic Basis of Veterinary Disease E-BOOK : Pathologic Basis of Veterinary Disease E-BOOK, Mosby, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=6837937. Created from upenn-ebooks on 2024-11-24 18:32:01.  ILCs ILCs ILCs (Group 1) (Group 2) (Group 3) TNF and IFNγ IL-4, IL-5, IL-9, and IL-13 LT, TNF, IL-17A, and IL-22 Activate mucosal epithelial cells to produce antimicrobial peptides Activate macrophages Activate Destroy mucosal and eosinophils Mucosal macrophage epithelial cells Increased Synthesis and to kill microbes to kill microbes intestinal release of epithelial peristalsis mucus to entrap cell (muscle contraction the helminth to expel helminth) Goblet Antimicrobial Virus cell Smooth peptide muscle Mucus Bacterium cell Effector molecules Helminth ↑ resistance to ↑ resistance to intracellular microbes extracellular (luminal) bacteria (viruses, bacteria, and parasites) ↑ resistance to helminth parasites Figure 5.4 Role of Innate Lymphoid Cells (ILCs) in Defenses Against Microbes. ILCs have an important role in initiation of inflammatory responses at barrier surfaces in response to infectious organisms. Group 1 innate lymphoid cells (ILC1) provide increased resistance to viruses, intracellular bacteria, and parasites by producing tumor necrosis factor (TNF) and interferon-γ (IFN-γ). Group 2 innate lymphoid cells (ILC2) provide increased resistance to helminth parasites by producing interleukin (IL)-4, IL-5, IL-9, and IL-13. Group 3 innate lymphoid cells (ILC3) provide increased resistance to extracellular bacteria by producing lymphotoxin (LT), TNF, IL-17A, and IL-22. (Courtesy Dr. P.W. Snyder, School of Veterinary Medicine, Purdue University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Id2 lymphoid precursor cell Activating molecules