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to protect the host from invasion of foreign organisms by distinguishing "self" from "nonself."
A well-functioning immune system : protects the host from external factors such as microorganisms or toxins and prevents and repels attacks by endogenous factors such as tumors or autoimmune phenomena. Dysfunction or deciency of components of the immune system : leads to a variety of clinical diseases of varying expression and severity, ranging from atopic disease to rheumatoid arthritis, severe combined immunodeciency, and cancer. This chapter introduces the intricate physiology of the immune system and abnormalities that lead to diseases of hypersensitivity and immunodeciency
anatomy
Mononuclear phagocytes
Macrophage, dendritic cells (DC) Macrophages derived from blood monocyte phagocytosis, antigen presentation, tissue repair, secretion of immune mediators, proteolytic enzymes, cytokines etc. Dendritic cells process and transport antigen from skin, respiratory, and GI surfaces to regional lymphoid tissues
Mononuclear phagocytes
Lymphocytes Basophiles
Polymorphonuclear phagocytes
granulocytic cells that originate in the bone marrow and circulate in blood and tissue. Primary function : antigen-nonspecic phagocytosis and destruction of foreign particles and organisms. Contain cytoplasmic granules lled with degradative enzymes and can also produce oxidative metabolites with potent antimicrobial properties like hydrogen peroxide, superoxide, and hypohalous acid.
Lymphocytes
Responsible for the specic recognition of antigen and for immunologic memory, features of the adaptive immunity. They are functionally and phenotypically divided into bursa-derived B lymphocytes and thymus-derived T lymphocytes.
Eosinophiles
Often found in inammatory sites or at sites of immune reactivity and play a crucial role in the host's defense against parasites. In the airway inammatory response in asthma, eosinophil-derived cytotoxic proteins, including major basic protein, lipid mediators (eg, leukotriene C4), oxygen radicals, and cytokines (eg, IL-3) can induce damage to airway epithelium and potentiate the allergic response.
Basophiles
Play an important role in both immediate- and late-phase allergic responses. Release many of the potent mediators of allergic inammatory diseases, including histamine, leukotrienes, prostaglandins, and platelet-activating factor (PAF), all of which have signicant effects on the vasculature and on the inammatory response. Present in the circulation, possess high-afnity receptors for IgE (FcRI), and mediate immediate hypersensitivity (allergic) responses.
Inammatory mediators
Mediators are released or generated during immune responses to coordinate and regulate immune cell activities to generate physiological or cytotoxic responses. The complement cascade : generates proteins that enhance opsonization, phagocytosis, and cytolysis of microbes. inherited deciencies of the early components of the classic complement cascade (C1, C4, C2) are associated with immune-complexmediated autoimmune disease. Cytokines are soluble polypeptide signaling mediators, produced after immune stimulation, that direct and regulate immune and inammatory reactions. They target many diverse cell types, can have antiviral, proinammatory, or anti-inammatory activities, act locally or systemically, and can be redundant in their actions A group of chemotactic factors (chemokines) regulate homing and migration of immune cells to sites of inammation. HIV may exploit certain chemokine receptors to infect host cells and natural mutations in these same chemokine co-receptors may confer a susceptibility or resistance to infection.
Physiology
The normal immune response. Cytotoxic T-cell response is shown on the left side of the figure and the helper T-cell response on the right side. As depicted on the left, most CD8 T cells recognize processed antigen presented by MHC class I molecules and destroy infected cells, thereby preventing viral replication. Activated T cells secrete interferon- that, along with interferon- and interferon- secreted by infected cells, produces cellular resistance to viral infection. On the right and at the bottom, CD4 helper cells (TH1 and TH2 cells) recognize processed antigen presented by MHC class II molecules. TH1 cells secrete interferon- and interleukin-2, which activate macrophages and cytotoxic T cells to kill intracellular organisms; TH2 cells secrete interleukin-4, -5, and -6, which help B cells secrete protective antibodies. B cells recognize antigen directly or in the form of immune complexes on follicular dendritic cells in germinal centers.
Mechanism of Inammation
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Elimination of foreign antigen by cellular or humoral processes is integrally linked to the inammatory response, in which cytokines and antibodies trigger the recruitment of additional cells and the release of endogenous vasoactive and proinammatory enzymatic substances (inammatory mediators). Inammation may have both positive and deleterious effects.
Tight control of inammatory mechanisms: promotes efcient elimination of foreign substances, killing of microbes, infected cells, and tumors, as well as prevention of autoimmune disease or hypersensitivity reactions. However, uncontrolled lymphocyte activation and unregulated antibody production can lead to tissue damage and organ dysfunction.
6 1 7
Pathogenic immune dysfunction is responsible for hypersensitivity reactions, immunodeciency, and many of the clinical effects of autoimmunity. Etiology: genetic defects, infection, neoplasms, and exposure to environmental triggers, although precise mechanisms that promote abnormal regulation and persistence of inammatory processes are complex and poorly understood.
Type 1
Immediate hypersensitivity: type I Pathologic Immune Mechanisms : IgE antibody Mechanisms of Tissue Injury and Disease : Mast cells and their mediators (vasoactive amines, lipid mediators, cytokines)
Type II
Antibody mediated: type II
Pathologic Immune Mechanisms : IgM, IgG antibodies against cell surface or extracellular matrix antigens
Type III
Immune complex mediated: type III Pathologic Immune Mechanisms : Immune complexes of circulating antigens and IgM or IgG antibodies Mechanisms of Tissue Injury and Disease :
Complement- and Fc receptor-mediated recruitment and activation of leukocytes
Type IV
T cell mediated: type IV Pathologic Immune Mechanisms :
CD4+ T cells (cytokine-mediated inammation) CD8+ CTLs (T cell-mediated cytolysis)
Allergic disease
The hallmarks of allergic diseases : activation of TH2 cells and production of IgE antibody. Strong genetic predisposition for the development of atopy. Allergens : The antigens that elicit immediate hypersensitivity Atopy : a genetically mediated predisposition to an excessive IgE reaction
Allergic Rhinitis
Clinical Presentation
the existence of type I (IgE-mediated) immediate hypersensitivity to environmental allergens that impact the upper respiratory mucosa directly. Allergic airway diseases: allergic rhinitis and asthma Characterized by local tissue damage and organ dysfunction in the upper and lower respiratory tract arising from an abnormal hypersensitivity immune response to normally harmless and ubiquitous environmental allergens. Clinical presentation: nasal, ocular, and palatal pruritus, paroxysmal sneezing, rhinorrhea, and nasal congestion. smear or scraping may support the diagnosis also.
Etiology
Environmental Allergens Allergic or atopic state : characterized by an inherited tendency to generate IgE antibodies to specic environmental allergens and the physiologic responses that ensue from inammatory mediators released after the interaction of allergen with mast cell-bound IgE. Allergens : seasonal tree, grass, and weed pollens or perennial inhalants (eg, house dust mite antigen, cockroach, mold, animal dander, and some occupational protein antigens). Conrmation: specic IgE antibodies to common allergens by in vitro tests such as the radioallergosorbent test or in vivo (skin) testing in patients with a history of symptoms with relevant exposures.
b Immediat
IL-4 IL-13
Allergen
IL-4 IL-13
Mast cell
REVIEWS
Immediate phase : type 1 reaction
b Immediate phase: type 1 reaction
Class switching to IgE Memory B cell IgE
Allergen
Basophil
IL-4 IL-13
Naive B cell FcRI IgE+ memory B-cell clonal expansion Mast cell
Degranulation Release of vasoactive amines, lipid mediators, chemokines and other cytokines
Histamine
TCR MHC class II molecule Allergen TH1 cell IFN TNF CD95L
Mast cell
Basophil
DC T-cell activation and proliferation by IgE-facilitated and non-IgE-facilitated presentation of allergens by inammatory DCs
Allergen
Basophil
Basophil entry to tissues, mast-cell and basophil degranulation, and release of monoamines, lipid mediators, chemokines and pro-inammatory cytokines
Atopic dermatitis TH1-cell-mediated induction of keratinocyte apoptosis TH1-cell-mediated epithelialcell activation, and release of chemokines and pro-inammatory cytokines
Clinical ManifestationAllergic rhinitis and asthma Eosinophil activation and release of mediators, TH2-cytokine-mediated IL-9, IL-13 chemokines and proinduction of increased inammatory cytokines Symptoms and signs! mucus production Laboratory ndings! Local production of IgE !! Sneezing paroxysms !!Nasal eosinophilia Eosinophil TH1-cell-mediated !!Nasal, ocular, palatal itching induction !of Evidence of Allergen-specic IgE by bronchial epithelial-cell apoptosis !!Clear rhinorrhea skin or RAST testing
IL-5 T H2 cell IL-13, KIT
!!Transverse nasal crease IgE IL-4, IL-13 !!Infraorbital cyanosis ("allergic shiners") TCR !!Serous otitis media !!Nasal congestion Memory B cellnasal mucosa !!Pale, bluish
CpG motif
A deoxycytosine deoxyguanosine sequence. Such sequences are prevalent in bacterial DNA but are rare in mammalian DNA. Unmethylated CpG is endocytosed by cells of the innate immune system and interacts with Toll-like receptor 9, activating a signalling cascade that results in the production of proinflammatory cytokines.
Figure 1 | Mechanisms of allergic reactions. a | Sensitization to allergens and development of specific B-cell and T-cell memory. Differentiation and clonal expansion of allergen-specific T helper 2 (TH2) cells leads to the production of cytokines (interleukin-4 (IL-4) and IL-13), which induce immunoglobulin class switching to IgE and clonal expansion of naive and IgE+ memory B-cell populations. IgE at the surface of allergen-specific IgE+ B cells and other IgEsensitized antigen-presenting cells facilitates antigen presentation. T-cell activation in the presence of IL-4 increases differentiation into TH2 cells. b | Type 1 hypersensitivity reaction (immediate phase of the allergic reaction). Crosslinking of mast-cell and basophil cell-surface FcRI (high-affinity receptor for IgE)-bound IgE by allergens leads to the release of vasoactive amines (such as histamine), lipid mediators (such as prostaglandin D, platelet-activating factor, leukotriene C4 (LTC4), LTD4 and LTE4), chemokines (CXC-chemokine ligand 8 (CXCL8), CXCL10, CC-chemokine ligand 2 (CCL2), CCL4 and CCL5) and other cytokines (such as IL-4, IL-5 and IL-13), and to the immediate symptoms of allergic disease. c | Allergic inflammation (late phase of the allergic reaction). Following migration to sites of allergen exposure under the influence of chemokines and other cytokines, allergen-specific T cells are reactivated and clonally expand. Local IgE-facilitated antigen presentation by dendritic cells (DCs) increases T-cell activation. Local IgE production is seen in allergic rhinitis and asthma but not in allergic skin inflammation (the main example of which is atopic dermatitis). Eosinophils are one of the main inflammatory cells (constituting up to 50% of the cellular infiltrate) in the lungs of asthmatic individuals but not in the skin of those with atopic dermatitis (12% of the cellular infiltrate). TH1 cells, which produce interferon- (IFN) and tumour-necrosis factor (TNF), contribute to the activation and apoptosis of keratinocytes (in the skin), bronchial epithelial cells and pulmonary smooth-muscle cells. Activation of mast cells and basophils, which release histamine, chemokines and other cytokines, also contributes to the late-phase allergic reaction. CD95L, CD95 ligand; SCF, stem-cell factor (also known as KIT ligand); TCR, T-cell receptor.
Immunodeciency disorders
| | Severe Combined Immunodeciency disease
phil
DC
cell
Atopic dermatitis TH1-cell-mediated induction of keratinocyte apoptosis TH1-cell-mediated epithelialcell activation, and release of chemokines and pro-inammatory cytokines
Clinical Manifestation
Absence of normal thymic tissue, and the lymph nodes, spleen, and other peripheral lymphoid tissues are devoid of lymphocytes. In these patients, the complete or near-complete failure of development of both the cellular and the humoral component of the immune system results in Symptom: mucocutaneous candidiasis, chronic diarrhea, and pneumonitis Vaccination with live viral vaccines or bacillus Calmette-Guerin (BCG) may lead to disseminated disease. Without immune reconstitution by bone marrow transplantation, SCID is inevitably fatal within 12 years.
Patients have been identied with defective recombination-activating gene (RAG1 and RAG2) products. RAG1 and RAG2 initiate recombination of antigen-binding proteins, immunoglobulins, and T-cell receptors. The failure to form antigen receptors leads to a quantitative and functional deciency of T and B lymphocytes. NK cells are not antigen specic and for that reason are unaffected.
HIV-infection
Questions
1. What are the specic and nonspecic components of the cellular and noncellular limbs of the immune system? 2. What is the role of macrophages in the immune system, and what are some of the products they secrete? 3. What is the role of lymphocytes in the immune system, and what are some of the products they secrete? 4. What is the role of eosinophils in the immune system, and what are some of the products they secrete? 5. What is the role of basophils in the immune system, and what are some of the products they secrete? 6. What are the primary and secondary lymphoid organs, and what roles do they play in the proper functioning of the immune system? 7. What are the components of and distinctions between the innate and adaptive forms of immunity? 8. Explain mechanisms by which antibodies can induce the elimination of foreign antigens. 9. What are the four types of immune reactions in the Gell and Coombs classication scheme, and what are some examples of disorders in which each is involved? 10.What are the major clinical manifestations of allergic rhinitis? 11.What are the major etiologic factors in allergic rhinitis? 12.What are the pathogenetic mechanisms in allergic rhinitis?
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