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What is the function of immune system?


Retno Murwanti DVM, MSc, PhD Faculty of Pharmacy Gadjah Mada University 2012

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

normal structure and function of the immune system

Anatomy physiology


Cells of immune system

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 leukocytes Eosinophiles

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.

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.

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.

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.

Organs of immune system

Primary lymphoid organs :bone marrow, thymus bone marrow : Pluripotent stem cells differentiate into lymphocyte, granulocyte, monocyte, erythrocyte, and megakaryocyte populations thymus : produce T lymphocytes and is the site of initial T-lymphocyte differentiation Secondary lymphoid organs : lymph nodes, spleen, gut-associated lymphoid tissue

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.

Innate and adaptive immune response


Immune response to antigens

What are the components of and distinctions between the innate and adaptive forms of immunity? Indicate the primary role of the immune system and the major classes of events by which this is accomplished. Innate immune response Adaptive immune response ( Humoral immune response and Cellular immune response)

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.

Immune response to antigens

Antigen processing and presentation

Most foreign antigens are not recognized by the immune system on their native form therefor need processing by APC APC (Antigen Presenting Cells) : DC, Macrophages, Langerhans cells, Kupffer cells, microglia, and B lymphocytes Steps : 1.Antigen uptake 2.Antigen processing 3.MHC biosynthesis 4.Peptide-MHC association

Antigen processing and presentation

Routes of antigen entry

Cellular immune response

Humoral immune response

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CD4+ cells : Helper T cell CD8+ T cells : cytotoxic T cells

Humoral Mechanisms of Antigen Elimination


Mechanism of Inammation

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.

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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.

Hypersensitivity Immune Responses

Hypersensitivity diseases are commonly classied according to ( Philip Gell and Robin Coombs) : the type of immune response the effector mechanism responsible for cell and tissue injury Classication: 1.Immediate hypersensitivity (Type I) 2.Antibody mediated (Type II) 3.Immune complex mediated (Type III) 4.T Cell mediated (Type IV)

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

Mechanisms of Tissue Injury and Disease :

Opsonization and phagocytosis of cells Complement- and Fc receptor-mediated recruitment and activation of leukocytes (neutrophils, macrophages) Abnormalities in cellular functions, e.g., hormone receptor signaling mediators, cytokines)

Type IV
T cell mediated: type IV Pathologic Immune Mechanisms :
CD4+ T cells (cytokine-mediated inammation) CD8+ CTLs (T cell-mediated cytolysis)

Pathophysiology of selected immune disorders

Allergic Rhinitis

Mechanisms of Tissue Injury and Disease :

Recruitment and activation of leukocytes Direct target cell killing, cytokine-mediated inammation

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.

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.

Mechanism of allergic reaction

Sensitization Immediate reaction Late phase allergic inammation

Sensitization and memory induction

a Sensitization and memory induction
Allergen DC MHC class II molecule Naive T cell TCR IL-4 IgE T cell Dierentiation into TH2 cells and clonal expansion TH2 cell IL-4 IL-13 IgM Class switching to IgE Memory B cell IgE

b Immediat

IL-4 IL-13

Naive B cell FcRI IgE+ memory B-cell clonal expansion


Memory IL-4 B cell



IL-4 IgE T cell Memory IL-4 B cell

expansion TH2 cell IL-4 IL-13

IL-4 IL-13

FcRI IgE+ memory B-cell clonal expansion

Mast cell

Immediate phase : type 1 reaction
b Immediate phase: type 1 reaction
Class switching to IgE Memory B cell IgE

vasoactive amines, lipid mediators, chemokines and other cytokines



Late phase: allergic inammation

c Late phase: allergic inammation
Smooth-muscle-cell activation and hyper-reactivity for contraction, and release of chemokines and pro-inammatory cytokines Increased endothelial-cell adhesion and inammatory-cell transmigration Eosinophil activation and release of mediators, chemokines and proinammatory cytokines IFN, TNF TH1 cell IL-13 IL-4, IL-13, CCL5 IL-4, IL-13, SCF, KIT FcRI IL-5 TH2 cell Eosinophil IL-9, IL-13 Allergic rhinitis and asthma TH2-cytokine-mediated induction of increased mucus production Local production of IgE TH1-cell-mediated induction of bronchial epithelial-cell apoptosis

Memory B cell IL-4, IL-13 IgE

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

Late phase of the allergic reaction

Clinical manifestations can be measurable (visible) two or more hours after allergen exposure but might appear much later. These manifestations peak at 69 hours after allergen exposure and have resolved by 2448 hours. Reactions are characterized by oedema and the infiltration of T helper 2 cells and eosinophils. Tissue reactions are characterized by oedema, pain, warmth and erythema (redness). Reactions in the lungs are characterized by airway narrowing and mucus hypersecretion.


TCR MHC class II molecule Allergen TH1 cell IFN TNF CD95L

Mast cell


DC T-cell activation and proliferation by IgE-facilitated and non-IgE-facilitated presentation of allergens by inammatory DCs



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


VOLUME 6 O CTOBER 2006 763

MHC class II molecule Allergen TH1 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.

Pathology and Pathogenesis

Characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. Pathology : Defective Cytokine Signaling (IL2 shared with IL-4,IL-7, IL-9, IL-15) Defective T-Cell Receptor Signaling Deciencies of both p56lck and Jak3 (Janus kinase 3) Defective Receptor Gene Recombination Defective Nucleotide Salvage Pathway (deciency of adenosin deaminase / ADA)

Defective Cytokine Signaling

X-linked SCID (XSCID) is the most prevalent form Resulting from a genetic mutation in the common chain of the trimeric () IL-2 receptor, shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients. A defect in the chain of the IL-7 receptor can also lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.

Defective T-Cell Receptor Signaling

A deciency of ZAP-70 (zeta-associated protein 70), a protein tyrosine kinase important in signal transduction through the T-cell receptor, leads to a total absence of CD8 T lymphocytes. Consequently, these patients possess functionally defective CD4 T lymphocytes and no circulating CD8 T lymphocytes but normal B-lymphocyte and NK cell activity. Deciencies of both p56lck and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction. P56lck is a T-cell receptorassociated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptorassociated signaling molecule.

Defective Receptor Gene Recombination

Defective Nucleotide Salvage Pathway

Approximately 20% of SCID cases are caused by a deciency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deciency and clinical presentation of this disorder, known as SCID-ADA, is identical to that of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease.

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.


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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