Immunology - Comp Exam

Question 1

Why do warm-blooded, long-lived animals require complex immune defenses?

Answer 1

Infectious agents such as bacteria can divide rapidly in warm-blooded creatures.

Question 2

What are the types of pathogenic organisms.

Answer 2

Question 3

How many bacteria are there in the world?

Answer 3

~ 4-6 x 10³⁰

Question 4

What are pathogenic bacteria?

Answer 4

Pathogenic Bacteria

• Able to cause disease.
• Only a few bacteria have the ability to cause disease in humans.

Question 5

Describe the bacterial wall.

Answer 5

Question 6

Describe how the immune system sees pathogens.

Answer 6

Question 7

Compare innate and adaptive immunity.

Answer 7

Innate and Adaptive Immunity

Question 8

Describe the innate immune cells.

Answer 8

Innate Immune Cells

• Immune responses of the innate immune system provide natural immunity against microorganisms via:
  
  • Phagocytosis and intracellular killing.
  • Recruitment of other inflammatory cells.
  • Presentation of antigens.
• Leukocytes include neutrophils, monocytes and tissue macrophages, eosinophils, and natural killer (NK) cells which are lymphocytes.
• These cells provide the first line of defense against most pathogens.

Question 9

Describe the recognition of microbes by the innate immunity.

Answer 9

Recognition by Innate Immunity

• Selectively recognize, alarm, and trigger responses against microbes.
• Innate immunity has Pattern Recognition Receptors (PRRs).
• Recognize Pathogen-Associated Molecular Patterns (PAMPs):
  
  • Mannose (Mannan)
  • Lipopolysaccharide (LPS)
  • Peptidoglycan
  • Bacterial DNA (rich in CpG motif)
  • dsRNA

Question 10

Describe the components of the bacterial wall.

Answer 10

Bacterial Wall Components

Question 11

Describe the general properties of PRRs.

Answer 11

PRRs - General Properties

Question 12

Describe the innate immune response.

Answer 12

Innate Immune Response

• Neutrophils are the first cells to arrive at the site of tissue damage.
• Activation of neutrophils leads to respiratory bursts and release of granules to control bacterial growth.
• Macrophages engulf organisms** by phagocytosis and release many **inflammatory mediators.

Question 13

Describe acute-phase proteins.

Answer 13

Acute-Phase Proteins

• Several circulating proteins are involved in defense against infections.
• These plasma proteins induced rapidly by cytokines after infection and called Acute-Phase Proteins.
• Plasma mannose-binding lectin (MBL) is a protein that recognizes microbial carbohydrates.
• MBL activates the complement cascade by the lectin pathway.
• C-reactive protein (CRP) binds to phosphorylcholine on microbes and coats the microbes for phagocytosis by macrophages.

Question 14

Describe the complement system.

Answer 14

Complement System

• About 30 proteins (numbered C1, C2, C3…) in the circulation form Complement System.
• The activation may be initiated by three distinct pathways.
• All pathways lead to the production of C3b (the early steps).
• C3b initiates activation of C5 component.
• Cascade of complement activation, culminating in formation of the “membrane attack complex“.
• It creates holes in plasma membranes and kill pathogens.

Question 15

Describe phagocytosis by and activation of macrophages.

Answer 15

Macrophages - Phagocytosis and Activation

• Macrophages express pattern-recognition receptors (PRRs).
• The Toll-like receptors (TLRs) plays a critical role in recognition of bacterial components (cell wall membranes, LPS, flagellin, CpG oligodeoxynucleotides).
• Interaction with any of these receptors initiates proinflammatory responses.
• Engagement of PRRs trigger signal pathways that promote phagocytosis.

Question 16

Describe cytokines.

Answer 16

Cytokines

• Macrophages responding to microbes produce cytokines that stimulate inflammation.
• Activated NK cells produce the macrophage-activating cytokine IFN-γ.
• The major cytokines of innate immunity are listed.
• NB! IFN-γ (type II interferon) is a cytokine of both innate and adaptive immunity.
• Interferons were named so because these cytokines interfere with viral infection.
• IFN-γ is a weak antiviral cytokine compared with the type I interferons, IFN-α and IFN-β.

Question 17

Describe the linking of innate and adaptive immune responses.

Answer 17

Linking Innate and Adaptive Responses

• Pathogen recognition through PRRs is an important bridge between innate and adaptive immunity.
• Causes activation and maturation of antigen-presenting cell (APC).
• APC** processed antigen is presented to **naïve T cells.
• Secreted cytokines assist development and maturation of T-cell.

Question 18

Describe properties of adaptive immunity.

Answer 18

Properties of Adaptive Immunity

Question 19

Describe the lymphoid cells.

Answer 19

Lymphoid Cells

Question 20

Describe the 2 types of adaptive immune system responses.

Answer 20

Adaptive Immune System - Responses

• Adaptive immunity has two types of response:
  
  • Cell-mediated immunity - mediated by thymus-dependent lymphocytes called T lymphocytes.
  • Humoral immunity - mediated by antibodies produced by B lymphocytes (called “B” which develop in the bursa of Fabricius in the avian species).

Question 21

Describe adaptive immunity.

Answer 21

Adaptive Immunity

• Humoral adaptive immunity is mediated by antibodies (Abs).
• Abs are secreted into the circulation** and **mucosal fluids.
• Abs neutralize** and **eliminate extracellular microbes and microbial toxins.
• Prevent dissemination of microbes (gaining access to host cells and connective tissues).
• Not effective against intracellular microbes that live and divide inside infected cells.
• Cell-mediated adaptive immunity is mediated by T cells and defends against intracellular microbes.

Question 22

Describe the maturation of lymphocytes.

Answer 22

Lymphocytes - Maturation

• B lymphocytes develop from precursors during lifetime.
• All T lymphocytes** are generated in **the thymus during fetal stage.

Question 23

Describe the recognition of Ags and the effector functions of B and T lymphocytes.

Answer 23

B and T Cells

• B cells recognize soluble or cell surface Ags and differentiate into Ab-secreting plasma cells.
• T helper cells recognize Ags on the surfaces of Ag-presenting cells (APCs) and secrete cytokines, which stimulate different mechanisms of immunity.
• Cytotoxic T lymphocytes (CTLs) recognize Ags on infected cells and kill these cells.
• Both Th cells and CTLs recognize protein Ags that are displayed by MHC molecules.
• NK cells recognize changes in MHC expression on the surface of infected cells and kill these cells.

Question 24

Describe the types of T cells.

Answer 24

T Cells - Types

• There are at least 2 types of T helper cells and CTLs.
  
  • T helper type 1 cells (Th1 cells) produce IFN-γ that activates macrophages to destroy microbes.
  • T helper type 2 cells (Th2 cells) produce IL-4, IL-5 and IL-10.
• Cytotoxic T lymphocytes, CTLs kill host cells that are harboring infectious microbes in the cytoplasm.

Question 25

Describe antigen-presenting cells (APCs).

Answer 25

Antigen-Presenting Cells (APCs) * **_Specialized cells_** are located in the epithelium and capture Ags. * The Ag capture is best understood for **_dendritic cells (DCs)._** * DCs capture **_protein Ags_** and process them into peptides. * DCs display peptide Ags for **_recognition by naïve T cells only._** * **_Macrophages_** (MΦ) are also capable of displaying protein **_Ags to effector (being activated by DCs) T cells only._**

Question 26

Describe the major histocompatibility complex.

Answer 26

Major Histocompatibility Complex * **_T cells**_ can only see _**peptide Ags_** presented by APCs in association with specialized molecules called MHC (Major Histocompatibility Complex). * This property of T cells is called **_“MHC restriction”._** * There are **_MHC class I**_ and _**MHC class II_**. * MHC class I is expressed on **_all nucleated cells_** of the body, including professional APCs. * MHC class II is expressed on **_professional APCs only._**

Question 27

Describe the structure of the TCR complex.

Answer 27

TCR Complex - Structure * The T-cell receptor (TCR) complex consists of 2 **_Ag-binding chains_**, α and β. * **_TCRs are identical (specificity)_** in each individual T cell. * Although TCR has a short cytoplasmic tail, **_signaling occurs via CD3_**. * **_CD3 is always expressed_** with TCR. * Each **_T helper cell**_ expresses _**CD4_**, required for interaction with APCs. * Each **_CTL**_ expresses the _**CD8_** co-receptor molecule. * Both **_CD4 and CD8 bind MHC_** molecules (not Ag!) on APCs.

Question 28

Describe how an Ag is recognized by the TCR.

Answer 28

TCR - Ag Recognition * T cell receptor(TCR) **_recognizes**_ a complex of a _**peptide Ag_** displayed by a MHC molecule. * Peptides bind to the MHC molecules by **_anchor residues._** * The TCR of every T cell **_recognizes**_ amino acid residues of the peptide (about 3-5 aa) and some (polymorphic) _**residues of the MHC molecule._**

Question 29

Describe professional APCs.

Answer 29

Professional APCs * The specialized cells that **_capture microbial Ags_** and display them for recognition by T lymphocytes are called APCs. * Naive T lymphocytes need to see Ags presented by **_Dendritic cells only_** to initiate immune responses against protein antigens. * Dendritic cell has the ability to display Ags and **_provide costimulatory signals**_ needed to activate _**naive T cells_**. * Differentiated **_effector T cells**_ (activated) can see Ags presented by _**various APCs._** * The professional APCs are **_dendritic cells, macrophages and B cells._**

Question 30

Describe the capture of Ag by APCs.

Answer 30

APCs - Capture of Ags * Microbes enter through an epithelium and are captured by **_DCs resident in the epithelium._** * DCs transport Ags to the **_lymph nodes**_ where protein Ags are displayed for _**recognition by T lymphocytes._** * **_Blood**_ borne Ags are presented by _**APCs in the spleen._**

Question 31

Describe Ag processing for Class II MHC.

Answer 31

Ag Processing for MHC-II * Exogenous Ags are processed in lysosomes of **_professional APCs._** * The α and β chains of **_MHC II**_ are _**produced**_ in the _**endoplasmic reticulum_** (ER). * A specialized invariant chain **_CLIP_** prevents binding of endogenous peptides in endosomes. * **_Endosomes**_ (class II MHC with CLIP) _**fuse**_ with _**lysosomes_**. * Enzymes within the lysosomes **_degrade CLIP_** that enables binding of exogenous peptide Ags into MHC II.

Question 32

Describe the structure of Class II MHC.

Answer 32

Class II MHC - Structure * Processed peptide **_(13-25 aa)_**. * Interact with the **_α1 and β1 domains_** on the class II MHC molecule. * Allows presentation to **_CD4⁺ T helper cells._** * Interactions with the TCR are **_stabilized by CD4_** recognition of conserved regions on the class II molecule.

Question 33

Describe Ag processing for Class I MHC.

Answer 33

Ag Processing - MHC I * Microbial **_PROTEINS**_ are degraded by _**proteasomes**_ to _**peptides._** * Degraded **_peptides are carried**_ into the rough endoplasmic reticulum (RER) _**by transporters of antigenic peptides_** (TAP-1, TAP-2). * Peptides are **_loaded into MHC_** class I complex. * The complex is routed through the **_Golgi**_ to the _**plasma membrane._**

Question 34

Describe the structure of Class I MHC.

Answer 34

Class I MHC - Structure * MHC I is associated with the **_invariant β2M_**, giving structure to the extracellular CDR, complementarity determining regions domain. * **_Presents**_ processed peptides _**for CD8⁺ CTLs_**. * **_CD8_** stabilizes **_interaction_** of TCR with **_Class I MHC_** complex. * **_Peptide Ags (8-9 aa)_** non-covalently interact with both: * **_Class I MHC_** via the α1 and α2 domains. * The TCR via **_complementarity determining regions_** (CDRs).

Question 35

Describe the properties of MHC molecules.

Answer 35

MHC Molecules - Properties

Question 36

Describe Ag recognition by T cells.

Answer 36

Ag Recognition by T Cells * Activation of **_CD4⁺ T cell_** is shown. * For activation, at least **_two TCRs**_ must bind Ag _**simultaneously_**. * **_Cross-linking_** of those Ag-bound TCRs leads to **_signaling**_ and _**activation_**. * **_CD3**_ and _**ζ (zeta)**_ are _**signaling subunits_** noncovalently attached to the TCR. * Activation of **_CD8⁺ T cells_** occurs in the similar manner. * **_CD4⁺ T cell and CD8⁺ T cell_** “know” which Ag to interrogate, class I or class II.

Question 37

Describe the activation of CD4⁺ T cells.

Answer 37

Activation of CD4⁺ T Cells * The TCR complex recognizes Ag and generates **_FIRST SIGNAL_**. * CD28 is a T cell receptor for B7 molecules on APC that delivers SECOND COSTIMULATORY SIGNAL. * But, **_TCR signaling is not enough_** to activate T cells. * **_A co-stimulation via B7-CD28 is required!_** * Cytokines produced by APCs provide the THIRD

Question 38

Describe the activation of T lymphocytes.

Answer 38

Activation of T Lymphocytes

Question 39

Describe T_H1 and T_H2 effector cells.

Answer 39

T_H1 and T_H2 Effector Cells * After activation by Ag and costimulation, naive **_CD4⁺ T cells**_ may differentiate into (or _**commit to_**) specific subsets of CD4⁺ T cells **_Th1 and Th2 cells_**. * The fate is **_controlled by commitment cytokines._** * **_IL-12**_ produced by microbe-activated _**MΦ and DCs**_ stimulates differentiation of _**Th1_** CD4⁺ T cells. * **_No IL-12_**, the T cells produce IL-4 that stimulates differentiation into **_Th2_** CD4⁺ T cells effectors.

Question 40

Describe the T_H1/T_H2 paradigm.

Answer 40

T_H1/T_H2 Paradigm

Question 41

Describe T cell-specific cytokines.

Answer 41

T Cell-Specific Cytokines

Question 42

Describe the humoral adaptive immune response.

Answer 42

Humoral Adaptive Immune Response * B cells can produce various classes of Abs, but only after an Ag-activated B cell is helped by activated CD4⁺ T helper cells and becomes a plasma cell.

Question 43

Describe T and B cell interaction.

Answer 43

T and B cell Interaction * Occurs in local lymph node.

Question 44

Describe T cell-mediated activation of B cells.

Answer 44

T Cell-Mediated Activation of B Cells

Question 45

Describe clonal activation of B cells.

Answer 45

Clonal Activation of B Cells * Mature B lymphocytes with receptors for many Ags **_develop before encounter_** with these **_antigens_**. * Each **_Ag_** activates a preexisting clone of specific B cells and **_stimulates**_ the _**proliferation**_ and _**differentiation_** of that clone. * Shown are **_surface Ags**_, but clonal selection also occurs for _**soluble Ags_**. * **_The same principle applies to T lymphocytes._**

Question 46

Describe the primary response to Ag.

Answer 46

Primary Immune Response to Ag * Adaptive immunity mounts **_more effective responses to repeated exposures_** to the same Ag. * The first exposure to Ag is called the **_primary (1⁰) immune response._** * Primary response is mediated by **_naive lymphocytes_** (see Ag for the first time). * Subsequent encounters with the same Ag lead to **_secondary (2⁰) immune responses_**.

Question 47

Compare primary and secondary immune responses.

Answer 47

Primary and Secondary Responses * The **_secondary response to Ag X is more rapid and robust_** than the primary response due to the memory. * Antibody **_levels decline with time_** after each immunization.

Question 48

Describe the secondary immune response to Ag.

Answer 48

Secondary Immune Response to Ag * Secondary responses are **_more rapid, larger, and better_** able to eliminate the Ag. * Secondary responses are the result of the activation of **_memory lymphocytes_**. * Memory lymphocytes are **_long-lived cells_** that were generated during the primary immune response. * Memory is also one of the reasons why **_vaccines confer long-lasting protection_** against infections.

Question 49

Describe the activation of B cells.

Answer 49

Activation of B Cells * Ag-activated B cells produce a **_small quantities of IgM_** - an explanation why IgM Abs appear first after immunization with Ag. * As a **_professional APC_**, activated B cell increases the expression of **_co-stimulatory molecules_** and receptors for cytokines. * It prepares B cell to “rendezvous” with **_activated CD4⁺ T cell_** (by dendritic cell) that recognizes and Ag from the same pathogen.

Question 50

Describe Ab structure and functional domains.

Answer 50

Ab Structure and Functional Domains * Ab is a tetramer of two pairs of **_identical heavy and light chains._** * Both heavy and light chain molecules have **_variable and constant domains._** * The variable region, termed F(ab')2 (fragment, Ag binding) confers **_Ag recognition._** * The constant region, termed Fc (fragment, crystalline), **_interacts with cell surface receptors_** (M receptor for Fc fragment). * The heavy chain contains a hinge domain that **_confers flexibility_** to allow optimal binding to antigen. * Distinct biological activity attributed to each end of the molecule - **_Fc fragment._**

Question 51

Describe the classes of Ab isotypes.

Answer 51

Classes of Ab Isotypes * Antibodies are **_classified_** according to which **_heavy chain_** they have. * The constant Fc regions of the heavy chain **_confers antibody function_**, representing five different classes, or isotypes. * The isotypes, IgM, IgD, IgG, IgE, and IgA, have **_characteristic properties_**. * There are four subclasses of the IgG isotype, called **_IgG1, IgG2, IgG3, and IgG4._** * IgA has two subclasses called **_IgA1 and IgA2_**.

Question 52

Describe the role of cytokines in Ab production.

Answer 52

Role of Cytokines in Ab Production

Question 53

Describe the major properties of Ab classes.

Answer 53

Ab Classes - Major Properties * The γ-globulin fraction of serum is primarily composed by three isotype - IgG, IgA, IgM. * IgE is present at low concentrations. * Only traces of IgD are found in the circulation.

Question 54

Describe the general properties of PRRs.

Answer 54

Question 55

Describe the interface between innate and adaptive immunity.

Answer 55

Question 56

Describe immune cells.

Answer 56

Immune Cells * Immune system cells are derived from **_pluripotent hematopoietic stem cells_** in the bone marrow. * Pluripotent hemopoietic stem cells differentiate into **_myeloid and lymphoid progenitor cells._** * **_The myeloid lineage:_** * Neutrophils, basophils/mast cells, eosinophils, erythrocytes, monocytes, and platelets. * **_The Lymphoid lineage:_** * B and T lymphocytes and Natural Killer (NK) cells.

Question 57

Describe TLR4.

Answer 57

TLR4 * LPS signaling in human monocytes.

Question 58

Describe the physical barriers of the immune system.

Answer 58

Question 59

Describe innate defense components.

Answer 59

Question 60

Describe the timeline for innate and adaptive immunity.

Answer 60

Question 61

Describe the causes of hypersensitivity.

Answer 61

Causes of Hypersensitivity * Type I: * Clinical manifestations result from the actions of MEDIATORS secreted by the mast cells. * Type II: * Abs against cell and TISSUE Ags may cause tissue injury and disease. * Type III: * IMMUNE COMPLEX diseases, Abs may bind to circulating Ags to form immune complexes, which deposit in vessels, leading to inflammation in the vessel wall (vasculitis). * Type IV: * T cell-mediated diseases which result from inflammation caused by CYTOKINES produced by CD4⁺ Th1 and Th17 cells, or killing of host cells by CD8⁺ CTLs.

Question 62

Describe type I hypersensitivity.

Answer 62

Type I Hypersensitivity * IMMEDIATE type I hypersensitivity is a type of pathologic reaction that is caused by the release of mediators from mast cells. * This reaction is most often triggered by the production of IgE Ab against environmental Ags and the binding of IgE to mast cells in various tissues. * Atopy refers to the genetic tendency to develop ALLERGIC DISEASES. * Individuals with a strong propensity to develop allergic reactions are said to be atopic. * Type I hypersensitivity reactions is controlled by the binding of IgE Abs to FcεR1 located on the membrane of mast cells, basophils and eosinophils. * The IgE-FcεR1 binding has high (subnanomolar) affinity for IgE. * Most of the IgE produced following initial contact (priming) with Ag becomes 'fixed' on the surface of mast cells and basophils. * Upon a second contact with Ag, the Ag-Ab reactions occurs predominantly on the mast cell and basophil membrane. * The SEQUENCE of events in the development of immediate hypersensitivity reactions begins with: 1. PRODUCTION of IgE after activation of Th2 cells by 1⁰ exposure to allergens. 2. BINDING of the IgE to Fc receptors of mast cells. 3. RELEASE of mediators by mast cell after 2⁰ exposure to the Ag and cross-linking of the membrane-bound IgE by Ags. * The most important MEDIATORS produced by mast cells are vasoactive amines, proteases, prostaglandins and leukotrienes, and cytokines. * HISTAMINE - the major amine, causes the dilation of small blood vessels and increases vascular permeability. * PROTEASES - may cause damage to local tissues. * PROSTAGLANDINS - cause vascular dilation. * LEUKOTRIENES - stimulate prolonged smooth muscle contraction. * CYTOKINES - induce local inflammation (the late-phase reaction). * Thus, mast cell mediators are responsible for acute vascular and smooth muscle reactions and inflammation, the HALLMARKS OF IMMEDIATE HYPERSENSITIVITY.

Question 63

What are some examples of Type I Hypersensitivity?

Answer 63

Type I Hypersensitivity - Examples

Question 64

Describe type II hypersensitivity.

Answer 64

Type II Hypersensitivity * Abs specific for cell and TISSUE Ags may deposit in tissues and cause injury by inducing local inflammation. * Abs (IgG and IgM) activate the COMPLEMENT SYSTEM by the classical pathway, resulting in the production of complement byproducts that recruit leukocytes and induce inflammation. * IgG antibodies bind to NEUTROPHIL and MACROPHAGE Fc receptors and activate these leukocytes, resulting in proinflammatory response. * Reactive oxygen species and lysosomal enzymes released DAMAGE the adjacent tissues.

Question 65

What are some examples of type II hypersensitivity?

Answer 65

Type II Hypersensitivity - Examples

Question 66

Describe type III hypersensitivity.

Answer 66

Type III Hypersensitivity * Ab-Ag COMPLEXES may be formed in the circulation and deposited in blood vessels and other sites. * These immune complexes induce VASCULAR INFLAMMATION, and subsequent ischemic damage to the tissues. * The major mechanism triggering tissue damage is classical activation of complement. * Mediated by the deposition of Ag-Ab complexes. * The complexes fix complement to release the anaphylatoxin products C3a and C5a. * Inflammatory cells (basophils and especially neutrophils) release VASOACTIVE AMINES. * Type III hypersensitivity reactions are caused by Ab-Ag complexes. * When significant quantities of such immune complexes are formed, they can deposit in tissues leading to a TISSUE DAMAGE is mediated by: * Complement activation. * Mast cell degranulation. * Neutrophil chemotaxis. * Inflammation caused by immune cells. * Human diseases caused by the deposition of immune complexes. * In the diseases, IMMUNE COMPLEXES are detected in the blood or in the tissues that are the sites of injury. * In all the disorders, injury is caused by complement-mediated and Fc receptor-mediated INFLAMMATION. * **_The ARTHUS REACTION is induced by subcutaneous administration of a protein Ag to a previously immunized animal; it results in the formation of immune complexes at the site of Ag injection, and a local vasculitis._**

Question 67

What are some examples of type III hypersensitivity?

Answer 67

Type III Hypersensitivity - Examples

Question 68

Describe type IV hypersensitivity.

Answer 68

Type IV Hypersensitivity * Type IV hypersensitivity (Delayed Type Hypersensitivity, DTH) is caused by activated Th1 cells. * The SENSITIZATION PHASE of DTH can be caused by intracellular pathogens (will be discussed later). * Upon re-encounter with Ag, the Ag-specific Th1 clones undergo further clonal expansion and secretion of IFN-gamma and TNF-beta which activate macrophages causing macrophage-dependent TISSUE DAMAGE. * Unlike type I, II and III reactions that can be transferred by serum containing abs, passive transfer of type IV requires the transfer of antigen-specific TH1 clones that orchestrate the macrophage response. * In immune-mediated inflammation, Th1 and Th17 cells secrete CYTOKINES that recruit and activate leukocytes. * Tissue injury results from the products of the recruited and activated neutrophils and macrophages, such as lysosomal enzymes, reactive oxygen species, nitric oxide, and proinflammatory cytokines. * The inflammation associated with T cell-mediated diseases is TYPICALLY CHRONIC. * Many organ-specific autoimmune diseases are caused by interaction of autoreactive T cells with self Ags, leading to cytokine release and inflammation. * T cell reactions specific for microbes and other foreign Ags may also lead to inflammation and tissue injury. * The classical T cell–mediated inflammatory reaction is called delayed-type hypersensitivity (DTH). * T cells play a DOMINANT ROLE in causing tissue injury but Abs and immune complexes may also contribute. * Multiple sclerosis, rheumatoid arthritis, and type 1 diabetes are autoimmune disorders. * Crohn′s disease, an inflammatory bowel disease, is likely caused by reactions against microbes in the intestine and may have a component of autoimmunity. * The other diseases are caused by reactions against foreign (microbial) Ags. * Delayed-type hypersensitivity (DTH) is an injurious cytokine-mediated inflammatory reaction resulting from the activation of T cells, particularly CD4⁺ T cells. * The reaction is called delayed because it typically develops 24 to 48 hours after Ag challenge. * Humans may be sensitized for DTH reactions by microbial infection (TB), by contact sensitization (Poison Ivy) or immunization (diphtheria toxin/Tetanus toxin). * Purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits a DTH reaction, called the tuberculin reaction.