Immunology - Comp Exam Flashcards
1
Q
Why do warm-blooded, long-lived animals require complex immune defenses?
A
Infectious agents such as bacteria can divide rapidly in warm-blooded creatures.
2
Q
What are the types of pathogenic organisms.
A
3
Q
How many bacteria are there in the world?
A
~ 4-6 x 1030
4
Q
What are pathogenic bacteria?
A
Pathogenic Bacteria
- Able to cause disease.
- Only a few bacteria have the ability to cause disease in humans.
5
Q
Describe the bacterial wall.
A
6
Q
Describe how the immune system sees pathogens.
A
7
Q
Compare innate and adaptive immunity.
A
Innate and Adaptive Immunity
8
Q
Describe the innate immune cells.
A
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.
9
Q
Describe the recognition of microbes by the innate immunity.
A
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
10
Q
Describe the components of the bacterial wall.
A
Bacterial Wall Components
11
Q
Describe the general properties of PRRs.
A
PRRs - General Properties
12
Q
Describe the innate immune response.
A
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.
13
Q
Describe acute-phase proteins.
A
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.
14
Q
Describe the complement system.
A
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.
15
Q
Describe phagocytosis by and activation of macrophages.
A
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.
16
Q
Describe cytokines.
A
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.
17
Q
Describe the linking of innate and adaptive immune responses.
A
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.
18
Q
Describe properties of adaptive immunity.
A
Properties of Adaptive Immunity
19
Q
Describe the lymphoid cells.
A
Lymphoid Cells
20
Q
Describe the 2 types of adaptive immune system responses.
A
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).
21
Q
Describe adaptive immunity.
A
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.
22
Q
Describe the maturation of lymphocytes.
A
Lymphocytes - Maturation
- B lymphocytes develop from precursors during lifetime.
- All T lymphocytes** are generated in **the thymus during fetal stage.
23
Q
Describe the recognition of Ags and the effector functions of B and T lymphocytes.
A
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.
24
Q
Describe the types of T cells.
A
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.
25
Q
Describe antigen-presenting cells (APCs).
A
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.
26
Q
Describe the major histocompatibility complex.
A
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.
27
Q
Describe the structure of the TCR complex.
A
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.
28
Q
Describe how an Ag is recognized by the TCR.
A
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.
30
Q
Describe the capture of Ag by APCs.
A
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.
31
Q
Describe Ag processing for Class II MHC.
A
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.
32
Q
Describe the structure of Class II MHC.
A
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.
33
Q
Describe Ag processing for Class I MHC.
A
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.
34
Q
Describe the structure of Class I MHC.
A
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).
35
Q
Describe the properties of MHC molecules.
A
MHC Molecules - Properties
36
Q
Describe Ag recognition by T cells.
A
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.
37
Q
Describe the activation of CD4+ T cells.
A
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
38
Q
Describe the activation of T lymphocytes.
A
Activation of T Lymphocytes
39
Q
Describe TH1 and TH2 effector cells.
A
TH1 and TH2 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.
40
Q
Describe the TH1/TH2 paradigm.
A
TH1/TH2 Paradigm
41
Q
Describe T cell-specific cytokines.
A
T Cell-Specific Cytokines
42
Q
Describe the humoral adaptive immune response.
A
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.
43
Q
Describe T and B cell interaction.
A
T and B cell Interaction
- Occurs in local lymph node.
44
Q
Describe T cell-mediated activation of B cells.
A
T Cell-Mediated Activation of B Cells
45
Q
Describe clonal activation of B cells.
A
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.
47
Q
Compare primary and secondary immune responses.
A
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.
49
Q
Describe the activation of B cells.
A
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.
50
Q
Describe Ab structure and functional domains.
A
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.
51
Q
Describe the classes of Ab isotypes.
A
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.
52
Q
Describe the role of cytokines in Ab production.
A
Role of Cytokines in Ab Production
53
Q
Describe the major properties of Ab classes.
A
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.
54
Q
Describe the general properties of PRRs.
A
55
Q
Describe the interface between innate and adaptive immunity.
A
56
Q
Describe immune cells.
A
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.
57
Q
Describe TLR4.
A
TLR4
- LPS signaling in human monocytes.
58
Q
Describe the physical barriers of the immune system.
A
59
Q
Describe innate defense components.
A
60
Q
Describe the timeline for innate and adaptive immunity.
A
62
Q
Describe type I hypersensitivity.
A
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:
- PRODUCTION of IgE after activation of Th2 cells by 10 exposure to allergens.
- BINDING of the IgE to Fc receptors of mast cells.
- 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.
63
Q
What are some examples of Type I Hypersensitivity?
A
Type I Hypersensitivity - Examples
64
Q
Describe type II hypersensitivity.
A
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.
65
Q
What are some examples of type II hypersensitivity?
A
Type II Hypersensitivity - Examples
66
Q
Describe type III hypersensitivity.
A
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.
67
Q
What are some examples of type III hypersensitivity?
A
Type III Hypersensitivity - Examples
68
Q
Describe type IV hypersensitivity.
A
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.
