Immunology Flashcards

Question

Effector functions of antibodies

Answer 1

* **•Neutralizing** toxins * **•Block entry of pathogens** into cells and across mucosa * •**Activating the complement cascade** (IgG and IgM) through the classical pathway * **•Opsonizing** a pathogen or antigen and enhance phagocytosis by other cells (IgG) * **•Antibody-dependent cytotoxicity (ADCC)** * •Fc receptors expressed on the phagocytic and cytotoxic cells recognize the Fc fragments of the different isotypes

Answer 2

* •IgE binds to helminths * •Eosinophils bind to the IgE Fc via FcεRI * •Binding IgE leads to release of eosinophil mediators to destroy the helminth * •TH2 CD4+ T cells release IL-5 that enhances eosinophil activity

Answer 3

* •Naïve B cells (Marginal zone B cells or mucosal B cells) **recognize antigen** through the IgM BCR * •**Co-stimulation** occurs through **complement receptors (e.g. CD21) and/or TLRs** * •Antigen-specific B cells differentiate to **short-lived plasma cells** and **produce predominantly IgM** * •Limited isotype switch can occur (IgG, IgA) * •No effective affinity maturation * •Limited memory

Answer 4

Naïve B cells (outside of the germinal centers) * **•Recognize antigen** through the IgM BCR * **•Internalize the antigen** on the IgM * •Degrade antigen to peptides to **present on MHC class II** * •Express CD40 and B7 (CD80/86) * •Can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines * •After binding antigen and activation, **B cells migrate towards B cell-T cell zone border** (secondary lymphoid tissue) Antigen-activated B cells (B cell-T cell zone border outside germinal center) * •Interact with antigen-activated CD4+ T helper cells * •Differentiate to **short-lived plasma cells** (plasmablasts) * •Produce and **secrete IgM antibody** * •Antibody is relatively low affinity for antigen Antigen-activated B cells (inside the germinal centers) * •Further interact with antigen-specific activated CD4+ T helper cells (particularly through **CD40:CD40L**) * •Rapidly proliferate * •Undergo **isotype switching** and **somatic hypermutation** * **•Supported by IL-4 and IL-5** (TH2 CD4+ T helper cells) * •Interact with follicular dendritic cells and antigen-presenting cells to select for high affinity antibody * •Late germinal center: * •B cells with high affinity antibodies differentiate into memory B cells or plasma cells

Answer 5

5-10 days * •The primary antibody response takes about 5-10 days * •First antibody produced is IgM * •The earliest IgM produced is specific for antigen, but relatively low affinity * •After a few days, germinal centers form * •B cells undergo isotype switching and somatic hypermutation In the late primary antibody response * •The high affinity B cells in the germinal center differentiate to plasma cells and memory B cells * •Antibodies of other isotypes are produced (e.g. IgG) * •Affinity maturation has occurred

Answer 6

1-3 days * •The **secondary antibody response** arises from memory B cells and T cells. * •It occurs much more rapidly (develops in 1-3 days) * •Leads to a more robust class-switched (IgG) antibody response

Answer 7

* •Successive exposure to a **T cell dependent antigen** leads to **increased affinity of the B cell receptor/antibody** * •After repeat antigen exposure * •Antigen-specific memory B cells interact with the antigen-specific T cells in the germinal center * _•Somatic mutations and selection lead to increasingly more specific antibodies_

Answer 8

* •Antigen-antibody complexes can have harmful effects * •Activate complement through classical pathway * •IgG production leads to feedback inhibition * •FcγRIIB on the surface of B cells * •Binds the Fc portion of IgG * •Signals through an immunomodulatory tyrosine-based inhibition motif (ITIM) * •Terminates the B cell response to antigen

Answer 9

* •IgG \>\> IgA \> IgM \> IgD, IgE * •Evaluation of altered serum antibody levels can help identify immunodeficiency * •IgD not typically measured * •IgE requires different techniques

Answer 10

* •Deficiency in **Bruton’s tyrosine kinase** (required for B cell development) * •No circulating antibodies, absence of secondary lymphoid tissues * •Life-threatening infections * •Encapsulated bacteria * •Enterovirus * •Vaccine associated poliomyelitis

Answer 11

* •Most common immunodeficiency * •Frequently asymptomatic * •Increased risk for mucosal infections * •Particularly viral infections * •Autoimmune association * •Blood transfusion risk (antibodies against IgA)

Answer 12

mediates recombination

Answer 13

* •Multiple etiologies and numerous underlying mutations * •Underlying defect in B cells or helper T cells * •Overall low immunoglobulins * •Low IgG, low IgA, and low or normal IgM * •Decreased memory B cells * •Increased risk for bacterial, enteroviral and Giardia lamblia infections in late childhood and adulthood * •Autoimmune association and increased risk for lymphoma

Answer 14

viral peptides presented on MHC class II

Answer 15

* •Impaired or absent adaptive immune response * -No or very limited B cells and T cells +/- NK cells * -Intact innate immunity * •Severe, life-threatening infections * •Different mutations with different disease phenotypes * -Adenosine deaminase deficiency, RAG gene mutation, common gamma chain (X-linked) * •Stem cell transplant is the current therapy

Answer 16

* CD19+ CD20+ * -Major component of **adaptive immunity (humoral** immunity) * -~20% of circulating lymphocytes * -Express a**ntibody** (immunoglobulin) on the cell surface * -Differentiate into plasma cells and memory cells * -Antigen-presenting cells * Originate and mature in BM (and fetal liver) * Antigen NOT required for early B cell development * Million produced daily

Answer 17

* •Plasma cells (CD38+, CD138+) are responsible for producing antibodies * •Antibodies are critical for immunity

Answer 18

* •B cells originate and mature in the bone marrow * •Antigen is not required for B cell maturation * •The maturation steps are from lymphoid progenitor to pro-B cell to pre-B cell (μ heavy chains) to immature B cell (IgM BCR) to naïve B cell (IgM and IgD).

Answer 19

is surface IgM or IgD Diversity: * •Each B cell has a BCR specific for one antigen * •~10 million specificities of BCRs * **•VDJ recombinase (RAG1 and RAG2 genes)** * -V, D, and J segments for heavy chain * -V and J segments for light chain * •RAG1/2 also involved in TCR gene rearrangement * •RAG1/2 gene mutations can give rise to SCID -------- * •The B cell receptor (BCR) is an antibody (IgM and IgD in naïve B cells) that has a transmembrane domain and is associated with Igα (CD79a) and Igβ (CD79b) * •BCR diversity occurs through combinatorial and junctional diversity * •The variable regions of the heavy chains are formed from VDJ genes and the variable regions of the light chains are formed from VJ genes * •Successful gene rearrangement and production of IgM is essential for B cell development

Answer 20

* •Nucleotides are added and removed during recombination * •Occurs at the joining ends of the gene segments * •Significantly increases diversity of the VDJ and VJ regions * •These regions are known as “hypervariable regions”

Answer 21

* •The isotype of the antibody is determined by the constant region of the heavy chain * •The constant region genes join to the variable region genes * •IgM is produced first * •Successful gene rearrangement and protein production leads to B cell development

Answer 22

B cells/ Central tolerance * -Removal of immature B cells with expression of IgM that is **reactive to self** * - If the IgM binds to self antigen the cell can **die by apoptosis or undergo receptor editing** Receptor Editing: occurs if the BCR binds to self antigen * **-RAG genes are re-expressed** * -the V-J recombination is repeated to express the s**econd type of light chain** * -the new light chain and original heavy chain can generate a specificity that does not recognize self

Answer 23

**•B cell anergy (peripheral tolerance)** * -Some **self-reactive B cell** escape deletion in the bone marrow * -When it **encounters self-antigen in the absence of co-stimulation**, the cells becomes **anergic (do not respond)**

Answer 24

* •A single B cell expresses protein from only one light chain gene and one heavy chain gene at a time * •Although alleles from both parents are present, one set of genes is silenced * •This silencing is known as **allelic exclusion** _•Each mature B cell/plasma cell only expresses kappa or lambda light chains_ * heavy chain variable region is identical in naive B ells with both IgM and IgD

Answer 25

* •The antibody variable region of the BCR recognizes and binds a specific antigen * •Binding leads to receptor cross-linking in association with Igα/Igβ (_CD79a/CD79b)_ and p**hosphorylation of ITAMs (Immunoreceptor tyrosine-based activation motifs)** * •ITAM phosphorylation triggers downstream signaling pathways

Answer 26

**----------------- CD21-------------** * •CD21 (CR2) is a complement receptor expressed with CD19 on the B cell surface * **•CD21 interacts with the C3d complement component** bound to antigen (alternative complement pathway) * •Enhances B cell activation ~1000 fold * •This can serve as a **second signal** **----------------- CD40-------------** * •After binding of antigen, the B cell upregulates co-stimulatory molecules (B7 and CD40) * •The BCR then takes up the antigen and expresses protein antigens on the MHC class II protein

Answer 27

* •In the germinal center of the lymphoid tissues, antigen activated B cells: * -Rapidly divide * -Interact with antigen-specific T cells, APCs, and follicular dendritic cells * -Undergo isotype switching, somatic hypermutation, and affinity maturation ---------------- * •The B cells are antigen-selected in the germinal center * **_•Antigen-specific B cells interact with antigen-specific CD4+T cells, antigen-presenting cells, and follicular dendritic cells_** * •The B cells mutate the antibody genes to improve binding to antigen

Answer 28

* •In response **to certain cytokines in the setting of CD40 binding by CD40L** * **-B cells switch the heavy chain constant region** from the IgM constant region to a downstream isotype (IgG, IgA, or IgE) * -the antigen specificity (VDJ) is not altered by isotype switching * •Different antibody isotypes are specialized for different protective responses * •Class switching requires deleting the intervening heavy chain DNA * **_•B cells cannot revert back to expressing IgM antibodies_** after isotype switching has occurred

Answer 29

* •Follicular dendritic cells (FDCs) capture complement/antigen complexes on the cell surface * •FDCs present antigen complexes to B cells and allow selection for B cells with higher affinity/avidity antibodies

Answer 30

* •After T cell co-stimulation, the B cells undergo **somatic hypermutation** in the germinal center * •The antibody variable regions are subject to random point mutations (activation-induced cytidine deaminase (AID)) * •Some of the mutations give rise to higher affinity/avidity antibodies which are selected for by the FDCs and T cell interactions * •The process of selection for increased affinity/avidity is **affinity maturation**

Answer 31

•In the germinal center, B cells that are highly specific for antigen differentiate into - antibody-producing plasma cells - long-lived memory B cells

Answer 32

* Expressed on B cell surface and a component of the BCR complex.

Answer 33

•B cell receptor associated proteins (Igα/Igβ) involved in signal transduction after antigen cross-linking, leads to the phosphorylation of ITAMs to trigger downstream signaling pathways.

Answer 34

•Another protein expressed on the B cell surface (targeted by rituximab)

Answer 35

•Complement receptor (CR2) which binds to complement component C3d in association with antigen to dramatically enhance B cell response (also the receptor for Epstein Barr Virus).

Answer 36

•Co-stimulatory molecule expressed on B cell surface which binds to CD40L on helper T cells to provide second signal to B cells. Critical for class switching, affinity maturation, and differentiation.

Answer 37

•Proteins expressed on plasma cell surface.

Answer 38

* Hypersensitivity refers to an exaggerated or inappropriate immune response to external (non-self) antigen or self antigen * The exaggerated immune response causes harm to the host 4 types main Igs * I: IgE * II: IgG IgM * III: IgG IgM * IV: cell mediated

Answer 39

1. •A foreign molecule **cross-links or modifies a host cell to generate “new” epitopes** or antigens in the host cell that then become **recognized as foreign** * -Contact sensitivity occurs to “neoantigens” formed from chemicals binding self-proteins and activating a _T cell immune response_ 2. •Cross-reactivity or an antibody of T cell receptor specific for a foreign antigen that has some capacity to bind to self-antigens (molecular mimicry) * -Rheumatic fever occurs when antibodies against streptococci react with cardiac myosin due to antigenic similarity 3. Sensitization to antigen: * •In most types of hypersensitivity, the immune system has “seen” the antigen (or a closely related antigen) before * •The primary antigen exposure gives rise to an immune response with production of antibodies and/or memory T cells * •The hypersensitivity response typically occurs on a subsequent exposure

Answer 40

* **•In most types of hypersensitivity, the immune system has “seen” the antigen (or a closely related antigen) before** * •The primary antigen exposure gives rise to an immune response with production of antibodies and/or memory T cells * •The hypersensitivity response typically occurs on a subsequent exposure

Answer 41

* •Express receptors for Fc portion of IgE (important in anaphylaxis) * •Release histamine and other cytokines **Histamine is preformed in granules and has immediate effects** * •Vasodilation * •Increased vascular permeability * •Smooth muscle contraction * •Itching * •Kinins and kininogenase **Additional preformed mediatiors:** * Serotonin * TNF * Proteases * Numerous other molecules Some that must be produced and have **delayed effects:** * **•Arachidonic acid metabolites** * -Leukotrienes: delayed but similar to histamines * -Prostaglandins * **•Cytokines** * **•Chemokines**

Answer 42

Antibody mediated: Very fast, develops in minutes * **•Cells and antibodies involved** * **-Mast cells and basophils** * **_-Preformed IgE_** (Prior B cell response driven by _TH2 helper T cells_) * •Mechanism * -First exposure sensitization to form IgE antibodies * -Subsequent exposure: **IgE binds antigen and crosslinks mast cell Fc receptors** * -Mast cells **release preformed mediators** and produce additional mediators * Examples: Anaphylaxis, allergic rhinitis, hives

Answer 43

Minutes to hours, Antibody mediated * **•Cells and antibodies involved** * **-CD8 + cytotoxic T cells, NK cells, and/or neutrophils** * **-Preformed IgG/IgM** (produced by B cells, driven by TH2 CD4+ helper T cells or naturally-occurring) * **•Mechanism** * -Preformed IgG or IgM antibody binds to fixed cell surface or extracellular matrix antigens. * -Binding leads to **complement activation** and opsonization/phagocytosis and/or **antibody-dependent cell-mediated cytotoxicity** (ADCC) by NK or CD8+ cytotoxic T cells. * Examples: Some drug allergies, incompatible blood transfusions, Goodpasture’s syndrome (antibody against basement membrane) FIgure: ADCC, Complement

Answer 44

Hours to days, antibody mediated * **•Cells and antibodies involved** * **-Antigen and antibody complex (typically IgG)** * **-Neutrophils** * **•Mechanism** * -When antigen is abundant, soluble immune complexes (antigen bound to antibody) form and deposit in tissues (particularly in vessels) * -Immune complex deposition can activate complement and lead to inflammation (chemotaxis of neutrophils, vessel leakage, and vessel damage) * Examples * •Serum sickness (e.g. drugs) * •Systemic lupus erythematosus * •Arthus reaction: -Local injection of antigen that reacts with preformed IgG

Answer 45

Days to weeks to months * **•Cells involved** * **-Antigen-presenting cells, TH1 CD4+ helper T cells, and sometimes CD8+ cytotoxic T cells** * •Mechanism * -Antigen-presenting cells prime T cells to respond to antigen and drive a **TH1 CD4+ helper T cell response** * -On subsequent response to the antigen, the previously primed T cells (memory cells) proliferate rapidly and activate a macrophage response and cytokine release * Examples: granuloma formation in TB chronic infection, contact dermatitis (posions ivy), GVHD, * •In M. tuberculosis and PPD (purified protein derivative) testing, the T cells recognize the microbial peptides. * •In contact dermatitis (e.g. poison ivy), the T cells recognize chemically modified self proteins.

Answer 46

Classic delayed type hypersensitivity reaction * •The PPD assay is used to evaluate for a cell-mediated immune response to M. tuberculosis suggestive of infection or prior vaccination. * •Protein derivatives from M. tuberculosis are injected intradermally. * •**TH1 CD4+ T helper cells specific to the M. tuberculosis antigens p**roduce cytokines that lead to an increase in the permeability of local blood vessels, the recruitment of T cells and macrophages, and local tissue destruction. * •Produces swelling/induration of the skin ~48 hours after injection.

Answer 47

* **•CD8+ T cells (cytotoxic)** mediate direct cellular killing * **•Perforins and granzymes are present in the granules and released** * **•Perforins** are inserted into the cell membrane and form a channel * **•Granzymes are proteases** that degrade proteins in the cell membrane * •Activate caspases (leading to apoptosis) * **•FasL** is expressed on the cytotoxic T cells that binds to Fas * •Fas and FasL interact and the target cells dies by apoptosis

Answer 48

1. •Antigen-presenting cells (macrophages and dendritic cells) 2. •CD4+ helper T cells (TH1 subset) 3. •CD8+ cytotoxic T cells 4. •NK cells 5. •B cells also play a contributory role * •Antibody-dependent cellular cytotoxicity (ADCC)

Answer 49

* **Naïve T cells** encounter antigen in the secondary lymphoid organs * **•Antigen receptor engagement as well as co-stimulatory signals** are required for activation * •Typically dendritic cells are the antigen-presenting cells * **•Effector T cells** can encounter antigen in other tissues * •Antigen receptor engagement **_but not_** co-stimulatory signals are required for activation

Answer 50

* **•Antigen-presenting cells** ingest organisms * **•Recognition of PAMPs** by the pattern recognition receptors (e.g. TLRs) **stimulates cytokine production (IL-12)** and expression of co-stimulatory molecules * •Pathogen peptides are expressed on MHC class II to **CD4+ T helper cells** which differentiate to **TH1 cells**

Answer 51

Activates CD8+ and APCs * •The TH1 CD4+ T cells secrete IFNγ which * •Activates the APCs to kill the phagocytosed pathogens * •Activates the CD8+ cytotoxic T cells to become effector cells * •The CD8+ T cells recognize peptides presented by any nucleated cell and can kill the cells

Answer 52

* **•APCs** are primarily located under the **epithelial surfaces** and **T cells are in the lymphoid tissues** * •When APCs ingest a microbe, they **upregulate chemokine receptors (CCR7)** for the chemokines produced by the T cells * •The **chemokine gradient produced by the T cells attracts the APCs** through the lymphatics to the lymphoid tissue to interact with the T cells and B cells

Answer 53

* •CD8+ cytotoxic T cells * •NK cells * •B cell activation and antibodies also play a role * •Antibodies * •Neutralize the virus * •Increase phagocytosis * •Activate complement * •Mediate antibody-dependent cell cytotoxicity (ADCC) ------------- * **•In cell-mediated immunity against viruses the CD8+ cytotoxic T cells** recognize viral peptides presented on the MHC class I proteins of all nucleated cells * •The **cytotoxic T cells can directly kill** viral-infected cells * **•CD8+ cytotoxic T cells can cause tissue injury** even if the virus itself is not pathogenic * •Immunopathogenesis

Answer 54

* •Humoral immunity plays a primary role in protection against some viruses and CD8+ cytotoxic T cells play a primary role in others * •Viruses can evade antibody immunity by producing variable antigens (influenza, rhinovirus, HIV) * •Viruses can evade CD8+ cytotoxic T cell immunity by downregulating expression of MHC class I in infected cells

Answer 55

* **•NK cells (innate immunity) and interferons** are also involved early in the anti-viral immune response * **•NK cells** identify infected cells through lack of MHC class I or via ADCC (IgG) * **•NK cells** produce cytotoxic proteins (granzyme and perforin) that release and kill the target cell * NK cells express inhibitory receptors

Answer 56

* •Persistence of viral nucleic acid in the cell * •Active viral particles are not produced * •Intact **cell-mediated immunity** is important in maintaining **viral latency** * -If the virus begans producing proteins, memory T cells will recognize the proteins and kill the cell * -Cells with latent virus will survive

Answer 57

* **•Endogenously synthesized proteins (intracellular proteins)** are cleaved by a proteasome to peptide fragments that associate with a **TAP (transporter associated with antigen processing) transporter** * •The TAP transporter transports the fragment to the **endoplasmic reticulum (ER)** * **•Peptide fragments in the ER associate with the MHC class I molecules**

Answer 58

* **•Extracellular proteins** are engulfed by phagocytosis or endocytosis into **phagosomes or endosomes** respectively * •The phagosome or endosome will **fuse with lysosomes** which contain proteases that can degrade the polypeptides into short peptide fragments * **•The peptide fragments are able to associate with the MHC class II molecules in specialized endosomal intracellular vesicles** * MHC class II proteins are prevented from binding to endogenous peptides by **binding of a protein called the invariant chain (Ii)** in the ER * •The **placement of an extracellularly derived peptide** in the MHC class II molecule **requires protease** removal in specialized **endosomal intracellular vesicles**

Answer 59

* •Mycobacterial organisms **survive within a phagosome** by preventing fusion with the lysosome and acidification * •Infection is controlled by a cell-mediated immune response but not always eradicated * •Mycolic acid and lipids * •Essential for survival in host * •May alter the host immune response

Answer 60

* •A **pathologic immune response** can occur to intracellular pathogens that persist * •The classic example of cell-mediated immunity that can lead to persistent inflammation is the granulomatous response to M. tuberculosis * •The **chronic antigenic stimulation** of the organism drives **CD4+ TH1 T cell responses** (production of IL-2 and IFNγ) * **•IFNγ drives macrophages to secrete IL-12** and the cycle of activation continues * •The macrophages secrete hydrolytic enzymes and form granulomas which often have central necrosis * • These pathways lead to tissue damage, but can keep the organism dormant delayed type hypersnseitiy and granuloma formation

Answer 61

Classic delayedtype hypersensitivty reaction * •The PPD assay is used to evaluate for a cell-mediated immune response to M. tuberculosis suggestive of infection or prior vaccination (BCG). * •Protein derivatives from M. tuberculosis are injected intradermally. * •TH1 CD4+ T helper cells specific to the M. tuberculosis antigens produce cytokines that lead to an increase in the permeability of local blood vessels, the recruitment of T cells and macrophages, and local tissue destruction. * •Produces swelling/induration of the skin ~48 hours after injection.

Answer 62

Measles Cytomegalovirus

Answer 63

* •Mycobacterium leprae * •Cause of leprosy * •Tuberculoid leprosy * •TH1 driven, intense cell-mediated response * •Few bacteria, non-caseating granulomas * •Lepromatous leprosy * •TH2 driven response, no cellular immune response * •Many bacteria

Answer 64

* **•Numerous bacteria (particularly intracellular bacteria (e.g. mycobacterium)), viruses (e.g. CMV, HHV8), and fungi (e.g. Candida)** * •In addition, d**eficiencies in cell-mediated immunity significantly increase the risk of neoplasia**, particularly with viral-driven tumors

Answer 65

* **•Pathogens that rarely cause disease in an immunocompetent individual** * •Patients with **decreased cell-mediated immunity are susceptible** to infections with **_opportunistic pathogens_** * •HIV/AIDS, immunosuppression (such as in transplant), inherited T cell deficiencies (e.g. SCID, DiGeorge syndrome)

Answer 66

* Active HIV infection leads to decreased CD4+ T cells * The loss of CD4+ T cells leads to decreased cell-mediated immunity

Answer 67

* •Organ rejection (acute and chronic) is driven predominantly by cell-mediated immunity * **•CD8+ cytotoxic T cells** mediate the direct damage to the organ, CD4+ T cells play a role * Non-self MHC proteins are the major protein targets of the immune response in organ rejection

Answer 68

* •T cells are the main mediators of cell-mediated immunity and secrete and are activated by IL-2. IL-2 is critical in amplifying the cell-mediated immune response. * •When T cells are activated they: * -upregulate expression of interleukin-2 (IL-2), the T cell growth factor * -upregulate expression of IL-2R * •The autocrine effect of IL-2 binding to the IL-2 receptor allows clonal growth and proliferation of the antigen-specific activated T cells.

Answer 69

IL-12 produced by APCs drives the differentiation of CD4+ TH1 helper cells that in turn produce IFNγ. IFNγ activates CD8+ cytotoxic T cells and NK cells, and the APCs. This loop is essential in effective cell-mediated immunity, particularly in controlling mycobacterial infections.

Answer 70

Adaptive immunity * **-CD3+** * **-CD4+ helper and CD8+ cytotoxic** * -Originate in bone marrow * -Mature in the thymus * -Cell-mediated immunity * -T cell receptor recognizes **_protein_** antigens

Answer 71

T cell receptor (TCR) * -Antigen specific surface receptors * -αβ heterodimer in complex with CD3 and other molecules * -Small subset express γδ heterodimer (innate immunity) * •Antigen binding to the receptor signals through **immunoreceptor tyrosine-based activating motifs (ITAMs)** * •The TCR only recognizes peptide in the context of an MHC protein

Answer 72

* Proteins responsible for presenting peptides of proteins on the cell surface to T cells * Antigen presentation occurs when peptide fragments associate with MHC molecules expressed on antigen-presenting cells * CD4 and CD8 are co-receptors necessary for the TCR to recognize and bind the peptides bound to the MHC molecules

Answer 73

* •T cells are selected for their ability to bind weakly to self-MHC molecules * •T cells that bind MHC weakly survive * •T cells only recognize peptide bound to a self-MHC molecule * •Key factor in self vs. non-self discrimination and transplant tolerance * -MHC are the major proteins recognized as foreign in transplant rejection

Answer 74

**_Cortex: double negative thymocyte selection_** * •Early T cell precursors are called **thymocytes** * •When the T cell precursor transits from the bone marrow to the thymus it is **negative for surface CD3, CD4, and CD8 surface molecules** * -Surface CD3 expression is increased as the thymocytes develop * •The first stage is in the **thymic cortex** * •The first stage is the **CD4-CD8- (double negative)** stage which does not express a TCR **_Double positive thymocyte in the cortex_** * •RAG genes are expressed, and produces a TCR with unique antigen specificity * •The next stage is the double positive (CD4+CD8+) stage * -Surface CD3 is expressed with the TCR. * •Cortical epithelial cells express MHC class I and II molecules * •When the TCR with CD4 or CD8 binds weakly to self-MHC molecules, that cell will survive **_Single positive thymocyte in the medulla: negative selection_** * •Cortical epithelial cells express MHC class I and II molecules * •The autoimmune regulator (AIRE) transcription factor synthesizes self proteins to be expressed in the MHC molecules * •Strong binding of the TCR to self-antigen/MHC molecules: Cell death or becomes regulatory T cell * •Weak/no binding of the TCR to self-antigen/MHC molecule: Survive and go to periphery

Answer 75

* •RAG1/RAG2 gene expression * -VDJ gene rearrangement on the beta chain * -VJ gene rearrangement on the alpha chain

Answer 76

* **•Positive selection:** An inclusive type of selection which checks all thymocytes for the ability to recognize peptides on self-MHC * **•Negative selection:** An exclusive type of selection which eliminates potentially autoreactive T cells * -Positively selected thymocytes migrate into medullary region of thymus * -Those which react with high affinity to self-peptides/MHC complexes (peptides produce by the activity of AIRE) will undergo apoptosis or potentially become regulatory T cells * -Those that react with a lower affinity are allowed to survive and leave the thymus as mature T cells

Answer 77

Thymic aplasia due to a developmental defect in the third and fourth pharyngeal pouches Marked deficiency in T cells. Infants with DiGeorge’s syndrome develop severe viral, fungal, and protozoal infections and some patients also have pyogenic infections Patients also have hypocalcemia due to lack of parathyroid glands

Answer 78

* •Patients with mutations that eliminate the expression of RAG1 or RAG2 genes have severe combined immunodeficiency (SCID) * •No B cells or T cells, but normal NK cells * -The genes are required for VDJ recombination and successful development of both B cells and T cells * •Mutations that cause lower than normal RAG expression can cause Ommen Syndrome * -Autoimmune manifestations and immunodeficiency

Answer 79

* •T cells that leave the thymus and react with antigen in the absence of co-stimulation will become anergic (non-responsive) * •Anergy is antigen-specific * •Clonal deletion occurs through apoptosis when T cells repeatedly encounter high levels of self-antigen in the periphery * •Regulatory T cells (Tregs) also participate in suppressing self-reactive T cells * •T cells originate in the bone marrow and mature in the thymus; thymocyte maturation goes from CD4-CD8- to CD4+CD8+ to single CD4 or CD8 positive. * Only T cells that weakly bind to self-MHC proteins survive and subsequently bind to foreign antigen expressed by self-MHC proteins (MHC restriction)

Answer 80

* -Secrete IFNγ which promotes and activates macrophages to more effectively kill intracellular oganisms * -Secretes IL-2 which promotes T cells * -Driven by IL-12 and IFNγ

Answer 81

* -Secrete IL-4, IL-5, and IL-13 * •Promote IgE, IgG, and IgA class-switching and differentiation in B cells * -Secrete IL-10 which is anti-inflammatory. * -Driven by IL-2 and IL-4.

Answer 82

* -Produce IL-17 to promote neutrophilic inflammation * •Response to extracellular pathogens * -TH17 cells enhance mucosal immunity

Answer 83

* •Deficiency of TH17 cells (from STAT3 mutation) * •Impaired recruitment of neutrophils to sites of infection and increased levels of IgE * •The clinical manifestations are staphylococcal abscesses without inflammation and eczema

Answer 84

* -T cells that inhibit the effector function of CD4+ helper T cells and CD8+ cytotoxic T cells * -Typically CD4+CD25+ and express FoxP3 * -Express CTLA-4 which inhibits T cell B7:CD28 co-stimulation * -Secrete anti-inflammatory cytokines (IL-10 and TGFβ)

Answer 85

* •CD8+ T cells (cytotoxic) mediate direct cellular killing. * -Perforins are inserted into the cell membrane and form a channel * -Granzymes are proteases that degrade proteins in the cell membrane * -Activate caspases (leading to apoptosis) * -FasL is expressed on the cytotoxic T cells that binds to Fas * •Fas and FasL interact and the target cells dies by apoptosis.

Answer 86

FIRST SIGNAL * **•Antigen recognition** in the context of the MHC by the TCR * •After binding of the antigen by the TCR, I**TAMs are phosphorylated** * •ITAM phosphorylation recruits and activates **ZAP70 tyrosine kinase** which triggers a cascade of signaling * -increased expression of cytokines, cytokine receptors, and cell proliferation genes. * •The longer the antigen is bound, the more the ITAMs are phosphorylated. SECOND SIGNAL * •Binding of activating co-stimulatory molecules or cytokines * -CD28 is the usual co-stimulatory receptor * -Cytokines binding to cytokine receptors on the T cells can also provide the second signal

Answer 87

CD8+ cytotoxic T cells * 1st signal: The TCR and co-receptor CD8 recognize and bind the peptide in MHC class I * 2nd signal: Cytokines (particularly interleukin-2 (IL-2)) secreted from CD4+ cells or co-stimulatory molecule engagement

Answer 88

* **•CD28** expressed on the T cells which binds to **B7** (CD80/CD86)on the antigen-presenting cells * -2nd signal is received after antigen binding, the T cell is activated * -2nd signal is not received, the T cell becomes anergic

Answer 89

T cell inhibitory molecules ## Footnote * Inhibitory molecules expressed on the surface of T cells help to control and down-regulate the immune response * CTLA-4 and PD1 are upregulated about 48-96 hours after the initial T cell activation. * Binding of CTLA-4 by B7 - blocks binding of B7 to CD28 - inhibits IL2 synthesis * PD1 is expressed on T cells * When it interacts with its receptor PDL1 on APCs (macrophages and dendritic cells), the immune response is inhibited * Target for immunotherapy in cancer treatment -Some cancer cells express PDL1

Answer 90

* •Certain toxin proteins (e.g staphylococcal enterotoxins and toxic shock syndrome toxins) directly bind the T cell receptor and the MHC class II protein without internal processing * •Binding activates multiple T cells at once (regardless of TCR antigen specificity) * -Uncontrolled release of cytokines from both the T cell and the APC (IL-2, IL-1, and TNF) * -The cytokine release can contribute to illness and death

Answer 91

* •Antigen-specific T cells that have gone through a first primary immune response to antigen * •Live for years * •Subsequent recognition of antigen * -activation with a lower level of co-stimulation * -rapid and more robust production of cytokines * •Numerous subsets of memory T cells

Answer 92

•Promotes B cell growth and class switching to IgE and IgG and promotes differentiation of TH2 CD4+ T cells and inhibits differentiation of TH1 CD4+ T cells.

Answer 93

•Differentiation/activation of eosinophils, class switching to IgA

Answer 94

•Turns off immune response (anti-inflammatory)

Answer 95

Activation of eosinophils

Answer 96

Promotes neutrophilic inflammation

Answer 97

Stimulates phagocytosis by macrophages, increases expression of MHC class I and II, promotes TH1 and inhibits TH2 CD4+ T cell response