Immunology Test 4

Apoptosis

-Occurs during normal cell turnover, in infected cells by CD8 T cell, and during T or B cell development to kill auto-reactive cells, etc. Controls lifespan of immune cells. During an infection, they proliferate but afterward these numbers are brought back to normal levels by this process.

TI-1 Antigens

To respond to _____ ____________, a B cell needs more than just ligation of BCR and co-receptor. It also needs signaling from receptors of the innate IR (TLRs).

CD8 kills the target cell as well as the pathogen.

WHY is activation of CD8 Cells so heavily regulated?

LFA-1

When TCR engages peptide:MHC on a target cell AND LFA-1 engages ICAM-1 -> confromational change in _______ so it binds strongly.

Centrocyte

When a B cell is activated and sent to the germinal center, the_______________ can either have high or low affinity surface immunoglobulin. If the Ig is high affinity, the BCR is cross-linked and antigen is presented to the helper T cell, so the this receives help, survives and divides. If not, None of this happens and this dies by apoptosis.

Phagocytic

______________ cells have receptors for these apoptotic bodies/cells and ingest them -> their elimination in a "neat" manner so no inflammation is triggered.

Immature Dendritic Cell

________________ ____________ _____ is best at phagocytosis (i.e. capture and uptake of antigen). Can't present antigen yet. Found in tissues (e.g. Langerhans cells in the skin).

Proliferation

________________ of activated T cells is driven by IL-2 and inflammatory cytokines which also induce proapoptotic products which can slow/brake T cell this. During an infection, this death signal is PX by costimulatory signals and inflammatory cytokines so overall impact is this. I.E. Antiapoptotic signals > apoptotic signals.

Crosslinking

_________________ of BCR is necessary but not sufficient to activate a B cell. Need signals from B cell co-receptor (which consists of CR2, CD19, and CD81)

T Cell Synapse (Immunological Synapse)

Region of contact between APC and T cell is called the ___ _________ __________.

Tuberculoid (Neural) Leprosy

-Th1 dominated -Mild, nonprogressive form -Associated with delayed-type hypersensitivity -Damaged nerves and regions of skin that have lost sensation and are surrounded by a border of nodules. -Organisms preset at low undetectable levels (low infectivity) -Normal serum immunoglobulin levels. -Normal T cell responsiveness. -Specific response to M. leprae antigens. -IL-2, IFN-gamma, LT cytokines.

Lepromatous (Progressive) Leprosy

-Th2 dominated -Skin tissue killed, leading to progressive loss of facial features, fingers, toes and other structures. -Disfiguring nodules form all over the body. -Organisms show florid growth in macrophages (high infectivity). -Disseminated infection. Bone cartilage, and diffuse nerve damage. -Hypergammaglobulinemia. -Low or absent T cell responsiveness. -No response to M. leprae antigens. -IL-4, IL-5, IL-10 cytokines

CTLA4

Once B7 and CD28 bind, the T cell up regulates expression of ______________ which also binds B7 but is 20X stronger. This leads to down regulation of the T cell and limits cell proliferation.

Macro-Pinocytosis

A route of antigen processing and presentation by dendritic cells. Type of pathogen presented: extracellular bacteria, soluble antigens, virus particles. MHC molecules loaded: MHC class II. Type of naive T cell activated: CD4 T cells.

Receptor-Mediated Endocytosis

A route of antigen processing and presentation by dendritic cells. Type of pathogen presented: extracellular bacteria. MHC molecules loaded MHC class II. Type of naive T cell activated CD4 T cells.

Cross-Presentation After Phagocytic or Macropinocytic Uptake

A route of antigen processing and presentation by dendritic cells. Type of pathogen presented: viruses. MHC molecules loaded: MHC class I. Type of naive T cell activated: CD8 T cells.

Viral Infection

A route of antigen processing and presentation by dendritic cells. Type of pathogen presented: viruses. MHC molecules loaded: MHC class I. Type of naive T cells activated: CD8 T cells.

Transfer From Incoming Dendritic Cell to Resident Dendritic Cell

A route of antigen processing and presentation by dendritic cells. Types of pathogen presented: viruses. MHC molecules loaded: MHC class I. Type of naive T cell activated: CD8 T cells.

IL-2

APC activates CD4 T cell to make _______ and naive CD8 T cell to express these receptors. This secreted by activated CD4 T cell is bound by CD8 T cell.

CD4

APC stimulates effector ______ T cell which in turn activates the APC. Activated APC expresses B7, which co-stimulates naive CD8 t cell.

VLA-4

Activated T cells express __________ (not L-selectins) so they do not enter lymph nodes. Instead this binds to VCAM-1 found on infected or inflamed tissues.

Classical

Antibodies can activate complement via the ____________ pathway.

Natural Killer Cell

Antibody binds antigens on the surface of target cell -> Fc receptors on _______ ____________ _________ recognize bound antibody -> cross-linking of Fc receptors signals this to kill the target cell -> target cell dies by apoptosis.

T Independent Antigens

Antibody response to certain antigens does not require T cell help and are called __ _____________ __________ . There are two types. Do not get these confused with B cells that are T independent.

B cells

Antigen activated ____ __________ endocytose, process, and present Ag on MHC class II molecules. They are also drawn to the interface between B and T cell zones which allows interaction with effect Tfh cells.

Activated

Antigen binding to BCR delivers the first signal to the B cell. T helper cell delivers the second signal via CD40 ligand and cytokines. B cell is then _____________ to divide and differentiate.

IL-10

Antigen-selected centrocyte mature under the influence of ________ secreting helper T cell. Centrocytes differentiate into plasma cells. Make antibodies that fight and terminate the current infection.

IL-4

Antigen-selected centrocytes nature under the influence of an ___________ secreting helper T cell. Centrocytes differentiate into memory B cells. The investment that prevents future infections from causing disease.

Isotype Switching

As IR progresses -> increased ____________ _________ -> changes in the number of antigen binding sites, flexibility, ability to activate complement, ability to deliver pathogens to phagocytes.

CD69

B cells enter lymph nodes via HEVs. Pass through T cell area -> B cell follicle. IF BCR is specific for antigen displayed on the FDC or subcapsular macrophage. Antigen signaling impacts B cell _> expression of ____________ which keeps these B cells in LN.

FCepsilonRI

Bind IgE (not bound to pathogen) with such high affinity that there is not much circulateing IgE. This receptor is found on mast cells in connective tissues, basophils in blood, activates eosinophils in mucosal tissue. Once the IgEs on these sensitized cells are bridged by their specific Ag -> degranulation of performed mediators of inflammation (histamine, etc). ->expulsion of parasite OR allergic S/SX.

IgA

Binding of _______ to receptor on basolateral face of epithelial cell. Receptor mediated endocytosis of this. Transport of this to apical face of epthelial cell. Receptor is cleaved, this is bound to mucus through secretory piece. It is an important neutralizer of viral infections and can neutralize bacteria on mucus membranes.

Erythrocyte

CR1 on an ______________ surface binds C3b-tagged immune complex. This carries immune complex to the liver or spleen, where it is detached and taken up by a macrophage.

Activated Macrophages

Cause phagosomes containing pathogens to more efficiently fuse with lysosomes. Increased synthesis of ROIs and RNIs. For these in LN, increased expression of MHC class II molecules and B7 molecules so can activate more naive T cells.

Hansen's Disease (Leprosy)

Caused by Mycobacterium leprae: invades peripheral nerve and skin cells becoming obligate intracellular parasite. Humans are the only significant resevour; transmitted after prolonged exposure to infected individuals, probably spread in nasal secretions. Clinical manifestations: incubation usually 3 to 5 years, initial symptoms pigmented skin eruption, development of diseases is thought to be related to strength of cell-mediated immune response to bacterium.

Th1

Cell mediated immune response = ______ dominated response.

Activates T cell

Co-stimulatory signal and specific signal -> ________________ ____ ________.

No Effect on T Cell

Costimulatory signal alone (no specfifc signal on T cell) -> _______ _______ ___ ___ ________.

Antigen

Dendritic cells bearing ________ enter the draining lymph node, where they settle in the T-cell areas.

Toll Like Receptors

Dendritic cells carry all of ________ _________ _______________ except this 9 so they are very capable of detecting most infectious agents. When these on a dendritic cell is engaged, changes gene expression in dendritic cell -> its activation and maturation -> increased MHC I and II. Dendritic cell expresses CCR7 which helps the dendritic cell enter LN,

CD8

Dendritic cells express high levels of B7 and active naive ____ T cells. Activated these T cells make IL-2, driving its own proliferation and differentiation.

Draining Lymphatic Vessel

Dendritic cells take up bacterial antigens in the skin and then move to enter a ___________ ____________ __________.

IgG

FCgammaRIIA, FCgammaRIIIA, and FCgammaRIIIb bind only _______ bound to its antigen. FCgammaRIIB2 and FCgammaB1 are inhibitory (turn down the IR)

FcRn

Fluid-phase of IgG from the blood by endothelial cells of the blood vessel. The acidic pH of endocytic vesicle causes the association of IgG with __________- protecting it from proteolysis (also helps IgG cross the placenta). On reaching the basolateral face of the endothelial cell, the extra basic pH of the extracellular fluid dissociates IgG from this.

Skin, Peripheral Tissues

For antigens found in ______ and ____________ _________, antigen carried to draining lymph node to activate T cells.

Blood

For antigens found in ___________, antigen enters spleen and there they are presented to T cells.

Respiratory Tract

For antigens found in ________________ _____________, activate T cells in tonsils and other BALT.

Gastrointestinal Tract

For antigens found in _____________________________ __________, activate T cells in Peyer's patches, appendix, and other GALT.

Cytokines

Helper T cell adheres to the B cell and begins to synthesize _______________ and CD40 ligand. The helper T cell reorients its cytoskeleton and secretory apparatus toward the B cell. These are released in the narrow space between the B and T cells.

Th2

Humoral immune response = _____ dominated response.

Specific Pathogen

IF there is an infection with that ______________ ___________ within a day(s) that T cell will enter the LN that contains the DCs that have migrated there from the site of infection. LN serves as a place to concentrate the Ag. Once T cell encounters Ag:MHC on DC, it takes days to activate, proliferate and differentiate -> effector T cell. Effector T cell leaves LN via efferent lymphatic and then enter blood.

Efferent Lymphatic

If T-cell receptor is not specific for antigen:MHC complex on DC, it leaves lymph node via ______________ ______________ and circulates through other lymph node, etc.

Effector T Cell

If T-cell receptor of T cell is specific for Antigen_MHC complex on DC/macs it is retained and lymph node and activated -> proliferate and differentiate into an ________________ ______ __________.

Afferent Lymph Vessels

If T-cells enter via ______________ ______________ ___________, enter T cell zone directly.

Activation

If no co-receptor needed >10,000 TCR:Peptide:MHC interaction -> ______________.

High Endothelial Venules

If they enter via _______________ _______________ __________, enter (para)cortical region and encounter DCs/Macs with their antigen-MHC complexes.

Conjugate

In adults, they can adequately protect from pneumococcal pheumonia by vaccinating with 23-valent polysaccharides (PPSV23) but they must use the _____________ in children because children do not mount an adequate IR to carbohydrate antigens. E.g. the B cell recognizes the carbohydrate and presents the protein to the T cells whose TCR recognizes the protein of the pathogen.

Phosphorylated

In the resting T cell the ITAMS are not _______________________. Binding of MHC ligand to the TCR leads to this of the ITAMS by receptor-associated kinases. When the co-receptor binds to the MHC lidand, ZAP-70 binds to the this chain ITAMS and is this and activated by Lck.

CD40

Induction of isotype switching by T helpers also requires ligation of _________ on B cell by this ligand on T cell. People with hyperIgM syndrome, lack this ligand and can't make antibodiy to T-dependent antigens. Their LNs have no germinal centers.

Immunoreceptor Tyrosine-Based Activation Motifs (ITAMS)

Once TCR, co-receptors ligated -> ___________________ __________ ______________ ____________ ___________ are phosphorylated by tyrosine kinases ->signal transduction and new gene expression.

IgM

Initially, during IR, low affinity _______ is the first class of antibody to be released. Advatanges: carried through blood and lymph to the sites of infection, inflammation, and tissue damage, it has 10 binding sites -> strong bonding even if each interaction is low affinity, it's a strong activator of classical complement pathway -> C3b deposition -> pathogen destruction. Disadvantages: its large size limits its passive entry into infected tissues... eventually, see isotype switching to class IgG and IgA which also have high affinity Fab regions.

TC cells, Centrocytes

Interaction of ______ ________ and _____________ -> exchange of signals helps proliferate both B and T cells, expands the population of high affinity isotype switched B cells, cytokines from Th cells determine whether an antigen activated B cell becomes a plasma cell or a memory cell.

Macrophage

It takes hours for Th1 cells to produce these effector cytokines to activate ________________ since they are not performed as in CD8 cell. Must remain attached to this so one these cytokines are produced, it can focus its secretory vesicles to the point of contact with this and then release them. This ensures that the right this is activated (TCR:peptide:MHC classII)

Slower Acting Apoptosis Method

Kills target cell. Induced killing within minutes, CD8 cell moves from target cell to target cell -> many dead cells within hours by induction of programmed cell death. Ligation of death receptor, FasLigand, of T cell with Fas on target cell -> death.

Faster Acting Apoptosis Method

Kills target cell. Induced killing within minutes, CD8 cell moves from target cell to target cell -> many dead cells within hours by induction of programmed cell death. Release of perforin, granulysin and granzymes which are preformed and released upon signaling from TCR.

IgG, IgA

Later in IR high affinity _____ or monomeric _____ due to isotype switching. Advantages: their two binding sites are as effective as the 10 of IgM, small size allows better entry into infected tissue, active Tp of first into extracellular spaces due to FcRn (Brambell receptor). Disadvantages: it comes later in infection, but thanks to IgM this is usually ok.

Specific Peptide:MHC

Ligation of TCR and CD4 or CD8 with ______________ ___________ ____ complex is necessary but NOT SUFFICIENT to activate a naive T cell. Co-stimulatory signal is also needed = B7 molecules on APC binds to CD28 on T cell.

IL-2

Ligation of TCR receptor -> signal transduction to nucleus via NFAT -> increased _______ production and expression of high affinity this receptor. 1. This involves stabilization of cytokine mRNA -> increase 20-30X this production. 2. Co-stimulatory signal increases rate of transcription 3X. 3. Overall, increased 100 fold in this -> 2-3 division of T cell per day to get 1000s of T cells per week.

Necrosis

May result from tissue injury -> cell damage -> plasma membrane rupture. These cells release their cytoplasmic contents into extracellular space which triggers inflammation.

Effector T cells

Most ____________ ___ _______ die within 15 days after activation by antigen. This is probably due to inability of inflammatory cytokines to sustain their survival ... as now inhibitory and apoptotic signals are induced strongly. Only ~10% of T cells of that Ag specificity remain =memory T cells which are sustained by IL7 and IL15.

Polarize

Most infections results in both Th1 and Th2 cells but in some instances the response is this to one or the other. The end products of either type of cell also is involved in ___________ the response (positive feedback response).

Cognate Interactions, Conjugate Pairs

Naive CD4 T cells are activated by antigens presented by dendritic cells in LN. Naive B cells activated by antigen are trapped in the T cell zone of the LN. Antigen-activated B cells present antigen helper T cells, forming ________________ __________________ and ______________ ________.

Activation

Need 100 specific TCR:Peptide:MHC (1% of MHC) and co-receptor ligation -> __________________.

CD8

Need stronger co-stimulatory signal to become a _______ T cell. Need DC cells to activate naive these since only DCS can give enough co-stinulatory signals. CD4 cells often help the this become acitvated producing enough IL-2. Due to stringent requirements of activation -> importance of only activating them when needed.

FCgammaRI:IgG:pathogen

Once ________________________ this enhances engulfment. Antibody binds to bacterium -> antibody-coated bacterium binds to Fc receptors on cell surface -> macrophage membrane surrounds bacterium -> macrophage membranes fuse, creating a membrane-bounded vesicle, the phagosome -> lysosomes fuse with the phagosome creating the phagolysosome.

Effector T cell

Once a T cell is activated, it is now an _____________ ___ ________ and can act without co-stimulatory signals and expresses 2-4X CD2 and LFA-1 (cell adhesion molecules) as naive T cells. Thus, they can interact with targe cell with fewer ligands for these than an APC.

Mature Dendritic Cell

Once in SLT/LN cortex -> _____________ ___________ ______. Best APC and activator of naive T cells. Can't phagocytize and has increased dendrites.

Antigen

Once the immature form has ingested _________ it migrates toward draining SLT/LN cortex -> it stops phagocytosis and starts maturation process -> APC

Bacterial Components (Adjuvants)

Previously, they noted that immunizing using only proteins often led to a poor response. If included ___________ ____________ , this caused more co-stimulatory signals -> better IR. If too few of the bacterial components -> increased co-stimulatory signal -> anergy.

Regulatory CD4 T Cells

Produce high levels of CD25, alpha chain of IL2 receptor, FOX P3 and inhibitory cytokines such as TGF beta, IL4, and IL10. There are two ways this can supress the IR: -Direct contact the DCs that are initiating IR -Direct contact with effector T cells.

Apoptosis

Programmed cell death (cell suicide). There is no lysis, rather there are molecular changes that occur -> an order series of steps: -Loss of mitochondrial function -Nuclear condensation -Nuclease degredation of DNA between nucleosomes ->200 bp segments of DNA -Loss of plasma membrane asymmetry with phosphatidylserine on outside of membrane (membrane vesicles) -CD8 can induce this in 5 minutes even though cell death may not occur immediately (~40 min)

Cytotoxins

Proteins produces by CD8 T cells. Kill other cells.

Macrophages

Purpose of _____________ in LN (cortex and medulla) and spleen: phagocytize any pathogen before it gets in blood, activate naive T cells, phagocytize apoptotic cells.

Cytokines

Regulation of Th1 cells' activation of macrophages is due to _____________ released from Th2 cells. TGF beta, IL4 and 10 and IL 13 inhibit macrophage activation. Th1 cells stop producing IFN gamma and release macrophages if exposed to these products.

TI-2 Antigens

Repetitive Carbohydrate or protein epitopes of high density on microbes. Activate B cell by extensive crosslinking of BCRs and co-receptors. ->early antibody IgM of limited ability. No isotype switching or somatic hypermutation..

Inducible

Resting B cells of this type show growth, somatic hypermutation and isotype switching. While plasma cells of the same type don't.

Positive Selection

Self-restricted pool of T cells (can interact with MHC class I or II molecules) which become single positive, either CD4 or CD8 T cells.

Negative Selection

Self-tolerant pool of T cells (i.e. not reactive to self antigen)

Cytokines

Small secreted or membrane-bound proteins that alter behavior of other cells produced by CD4 or CD8 cells. When engage their receptor on the target cell -> change in gene expression. Autocrine and/or paracrine. Work in the immediate area where they were released for only short periods or if membrane-bound, act only on target cell (polarization).

T Cell Becomes Anergic

Specific signal on T cell alone (no co-stimulator on antigen-presenting cell) -> ____ ______ ______________ _________.

Lymph Node

T cells can enter __________ ___________ via HEV's or via afferent lymphatic vessel.

Cognate interactions and Form Conjugate Pairs

TCR of T cell specific for antigen on B cell interacts with Ag:MHC calss II of B cell -> ____________ _______________ ____ _______ ________________ _____

Cognate (linked) Recognition

Th2 cells activate B cells that recognize the same antigen as they do, but they recognize different epitopes of that antigen.

IgG

The flexibility of _____ molecule is crucial for its function of binding simultaneously to pathogens and effector molecules and receptors of the immune system. The four subclasses of this differ in the structure of the hinge. In the circulation of type 4 these molecules become functionally monovalent.

Medullary Cords

The primary focus for expansion of antigen-activated B cells is in the ________________ ______.

Germinal Center

The secondary focus for expansion of antigen-activated B cells is in the ________________ _____________

Cytokines

The type of _____________ released from a T helper cell onto a B cell influences the class of antibody the B cell produces.

FCalphaRI

There is a __________ that binds IgA bound to its pathogen.

Intrinsic

These properties of B cells have surface Ig and MHC class II on a resting B cell and high rate Ig secretionof a plasma cell.

Garnuloma

When a microbe resists lethal actions of macrophages ->chronic inflammation. Often there arises a structure called a ______________. In its center infected macrophages surrounded by Th1 cells, giant cells (fuse with macrophages) which contain the pathogens, enlarge macrophages (epitheliod cells) forms epithelial like region around the center. If cut off from blood supply and cells die due to lack of oxygen and nutrients the center undergoes caseation necrosis. If a person has too few Th1 cells to cause this, then they may dies due to disseminated infection (AIDS patients). This formation occurs in M. tuberculosis , M. leprae, etc. infections.

B Cells

____ __________ become activated when their receptors are cross-linked by antigens. Clustering of antigen receptors allows receptor-associated kinases to phosphorylate the ITAMs. Syk binds to doubly phosphorylated ITAMs and is activated on binding.

Th1 Cells

______ _________ help activate marcophages at the site of the infection so they can become more proficient in their phagocytic tasks. To activate a macrophage they need: TCR of this interacting with their peptide:MHC class II and CD40 ligand: CD40 and IFN gamma T cell: IFN gamma receptor.

CD8 T Cells

_______ ___ _________ have stored lytic granules (modified lysosomes containing cytotoxins). Naive T cells make inactive cytotoxins. When activated by specific Ag, they package them in these granules. When bind to target cell, have a focused release of the granule contents onto the target cell. Once cytotoxins induce apoptosis, this can detach, make more granules, attack another target cell.

Th2 Cells

_______ __________ activate B cells that recognize the same antigen as they do. CD40 ligand and IL4 are produced in the T cell and these help the B cell proliferate. IL5 and 6 drive B cell differentiation.

IgA, IgG

_______ and _______ can neutralized microbial toxins. The toxin initially binds to cell-surface receptor.-> endocytosis of toxin:receptor complex-> dissociation of toxin to release active chain, which poisons cell -> neutralizing Ig blocks binding of toxin to cell-surface receptor.

CD8

________ can also produce interferon gamma and thus activate macrophages.

IL-2

_________ plays an important role in T cell proliferation and differentiation. When the T cell engages APC presenting peptide:MHC, co-receptor:MHC, and costimulatory signal, then this is secreted by that T cell itself. The low affinity this receptor on naive T cell changes into a high affinity receptor.

Perforin

__________ makes pores in cell membranes.

Perforin, Granulysin

___________ and ___________ pore in cell membrane so that Tc cell delivers granzymes which initiate apoptosis cascade.

Cytotoxic T Cell (CTL)

____________ ___ _________ recognizes virus-infected cell -> programs target cell to die -> moves to another target cell -> first target cell dies.

Naive T Cells

____________ _____ ________ can enter lymph nodes in the afferent lymph as well as from the blood.

Follicular Dendritic Cells (FDCs)

____________ _______________ _______ play a role in the survival of B cells in the primary lymphoid follicles but also serve as a depository of antigens (not degraded) making them available for interaction with BCRs of B cells. They are perfect for this task since they have extensive decrites to display antigens and have receptors that take up antigens and lack phagocytic acitivity. Note subcapsular macrophages assist these with this task.

Antibodies

____________ can be made in large animals against animal venoms. These specific antitoxic this can be given to people bitten by a snake or insect and prevent serious tissue damage or even death.

Cytokine

____________ receptors consist of at least two chains, the cytoplasmic domains of which bind JAKs. This binding dimerizes the receptor, bringing together the cytoplasmic JAKs, which activate each other and phosphorylate the receptor. Transcribing factors (STATs) bind to the phosphorylated receptors and are, in turn, phosphorylated by the activated JAKs. Phophorylated STATs form dimers that move into the nucleus to initiate gene transcription.

Resting Mast Cell

_____________ ________ __________ has performed granules containing histamine and other inflammatory mediators.

Activated Mast Cell

_____________ ________ __________ multivalent antigen cross-links IgE antibody bound at the mast-cell surface, causing release of granule contents.

Mature Naive T Cell

_____________ _________ ___ ________ is self restricted, self tolerant, and single positive which now circulates through secondary lymphoid organs.

FCgammaRI

_____________ binds to IgG1 and IgG3 with high affinity even when they have not bound their antigen -> traps antigen at phagocyte's surface and targets them for uptake. This is found in macrophages, monocytes, and dendritic cells. It is inducible on neutrophils and eusinophils due to inflammation or infections. Binds IgG3>IgG1>IgG4>>>>>>>IgG2.

Dendritic Cells

______________ _______ capture antigens and carry these to secondary lymphoid tissues (often LN)

Granulysin

______________ acts in a detergent-like manner on membranes.

Specific

~1 in 1,000 or 1,000,000 of total circulating pool of T cells is ______________ for a particular pathogen. Most last years-decades without ever meeting their this antigen.