4) Basic Immunology Lectures and Diseases Specific Lectures Flashcards
What are the 3 +Coreceptors for the BCR?
CD21/19/81 (CD21, also known as complement receptor 2 or CR2, binds to C3d on antigen)
What is the -coreceptor for the BCR?
CD22
What are the signaling components of the BCR (Iga and Igb)?
First tyrosine kinase (src family): Blk, Fyn or Lyn (phosphorylate BCR’s
ITAMs)
Second tyrosine kinase (syk family): Syk
What are the coreceptors for the TCR?
CD4 or CD8 (binds to MHC Class II or I, respectively) which can bring in lck to the synapse
What the sigaling components of the TCR? (Signaling from the TCR (from CD3: e (2), d, g, z(2)))
First tyrosine kinase (src family): Fyn or Lck phosphorylates CD3 ITAMs
Second tyrosine kinase (syk family): Zap-70 activated by Lck, Zap70 in turn activates PLC-g, etc)
Signal transduction Calcium Pathways: Src kinase -> phosphorylated ITAMs -> (X) (BCR) or (Y) (TCR) -> phosphorylated adaptor protein ((Z) for BCR or Lat for TCR) -> (A) activation -> PIP2 is cleaved into (B) -> Calcium influx (2 influxes)
X = Syk Y = Zap-70 Z = Lab A = PLCg B = DAG and IP3
What are the 2 influxes of calcium in the calcium pathway?
1) First influx: IP3 binds to IP3R on ER, leading to calcium efflux from ER. The drop in ER calcium leads to STIM1 (on ER membrane) activation which signals Orai (on cell membrane) to form the CRAC channel and allows…
2) Second, larger, influx: Significant calcium influx from OUTSIDE the cell
Calcium Pathway: Higher calcium levels lead to (X) -> (Y) activation, which de-phosphorylates (Z) -> (Z) goes to the nucleus, leading to (A) transcription and proliferation.
X = calmodulin Y = calcineurin Z = NFAT A = IL-2
Cyclosporin A: key immunosuppressive drug that binds to (X) (cytoplasmic proteins) and as a complex they inhibit (Y), preventing its activation by calcium (thus blocking (Z) activation).
X = cyclophilins Y = calcineurin Z = NFAT
Tacrolimus (also known as (X)) is also an immunosuppressive drug and it works
similarly to cyclosporine. Tacrolimus ultimately prevents the dephosphorylation of
(Y)
X = FK-506 Y = NFAT
Tacrolimus: Mechanism: FK-506 binds to (X) (FK506 binding protein) to create a new complex which inhibits (Y).
Effect: Inhibits T cell (Z) and (A) transcription.
X = FKBP Y = calcineurin Z = signal transduction A = IL-2
Jak/Stat: Some cytokine
receptors associate with
(X). Cytokine binds to its receptor -> dimerization -> phosphorylation of the receptor and activation of the (X) -> Stats are recruited to the JAKs and are (Y) -> Stats (Z) and go to (A)
X = Janus kinases (JAKs) Y = phosphorylated Z = dimerize A = Nucleus
Costimulation: “Second signal” expressed on (X) cells that indicates “danger”, and is required for full activation of (Y) cells. [Signal 1 without Signal 2 -> anergy = functional inactivation, T cells are viable but don’t proliferate]. After activating costimulatory molecules turn the immune response on and the antigen has been eliminated, (Z) costimulatory molecules then turn the response off and there’s a return to homeostasis.
X = antigen presenting Y = T Z = inhibitory
Activating costimulatory molecules include:
B7-1/B7-2 (on the APC) interacting with CD28 (constitutively expressed on T cell surface). Engagement of CD28 leads to T cell expansion, differentiation, and survival
ICOSL (on the APC) interacting with ICOS (expressed at low levels on resting naïve T cells and quickly upregulated after TCR ligation and CD28 costimulation)
Regulates Tfh-B cell interactions in the germinal center. Different effects on T cell depending on the cell’s developmental stage, but important in promoting survival, proliferation, and memory in activated effector T cells and regulatory T cells
Inhibitory costimulatory molecules include:
iB7-1/B7-2 (on the APC) interacting with CTLA-4 (mostly upregulated after T cells have been activated). Engagement of CTLA-4 inhibits IL-2 production, blocks cell cycle progression, and inhibits proliferation.
PD-L1 (on B cells, T cells, DC, macrophages)/PD-L2 (on DC, macrophages) interacting with PD-1 (upregulated on T cells and B cells). Thought to have a more tissue-specific function than CTLA-4. Limits autoreactivity and establishes self-tolerance
Costimulation matters because its of huge therapeutic interest!
i. Blocking activating costimulatory molecules is a strategy being used to treat
(X) diseases (e.g. rheumatoid arthritis) and (Y).
ii. Stimulating activating costimulatory molecules or blocking inhibitory costimulatory molecules is used to boost (Z) immunity
X = autoimmune Y = transplant rejection Z = anti-tumor
How many primary immune deficiencies have been identified by the International Union of Immunological Societies?
Over 120
Immunodeficiencies: Combined T and B-cell immunodeficiencies (e.g. SCID)
1) DiGeorge syndrome
2) Rag, Artemis, IL-7Ra, ADA
3) X linked: Common Gamma chain
Immunodeficiencies: Predominantly antibody deficiencies (e.g. Bruton’s agammaglobulinemia)
Hyper-IgM syndrome
Immunodeficiencies: Other well defined Immunodeficiency syndromes. Give examples:
Wiskott-Aldrich, DNA repair defects like ataxia telangiectasias
Immunodeficiencies: Diseases of immune dysregulation. Give examples:
1) IPEX: due to FoxP3 mutation, lack of Tregs causes autoimmune enteropathy, dermatitis, autoimmune endocrinopathies, and autoimmune skin conditions.
2) APECED: due to AIRE mutation, there is lack of central tolerance in the thymus; there is lymphocyte infiltration into multiple endocrine tissues
3) XLP: Lack of SAP protein leads to widespread immune activation and lack of control of Epstein-Barr virus, which often leads to death from bone marrow
failure, hepatitis, and malignant lymphoma
Immunodeficiencies: Congenital defects of phagocyte number, function, or both: LAD1
LAD1: B2 integrin (also known as (X)) defect. (X) is a component of integrins including LFA-1, leading to failure of neutrophils to extravasate from the bloodstream to get to inflamed tissues through binding to (Y) on the endothelium. The major problem is in leukocyte (Z) the endothelium.
X = CD18 Y = ICAM-1 Z = sticking to
Immunodeficiencies: Congenital defects of phagocyte number, function, or both: LAD2
LAD2: lack of (X), which is a ligand of (Y) on the vascular endothelium, together with the (Z) blood phenotype. There is a failure of neutrophil extravasation because of lack of (A).
X = sialyl-lewis X Y = P and E-selectin Z = Bombay A = rolling
Immunodeficiencies: Congenital defects of phagocyte number, function, or both: LAD3
LAD3: lack of activation of all (X) integrins leading to a failure of (Y)
X = beta Y = extravasation
Immunodeficiencies:
Congenital defects of phagocyte number, function, or both: Chronic granulomatous disease
Lack of functional (X), with pneumonia, abscesses, suppurative arthritis, osteomyelitis, bacteremia,
fungemia, cellulitis and impetigo. People with CGD are more prone to (Y)
bacteria and the fungi (Z). Catalase produced by
bacteria breaks down the (A) species made by the cells, and without (X), the bacteria can survive.
X = NADPH oxidase Y = catalasepositive Z = Aspergillus and Candida A = reactive oxygen
Immunodeficiencies:
Congenital defects of phagocyte number, function, or both: Chediak-Higashi syndrome
Mutation in a (X) trafficking regulator protein, leading to decreases in phagocytosis and increased (Y) infections.
X = lysosomal Y = pyogenic
Immunodeficiencies: Defects in innate immunity (e.g. NEMO deficiency). Usually associated with (X) problems.
Mendelian susceptibility to mycobacterial infection: (Y)
TRIF, TLR3 and UNC93B deficiency: susceptibility to (Z)
X = skin Y = IL-12, IL-12R Z = herpes encephalitis
Immunodeficiencies: Autoinflammatory disorders (e.g. Familial Mediterranean fever). Excessive inflammation
causes (X) damage.
X = long-term
Immunodeficiencies: Complement deficiency (e.g. C1q deficiency that may predispose to lupus, C1-inhibitor deficiency that causes (X), paroxysmal nocturnal (Y))
X = hereditary angioedema Y = hemoglobinuria
Deficits in adaptive immunity are usually (X) and treatable by stem cell transplant (in the case of SCID) or (Y) replacement (in the case of antibody failure)
X = X-linked Y = immunoglobulin
Deficits in innate immunity are usually (X) gene defects (autosomal recessive) and difficult to treat
X = homozygous
The nature of the patient’s infection can provide a clue about what the immune deficiency is. For example, recurrent pyogenic bacterial infections (e.g. otitis, pneumonia, meningitis, osteomyelitis) after ~6 months of age (when protection by maternal IgG has waned) is indicative of an (X) deficiency.
X = antibody
Mechanisms of tolerance are driven by strength of TCR interaction with (X) and location of this
interaction
X = MHC and peptide
Central Tolerance (during thymic T cell or bone marrow B cell development):
o Deletion: if interaction with antigen is (X), cells die by negative selection
o Inactivation: if interaction with antigen is (Y)
o Deviation: T cells can become Tregs through (Z)
X = too strong Y = somewhat strong Z = positive selection
Peripheral Tolerance o Deletion o Inactivation: through (X) o Deviation: peripheral (Y) o Ignorance: don’t encounter antigen with signal 2 o Helplessness o (Z)
X = anergy Y = Tregs Z = Suppression
What’s a Treg?
A subset of CD4+ T cells that suppresses the activation and effector functions of other T cells that could be self-reactive.
How can you identify a Treg?
1) On the cell surface, expresses high levels of (X) and obviously CD4.
2) Expresses the (Y) transcription factors.
3) Secretes (Z) when activated
X = CD25 Y = FoxP3 and STAT5 Z = TGF-beta and IL-10
How are Tregs formed?
§ “(X)” Tregs are formed in the thymus, when a CD4 T cell recognizes (Y)
§ “(Z)” Tregs are formed in the periphery.
§ (A) are necessary for the development of Tregs (at least in vitro), and they
are produced by functioning Tregs. This production of (A) is critical for the suppressive effect of Tregs
X = Natural/Central Y = self antigen Z = Induced A = TGF-beta and IL-2
In what physiological/pathophysiological processes do Tregs play a role?
Autoimmune diseases (inflammatory bowel disease, type 1 diabetes, multiple sclerosis, skin diseases)
Allergic diseases (food sensitivity, asthma),
Inflammatory diseases
(atherosclerosis, obesity)
Tumor responses, etc.
People born without (X), the “master regulator” for Treg maturation and maintenance,
develop a multi-organ autoimmune disease called (Y)
X = FoxP3
Y = IPEX (immune dysregulation
polyendocrinopathy enteropathy X-linked inheritance)
People born without (X), a transcriptional elongation regulator which leads to
expression of peripheral antigens in medullary thymic epithelial cells (mTECS), develop a multi-organ autoimmune disease against endocrine tissues called (Y).
X = AIRE
Y = APECED (autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy)
Immune Reactant of Type I Hypersensitivity:
IgE
Immune Reactant of Type II Hypersensitivity
IgG
Immune Reactant of Type III Hypersensitivity
IgG
Immune Reactants of Type IV Hypersensitivity
Th1, Th2, and CTLs
Antigen and Effector mechanism of Type I Hypersensitivity
Soluble antigen
Mast Cell activation
Antigen and Effector mechanism of Type II Hypersensitivity
Cell or matrix associated antigen
FcR+ cells (phagocytes, NK cells)
Antigen and Effector mechanism of Type III Hypersensitivity
Soluble antigen
FcR+ cells, Complement
Antigen and Effector mechanism of Type IV (Th1 cells) Hypersensitivity
Soluble antigen
Macrophage activation
Antigen and Effector mechanism of Type IV (Th2 cells) Hypersensitivity
Soluble antigen
Eosinophil activation
Antigen and Effector mechanism of Type IV (CTL cells) Hypersensitivity
Cell associated antigen
Cytotoxicity
Examples of Type I Hypersensitivity Reaction
Allergic rhinitis, asthma, systemic anaphylaxis
Examples of Type II Hypersensitivity Reaction
Some drug allergies (e.g. penicillin)
Examples of Type III Hypersensitivity Reaction
Serum sickness, Arthus reaction
Examples of Type IV (Th1) Hypersensitivity Reaction
Contact dermatitis, tuberculin reaction
Examples of Type IV (Th2) Hypersensitivity Reaction
Chronic asthma, chronic allergic rhinitis
Examples of Type IV (CTL) Hypersensitivity Reaction
Contact dematitis
Protection against extracellular bacteria and extracellular fungi
Antibody, complement, neutrophils, Th17 cells, ILC3s (Th17-like)
Protection against Worms
IgE, Th2 cells, eosinophils, mast cells, ILC2s
Protection against Intracellular pathogens
Macrophages, Th1 cells, CTLs, NK cells, ILC1s
Human tumor immunotherapy:
Checkpoint blockade: (X) pathway blockade, reverses T cell exhaustion. Allows previously existing but exhausted CTLs that target cancer antigen to be reactivated by blocking (Y) of signal. Works best in cancers with many (Z) like melanoma and non-small cell lung cancer
X = anti-CTLA4 and PD1 Y = negative regulators Z = neoantigens
Chimeric antigen receptor (CAR) T cell therapy
o CAR is most often composed of an extracellular (X) against a tumor antigen with an intracellular (Y) domain
o Adoptive cell transfer: Patient’s cells are transformed with a CAR specific for their cancer and re-infused; allow killing of tumor cells
o So far mainly effective in (Z)
X = monoclonal antibody Y = TCR Z = leukemias
What are the timescales of rejection and characteristics of transplantation rejection?
a. Hyperacute: Complement mediated –pre-existing antibodies
b. Acute: T cell mediated within 10 days of transplant
c. Chronic: T cell mediated – months and years
Transplant: What are the 2 hypotheses for high frequency (up to 2%) of alloreactive T cells?
Determinant density (Host T cells see many foreign MHC molecules on donor cells)
Determinant Specificity (donor MHC presents many different peptides)
Transplant: What is it called when host T cells recognize donor MHCs?
Direct recognition
Transplant: What is is called when peptides from donor MHCs and other polymorphic non-MHC peptides (minor antigens) are presented on host APCs to host T cells?
Indirect (normal) recognition
What is the immune mechanism of rejection of hyperacute transplant rejection reaction?
Preexisting antibodies in host
circulation that bind to donor
antigens
What is the pre-screening method or pharmacologic treatment that can be given to prevent hyperacute transplant rejection?
ABO match
What is the immune mechanism of rejection of acute transplant rejection reaction?
Alloreactive T cells and antibodies that injure the graft parenchyma and blood vessels
What is the pre-screening method or pharmacologic treatment that can be given to prevent acute transplant rejection?
Panel reactive antibody
test, Calcineurin inhibitors (cyclosporine, FK506), rapamycin/sirolimus,
mycophenolate mofetil, OKT3, fingolimod
What is the immune mechanism of rejection of chronic transplant rejection reaction?
Delayed-type hypersensitivity
reaction to alloantigens in the
vessel wall
What does Cyclosporine do?
o Binds cyclophillin
o Inhibits calcineurin
o Inhibits NFAT, IL-2 expression
What does FK506/Tacrolimus do?
o Binds FKBP
o Inhibits calcineurin, same as above
o Inhibits NFAT, IL-2 expression
What does Rapamycin/Sirolimus do?
o Binds FKBP
o Inhibits mTOR
o Inhibits T-cell proliferation (IL-2-driven)
What does Azathioprine do?
o Antimetabolite
o Blocks nucleotide synthesis
What does Mycophenolate Mofetil do?
o Antimetabolite
o Blocks nucleotide synthesis
There is an absence of (X) responses in AIDS because of lack of (Y) help. The reason why some people do not progress to full blown AIDS is still unclear.
X = memory CTL Y = CD4+
Entry of virus into host cells depends on (X) and chemokine receptors ((Y) or (Z) depending on the virus, usually (Y) in vivo), thus HIV primarily infects (X) T cells.
X = CD4 Y = CCR5 Z = CXCR4
Other virus proteins contribute to impairment of host immunity:
o Viral Nef downregulates (X). HLA-C is not downregulated – presumably to keep NKs cells quiescent
o Viral Vpu downregulates a host restriction factor called (Y)
o Viral Vif downregulates APOBEC3G – a host restriction factor that converts (Z) when viral RNA is being reverse transcribed
X = CD4, HLA-A, and HLA-B Y = tetherin Z = Cs to Us
What are some of the many reasons why a protective vaccine (generating antibodies) against AIDS has not been successful?
o virus undergoes mutation at a high rate
o conserved epitopes such as CD4 binding site on gp120 are less immunogenic
o gp120 is heavily glycosylated
The immunological center of the allergic disease world is the (X)
X = mast cell
What leads to hypersensitivity reactions? On the first exposure to antigen, the antigen gets across the epithelium and induces
(X) cells, which provide help to B cells that then produce (Y) specific for the antigen. (Y) binds to Fc receptors on (Z). On the second exposure
to antigen, the antigen cross links the (Y) on the mast cell surface, the cells are activated and release chemical mediators such as (A), which then cause nearby blood vessels to dilate and become (B), and bronchial and visceral smooth muscle to (C)
X = CD4+ Th2 Y = IgE Z = mast cells and basophils A = CysLT, LTB4, histamine and proteases B = leaky C = contract
Late phase reactions from IgE-driven mast cell activation are caused by secretion of (X), (Y), and chemokines, which lead to (Z) recruitment and a second phase of symptoms at (A) hours.
X = TNF Y = IL-5 Z = eosinophil A = 8-12
What is a severe allergic reaction, immediate Type 1 hypersensitivity reaction, characterized by edema and a drop in blood pressure?
Anaphylaxis
Anaphylaxis: Systemic IgE mediated reaction, affecting what sytems?
Vascular, cardiac, skin, respiratory, GI and neuro
systems
Food allergy: increased over last two decades, most common allergies are to _____
Peanuts, tree nuts
and shellfish, milk, soy, egg and wheat
What is the atopic triad?
Asthma, allergic rhinitis, atopic dermatitis
Atopic triad is driven by (X) cells and (Y), and responds to (Z)
X = Th2 Y = Eosinophils Z = Corticosteroids
Acute flares of the atopic triad are driven by superimposed IgE mediated (X)
X = mast cell activation
What is characterized by episodic, reversible airflow obstruction; “a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial
hyperresponsiveness, and an underlying inflammation?”
Asthma
What are the classic signs and symptoms of asthma?
Intermittent dyspnea, cough, and wheezing (non-specific)
Asthma is driven by what 3 things?
Viral respiratory infections, aeroallergens, cold air
Asthma: Chronic obstruction driven by (X), (Y) stimulation of mucus production, fibrosis, and smooth muscle (Z)
X = Th2 Y = eosinophil Z = hypertrophy
What are the acute flares of asthma caused by?
Mast cell mediators
What are treatment options for asthma?
Beta-agonist bronchodilators, glucocorticoids (inhaled or systemic), leukotriene receptor antagonists, anti-IgE, anti-IL-4/13, anti-IL-5
What is a perennial or seasonal allergen-driven inflammation of the nasal
mucosa or conjunctiva?
Allergic rhinitis and conjunctivitis
What sign is atopic dermatitis known for?
Dry, thickened, red skin, frequently superinfected
Atopic dematitis: Defect in (X) function in AD, in some cases caused by (Y) loss of function mutations; itching caused by TSLP
X = epidermal barrier Y = fillagrin
What allergic disorder is a eosinophil-dominant inflammation of the esophagus?
Eosinophilic esophagitis
What is epinephrine used for?
Acute treatment of anaphylaxis
Corticosteroids: Mechanism of action is inhibiting (X) phase reactants, promoting apoptosis of (Y) cells, inhibiting Th2 cytokine production, inhibiting chemokine and (Z) production. But (A)% of asthmatics (with the non-allergic type) may be steroid resistant.
X = late Y = eosinophils and Th2 Z = leukotriene A = 20-30
What are some new monoclonal antibody based regimens in the treatment of allergic diseases?
New monoclonal antibody based regimens against IgE (Omalizumab), IL-4, IL-13, IL-5,
TNF-a, eosinophilopoeisis, TSLP
What is the treatment characterized by repeated injections or oral ingestion of allergen extract? Specific IgE levels decrease and IgG levels increase (perhaps moving the balance from Th2 to Th1).
Allergen immunotherapy
What can home and school environmental remediation do for treatment of allergic diseases?
Reduce allergen exposure
Infections may stimulate the immune system in such a way as to protect against allergy and asthma is known as the ____
Hygiene Hypothesis
Complement Initiation:
Classical pathway (requires (X), so it’s ADAPTIVE)
1. C1 (via C1q) binds (Y) complex on target cell or bacteria -> (Z) (activated)
2. C1s cleaves (A) -> C2bC4b (the C3 convertase)
3. C3 convertase: C3 -> (B) (inflammatory mediator) and (C) (an opsonin)
4. C2bC4bC3b = (D) convertase
5. C5 convertase: C5 -> C5a (inflammatory mediator)+C5b (initiates formation of (E))
6. C5bC6C7C8C9 = membrane spanning channel (the (E)) leads to (F))
X = Ab Y = Ag-Ab Z = C1s* A = C2 and C4 B = C3a C = C3b D = C5 E = membrane attack complex or MAC F = cell lysis
Complement Initiation: Alternative pathway (no (X), so it’s INNATE)
- C3 spontaneously cleaved, C3b -> (Y)
- C3b binds (Z)
- Factor D cleaves (Z) to Factor Bb -> C3bBb is the (A)
- (A): C3 -> C3a, C3b -> C3bBbC3b is the C5 convertase
- Then, same as before (classic pathway)
X = Ab Y = microbial surface Z = Factor B A = C3 convertase
Complement Initiation:
Mannan binding lectin pathway (no (X), so also INNATE)
1. Patterns of mannans on microbial surface get bound by the Mannan Binding Lectin Complex (including (Y))
2. These proteases cleave C4 -> (Z), C4b binds to microbial surfaces (via reactive (A) bond)
3. Rest is like classical pathway.
X = Ab Y = MASP proteases Z = C4a and C4b A = thioester
Complement Common End Pathway (Membrane Attack Complex formation)
i. Shared by all three pathways
ii. (X, 4 items) join (Y) to form C5b-C9 (MAC)
Forms channel in cell membrane to lyse the target cell
X = C6, C7, C8, C9 Y = C5b
Complement Regulation Molecules
- (X): causes C3 convertase dissociation
- (Y): blocks MAC formation
- (Z): blocks C1r/C1s
X = DAF Y = CD59 Z = C1 inhibitor
Complement Regulation Deficiencies:
- C1 inhibitor causes hereditary (X)
- GPI link defect leading to DAF, (Y) defect causes paroxysmal nocturnal hemoglobinuria
X = angioneurotic edema Y = CD59
PRR (not just on APCs)
To get an adaptive immune response you must activate an APC (usually a
dendritic cell) to get what 2 forms of upregulation?
- Upregulation of antigen processing and presentation
2. Upregulation of costimulatory molecules (B7, etc)
What are 3 mechanisms of programmed cell death?
Apoptosis, pyroptosis and necroptosis
Apoptosis, or cellular suicide, involves (X) activated shrinkage, chromatin condensation, membrane (Y) and fragmentation of cells, followed by non-inflammatory clearance by
(Z).
X = caspase Y = blebbing Z = macrophages
What are the two major pathways of apoptosis?
Mitochondrial
Death receptor
(X) are Cysteine dependent aspartate (Y) that cleave substrates after (Z) residues.
X = Caspases Y = proteases Z = D (Asp)
What is the Caspase active site sequence?
QACRG in active site – the C is critical
(X) is the “inducer caspase” for the mitochondrial pathway, and (Y) is a major inducer caspase for death receptor signaling
X = Caspase 9 Y = caspase 8
Executioner caspases such as (X) can be activated by inducer caspases (and also by (Y) which is a serine protease that cleaves after (Z) residues- like caspases but different active site residue).
X = caspase 3 Y = Granzyme B Z = D
An important (but one of many) substrate for caspase 3 is (X) which when cleaved, can no longer inhibit CAD
X = ICAD (inhibitor of Caspase Activated DNase)
Mitochondrial pathway of Apoposis: Induced by (X) only ligands that inhibit (Y) (a multi-domain (Y)-family antiapoptotic protein) on the mitochondrial outer membrane and activate (Z) (multi-domain (Y) family pro-apoptotic proteins).
(A) is a multi-domain anti-apoptotic (Y) family protein, often induced in activated lymphocytes
X = BH3 Y = Bcl-2 Z = Bax or Bak A = Bcl-XL
Mitochondrial pathway of Apoptosis: (X) and (Y) oligomerize to form a channel in the mitochondrial membrane allowing leakage of (Z) and other pro-apoptotic factors. (X) channels are in the outer membrane but channels linking both inner and outer membrane also form during the mitochondrial permeability transition
X = Bax Y = Bak Z = cytochrome c
Mitochondrial pathway of Apoptosis: Cytochrome c binds to (X) in the cytosol and activates (Y) -> capase 9, which is main executioner caspase of this pathway, leading to (Z) activation which breaks down the cell
X = APAF-1 Y = Procapase-9 Z = caspase-3
What is a prominent example of the death receptor pathway of apoptosis?
Fas pathway
Death Receptor Pathway: Fas-FasL interactions cause clustering of Fas, and thus of (X) and thus the clustering and activation of (Y) /FLICE. ((Y) can be inhibited by (Z)). (Y) is the executioner caspase of this pathway, and activates caspase-3 and cleaves tBid into Bid, which as a (A) only protein ties into the (B) pathway
X = FADD (Fas associated Death Domain) Y = Caspase-8 Z = FLIP A = BH3 B = mitochondrial
Death Receptor Pathway: Fas pathway is critical for (X) and for elimination of non-specific bystander (Y) during T-B collaboration
X = T helper AICD Y = B cells
BCL-2 family:
1. Anti-apoptotic: Bcl-2 (constitutive) and (X) (induced)
2. Pro-apoptotic: apoptosis results when BH3-only proteins interact with (Y), because they destabilize the mitochondrial membrane
“Receptors” = (Y) (wait for BH3-only protein)
“Ligands” (BH3-only proteins): (Z) (plays a role in negative selection), (A)
X = Bcl-XL Y = Bak or Bax Z = Bim A = Bid
What are 3 Executioner Caspases Underlying Different Apoptotic Pathways
- Mitochondrial: Caspase 9 (inducer/initiator caspase) -> caspase 3 (executioner caspase) -> DNA fragmentation
- Fas: Caspase 8 (also known as FLICE, another inducer caspase) -> activates
caspase 3 -> Cleaves Bid -> binds Bax and Bak -> mitochondrial membrane
leakage -> cytochrome c leaks out -> binds Apaf 1 -> which binds procaspase 9 (another inducer caspase) -> caspase 9 -> caspase 3 -> DNA fragmentation - ER stress: Leads to caspase 12 activation (inducer caspase) -> caspase 3 (executioner caspase) -> DNA degradation
How does caspase 3 work?
1. The executioner/effector caspase -> cell death by causing (X) to become
(Y) -> DNA fragmentation
X = ICAD Y = CAD (Caspase Activated DNase)
Immune modulation of apoptosis:
- Memory cells have high levels of (X) (anti-apoptotic)
- (Y) signaling induces Bcl-XL (anti-apoptotic)
- (Z) cells contact targets with FasL (pro-apoptotic in targets)
- Fas is important for germinal center B cell death ((A))
- Fas mutated in autoimmune lymphoproliferative syndrome
- Activated Bim causes clonal delection of (B) in thymus
X = Bcl-2 Y = pre-BCR and pre-TCR Z = Th1 A = pro-apoptotic B = double positive T cells
How do CTLs and NK cells use granzymes (Protease released by CTLs that enter a target cell via perforins). to kill targets?
Like caspases, they also cleave proteins after (X) residues, but they have a (Y) in the active site. They function like inducer caspases (since they activate the (Z) caspases).
X = aspartic acid Y = serine Z = executioner
Memory cells can survive in the absence of (X), and are hard-wired to be more readily activated by re-exposure to (X). Require cytokines for survival (such as (Y)).
X = antigen Y = IL-7 and IL-15
Memory T cells that express (X) return to lymph nodes and are called Central memory cells. Those that remain in the periphery and do not express (Y) are called Effector Memory cells.
X = CCR7 and L-selectin Y = CCR7
Central memory (Tcm) (L selectin+, CCR7+) can home to (X). Wait in (X) for antigen. If restimulated, generate effector cells
X = SLO
Effector memory (Tem) (L selectin-, CCR7-) patrol (X). If restimulated, secrete effector cytokines themselves
X = tissues, periphery
Memory B cells
i. Generated in (X)
ii. Await further appearance of antigen
iii. Live in spleen, near old (X) and marginal zone
iv. Can differentiate to (Y) cells
X = Germinal Centers Y = plasma
What are antigen-presenting cells with a unique ability to induce primary immune
responses?
Dendritic cells (DCs)
Are mouse DC subsets the same or different than human subsets?
A bit different
Within an animal, there is a lot of DC heterogeneity reflected by anatomic localization: Give examples
Skin epidermal Langerhans cells, dermal (interstitial) DCs, splenic marginal DCs,
germinal center DCs, thymic DCs, liver DCs, blood DCs, gut DCs, etc.
Immature DCs are very efficient in Ag capture and can use several pathways, such as: (3)
(a) macropinocytosis
(b) receptor-mediated endocytosis via C-type lectin receptors (mannose receptor, DEC-205) or Fcc receptor types I (CD64) and II (CD32) [uptake of immune complexes or opsonized particles]
(c) phagocytosis of particles such as latex beads, apoptotic and necrotic cell fragments (involving
CD36 and avb3 or avb5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major
The antigen/pathogen induces the immature DC to undergo phenotypic and functional changes that culminate in the complete transition from (X) cell to APC. DC maturation is intimately linked with their (Y) from the peripheral tissue to the draining lymphoid organs.
X = Ag-capturing Y = migration
Think about the problem of a virus that does not infect DCs—how do you activate CD8+ T cells to kill the infected cells?
o (X). Somehow antigens from outside the DC are endocytosed (which should land them in the (Y) antigen processing pathway) but leave the endocytic compartment and make their way to the (Z). From there, they are able to enter the ER via the (A) channel and get presented on (B) molecules, thus alerting CTLs to the viral infection
X = Crosspresentation Y = MHC II Z = cytosol A = TAP B = MHC I
Germinal Center Reactions:
Somatic hypermutation
i. In GC (X) zone
ii. Changes (Y) region with point mutations
iii. Leads to alteration in affinity of (Z) (and therefore antibodies, if they are ever
made)
iv. (A) mediated (C ->U, UNG removes U….)
v. Requires Th help, with (B) interaction
X = dark Y = VARIABLE Z = BCR A = AID B = CD40-CD40L
Class Switch Recombination
i. In GC (X) zone
ii. From (Y) -> IgA, IgE or IgG
iii. Yields new effector function with the (Z) antigenic specificity
iv. Which isotype is switched to depends on the cytokine environment
v. (A) mediated ((A) -> double strand breaks in two places, which can be re-ligated,
getting rid of the old constant region)
vi. Requires Th help, with (B) interaction
X = dark Y = IgM/IgD Z = EXACT SAME A = AID B = CD40-CD40L
What molecule tests an activated/proliferating B cell to become a Short or long-lived plasma cell, either before or after Bcl-6 signaling?
Blimp-1
