Flashcards in Day 2.2 Immuno Deck (183):
Upper limb, lateral breast
Superior mesenteric LN
Colic --> Inferior mesenteric LN
Rectum (lower part), anal canal above pectinate line
Internal iliac LN
Anal canal below pectinate line
Superficial inguinal LN
Superficial and deep plexuses --> para-aortic LN
Superficial inguinal LN
Superficial inguinal LN
Lateral side of dorsum of foot
What does the right lymphatic duct drain?
Right arm and right half of head
(So if you obstruct R lymphatic duct, will get non-pitting edema of R arm and R head)
What does the thoracic duct drain?
Everything except the R arm and R head (which are drained by the R lymphatic duct)
Where does the thoracic duct enter back into circulation?
Jn of L. Subclavian in the IJV
T cell stimulator
(Anti-IL2 drugs will shut down immune system)
Inhibits T cells and Macrophages
Il-4 and IL-5
Stimulates B cells
What are the components of the adaptive immune system?
Fns of lymph node
non-specific filtration by macrophages
storage and activation of B and T cells
Site B cell localization and proliferation.
Follicles are in outer cortex.
Where are Tcells found in LN?
Paracortex (bt follicles and medulla)
How do T and B cells enter the LN from the blood?
Through high endothelial venules in the paracortex of the LN
Where is the paracortex located w/in the LN?
Region of cortex, bt the follicles and the medulla.
Which part of the LN becomes enlarged during extreme cellular immune response?
Which part of the LN is underdeveloped in pts with DiGeorge syndrome?
DiGeorge = no Tcells
Paracortex houses Tcells
No Tcells = sml paracortex
Where are the plasma cells located in the LN?
Medullary cords (medulla)
Where are macrophages located in the LN?
Medullary sinuses (medulla)
Where are Tcells located in the spleen?
PALS periartierial lymphatic sheath
and in the red pulp
Where are Bcells located in the spleen?
Follicles and white pulp.
T cell location in LN, Spleen
B cell location in LN, Spleen
What is the fn of macrophages in the spleen?
Remove encapuslated bacteria
Which pts are more susceptible to encapsulated bacteria? What can be done to help them?
What vaccines do asplenic pts need?
Pneuomvax (pneumococcus, against S. pneumonia)
Why are asplenic/splenic dysfn pts susceptible to encapsulated bacteria?
They have decreased IgM, which means decreased complement activation, which means decreased C3b opsonization, which means increased susceptibility to encapsulated.
Why are pts asplenic?
Sickle cell (auto-infarct of spleen)
What is the Rx for hereditary spherocytosis?
Remove spleen (this is one option)
Post-splenectomy, what do RBCs look like?
More Howell-Jolly bodies (RBCs with nuclear remnants)
More target cells (excess mbr relative to amt of Hb)
Also will have thrombocytosis (high PLT count)
What is the classic presentation of infarction on CT?
Wedge/triangular lesion, with point/apex toward center of body and base of triangle toward outside/body wall
Why does lymph fluid have a milky appearance?
It is high in Chylomicrons, high in Triglycerides
Thymus is site of what?
Tcell differentiation and maturation.
Where does the thymus come from embryologically?
Epithelium of 3rd brachial pouches (IMP!)
What is the structure of the thymus?
Inner medulla, outer cortex.
Medulla = middle = mature Tcells
Where does Tcell selection occur in the thymus?
Tcells start as immature in cortex and mature as they go inward to medulla. Undergo selection as they mature.
What is positive and negative selection of Tcells in the thymus
Positive = MHC restriction
Negative = nonreactive to self
Where do Tcells and Bcells mature?
Bcells- bone marrow
What cells make up the innate immune system?
Dendritic cells (APCs- present to neutrophils and macrophages)
Each cell can do many different jobs.
What is the only lymphocyte that is part of the innate immune system?
The other lymphocytes (Tcells, Bcells) are part of the adaptive immune system.
Innate vs Adaptive: which is fast and non-specific?
Innate is also germline-encoded, whereas adaptive is not, it is learned.
Vaccines affect which, innate or adaptive?
Adaptive is the only system with memory.
How do NK cells kill virus-infected cells?
They use perforin and granzymes to cause apoptosis (in both virally infected and in tumor cells)
Which cytokines enhance NK cells?
Virus-infected cells release IFNs. What do IFNs signal?
They induce NK cells
They induce neighbor cells of the virus-infected cell to inhibit viral protein synthesis
What signals induce NK cells to kill?
Non-specific activation signals on the target cell, and/or absence of MHC-I on cell surface. MHC-I is found on most every cell in the body, so no MHC-I means it's not self.
What are the fns of B cells?
IgG Ab opsonize bacteria and neutralize viruses
IgE Ab mediate Type I HPS allergic rxns
IgG Ab mediate Type II HPS cycotoxic rxns and Type III HPS Immune complex rxns
Ab cause hyperacute organ rejection
What are the fns of T cells?
CD4+ Tcells help B cells make Ab
CD4+ Tcells make IFN-gamma, which activates macrophages
CD8+ Tcells kill virus-infected cells directly (the are cytotoxic)
Responsible for Type IV HPS- cell-mediated delayed HPS
Responsible for acute and chronic organ/allograft rejection
After positive selection of Tcells in the cortex of the thymus, what cells are left?
Start as CD4+ CD8+ and after pos selection are either CD4+ 8- or CD4- 8+
Depending on whether they bind MHC-I (CD8+) or MHC-II (CD4+)
Which happens first, pos selection or neg selection of Tcells?
Positive, then negative
What is negative selection?
Tcells that react to self are apoptosed. Occurs at corticomedullary jn
What is the fn of CD8+ cells?
Kills 3 things:
Donor graft cells
Similar to the NK cells of the innate immune system (NK cells are also lymphocytes)
How do cytotoxic CD8+ cells kill?
They rls cytotoxic granules which have perforin and granzyme.
Perforin helps perforate and deliver content of granules into cells.
Granzyme is a serine protease that activates apop w/in cell.
Cytotoxic CD8+ and NK cells are similar, but they differ with regards to MHC-I recognition. How?
NK cells recognize the absence of MHC-I, and kill cells with out it, since they are non-self.
Cytotoxic CD8+ cells use their CD8+ to recognize MHC-I on virally infected cells.
Do cytotoxic CD8+ cells cause inflammation?
No they cause apoptosis.
What cytokine induces CD4+ Thelper cells to become Th1?
IL-12 is produced by virally infected cells
What cytokine induces CD4+ Thelper cells to become Th2?
IL-4 is produced by Th2 cells (pos feedback)
What cytokines do CD4+ Th1 cells secrete?
Which cytokine inhibits Th2 production?
IFN-gamma, secreted by Th1 cells
What does IL-2 stimulate?
Tcells (e.g. CD8+ cytotoxic Tcells)
What does IFN-gamma stimulate?
Also inhibits Th2 production.
What cytokines does CD4+ Th2 produce?
What do IL-4 and IL-5 do?
Stimulate B cells to make Ab (IgE > IgG)
What does IL-10 do?
Inhibits Th1 and macrophages
What cytokine inhibits Th2 production?
IFN-gamma (secreted by Th1)
What cytokine inhibits Th1 production?
IL-10 (secreted by Th2)
In general, what kinds of cells do the Th1 and Th2 pathways stimulate?
Th1 - macrophages and Tcells (incl CD8+ cytotoxic Tcells)
Th2 - B cells. Inhibit Tcell production.
How do you identify cell surface proteins (e.g. CD4, CD 19, etc)
By flow cytometry
What are the cell-surface proteins on Helper Tcells
CD28 (binds to B7 on APC)
CD40L (binds to CD40 on B cells for class switching)
Cell surf proteins on Cytotoxic Tcells
Cell surf proteins on B cells
CD19, CD20, CD21 (receptor for EBV)
CD40 (binds to CD40L on Thelpers for B cell class switching)
MHC-II (bc B cells can be APCs)
B7 (bc B cells can be APCs- binds to CD28 on T helper)
Cell surf proteins on Macrophages
MHC-II (bc it's APC)
B7 (bc it's APC. binds to CD28 on Thelper)
Receptors for Fc and C3b. (Fc and C3b are opsonins, so macrophages have receptors to recognize them)
Cell surf proteins for NK cells
Receptor for MHC-I (all body cells have MHC-I. If not, it's not self, so NK will kill it)
CD16 (binds the Fc of IgG)
Cell surf protein for all cells except mature RBCs
If no MHC-I, it's not self, so NK will induce apoptosis
Cell surf proteins for RBCs, WBCs, Plts
These protect against complement-mediated dmg
Hot T-Bone stEAk
IL-1 = hot (fever)
IL-2 = T (stim's Tcells)
IL-3 = Bone (stim's bone marrow)
IL-4 = E (stim's IgE production- and also IgG)
IL-5 = A (stim's IgA production- and also eosinophil production)
What is the first signal in Thelper activation?
The TCR and the CD4 on the Thelper bind to the MHC-II on the APC
What is the second signal in Thelper activation?
CD28 on Thelper binds to B7 on the APC
What is the first signal in Cytotoxic Tcell activation?
TCR and CD8 on the cytotoxic Tcell bind to MHC-I on the infected cell. (All body cells have MHC-I, so can be any cell in the body that's infected)
What is the second signal in Cytotoxic T cell activation?
A Thelper cell must have already differentiated into Th1, and that Th1 must secrete IL-2.
IL-2 is the second signal which activates the cytotoxic cell to kill the infected cell. (via apop)
What is the first signal in B-cell class switching?
IL-4, IL-5, or IL-6 must be secreted from a Th2 cell
What is the second signal in Bcell class switching?
CD40 receptor on Bcell must bind to the CD40L on the Thelper cell.
What are the two ways macrophages are stimulated by bacterial toxins?
1. Superantigens (S. pyogenes, S. aureus)
How do superantigens stimulate macrophages?
S. pyogenes and S. aureus
They cross-link the Beta region of the TCR to the MHC-II on the APC. This results in uncoordinated rls of IFN-gamma from Th1 cells.
IFN-gamma stims macrophages.
Macrophages rls IL-1, IL-6, TNF-alpha
How do Endotoxins (LPS) stimulate macrophages?
LPS is on gram neg bacteria.
Directly stim's macrophages by binding to endotoxin receptor CD14 on macrophages.
(Tcells are not involved)
Macrophage = CD14!
What is the receptor for endotoxins?
CD14 (on macrophages)
What cytokines are rlsd by macrophgs?
These are the "acute phase cytokines"- they cause fever and increase immune response in general.
also IL-8 and IL-12 are secreted by macrophages.
IL-1 = Hot
Secreted by macrophgs, causes acute inflam.
Induces chemokine production to recruit leukocytes
Activates endothelium to express adhesion molecules
What are the endogenous pyrogens?
(secreted by macrophages)
IL-2 = T (Stim's Tcells)
Secreted by Th1 cells.
Stimulates growth of Thelper and cytotoxic Tcells
IL-3 = Bone (stim's bone marrow)
Secreted by activated Tcells
Supports growth/differentiation of bone marrow stem cells.
Has a fn similar the GM-CSF (which stim's bone marrow stem cells to differentiate)
Immunosuppresant drugs often block/antagonize which cytokine?
e.g. Cyclosporine, Tacrolimus (anti-rejection drugs)
What are the neutrophilic chemotactic factors?
LTB4 (leukotriene b4)
IL-4 = E
Secreted by Th2 cells
Promotes growth of B cells.
Enhances class switching to IgE and IgG
Causes Th --> Th2 differentiation (pos fdbk)
IL-5 = A
Secreted by Th2 cells
Promotes differentiation of B cells
Enhances class switching to IgA
Stim's production and activation of eosinophils
the "mucus' IL
Secreted by Th cells and macrophages.
Stim's production of acute-phase reactants and Igs
Endogenous pyrogen- causes fever
Secreted by macrophages
Mjr chemotactic factor for neutrophils.
Secreted by Regulatory T Cells.
Inhibits action of activated Tcells!
Activates Th2, inhibits Th1
Secreted by B cells and macrophages.
Activates NK cells
Causes Th --> Th1 differentiation
Secreted by Th1 cells
Activates Th1, inhibits Th2
Assoc'd w cell immunity- imp for anti-viral, anti-cancer (so helps w cytotoxic Tcells)
Secreted by macrophages
Acute phase cytokine
Mediates septic shock
Causes leukocyte recruitment and vascular leak.
Generalized inducer of the immune system.
What are the anti-TNFa agents?
What are the anti-TNFa agents used for?
Musculoskeletal- used for seroneg HLA-B27 disorders:
PAIR (psoriasis, ankylosing spondylitis, inflam bowel dz, reiters/reactive arthritis)
Also for non-arthritic psoriasis
Also for rheumatic arthritis
Which anti-TNFa agent is a TNF decoy receptor?
EtanerCEPT is a TNF decoy reCEPTor.
How does Infliximab work?
How does Adalimumab work?
It blocks the TNF-receptor on cells by binding directly to it, so that TNF can't bind to them.
How does Etanercept work?
It is a decoy receptor for TNF (so TNF binds to it, but nothing happens)
Recombinant form of human TNF receptor.
Toxicity of Infliximab?
Predisposes to infections e.g. reactivation of latent TB
so before giving, do a ppd test
Which cytokine has a similar fn to GM-CSF?
What is the mechanism by which interferons work?
Interferons are proteins that make uninfected cells go into an anti-viral awareness state. They induce the production of a ribonuclease that inhibits viral protein sythesis by degrading viral mRNA, but not host mRNA.
Interferon has three types- alpha, beta, gamma.
Interferon INTERFERes with viruses
What are the functions of alpha and beta interferons?
They inhibit viral protein synthesis (viral mRNA)
They activate NK cells to kill virus-infected cells
What is the function of gamma interferons?
They increase MHC-I and MHC-II expression
Increase Ag expression
In all cells
When are exogenous interferons given to patients?
alpha interferon: HBV, HCV, Kaposi's sarcoma, leukemias, malignant melanoma
beta interferon: MS
gamma interferon: chronic granulmatous dz (NADPH oxidase deficiency
List the recombinant cytokines
What is Aldesleukin used for?
Used in RCC renal cell carcinoma and metastatic melanoma (skin cancer)
What is Erythropoetin (epoetin) used for?
Recombinant cytokine used for anemias, esp in renal failure- chronic kidney dz/dialysis pts, or in chemo.
Give in renal failure bc EPO normally comes from kidneys- if they're failing they're not mkg it.
What are Filgrastin and Sargramostim used for?
Recombinant cytokines used for recovery of bone marrow after chemo
What is Oprelvekin used for?
Used for Thrombocytopenia (stim's plt production in bone marrow)
What is Thrombopoetin used for?
Used in Thrombocytopenia (stim's plt production in bone marrow)
What's the cell-surface receptor for EBV?
CD21 on B cells
What is the basic structure of an Ab?
2 heavy chains, 2 light chains.
Held together by disulfide bonds
Fab region binds Ab and is the N-terminal
Fc region binds complement and is the C-terminal
Only one Ab type expressed per B cell.
What part of an Ab recognizes Ag?
The Fab part;
The end of both the heavy and light chain is the "variable" part- V-H and V-L.
What parts (Fab, Fc) do the heavy and light chain contribute to?
Heavy makes up both Fc and Fab
Light is only Fab
Which Ab fix complement? What part of the Ab fixes it?
Fc part of IgM and IgG
(IgM is immediate, IgG is delayed)
Where are disulfide bonds found on Ab's?
Disulfide bonds bind:
Heavy and light chains together
Heavy chains to each other
w/in heavy chains
w/in light chains
For Ab, which end is the N-terminus? Which is the C-terminus?
N-terminus = Fab
C-terminus = Fc
All B cells express only one type of Ab. In what illness are there lots of B cells all expressing the same thing?
Multiple Myeloma (B cell tumor)
Fc: C is for...
Complement-binding (IgM and IgG only)
Carbohydrate side chains
and it determines the isotype (IgD, IgE, etc)
What are the 5 types of heavy chain?
mu, delta, gamma, alpha, epsilon
(IgM, IgD, IgG, IgA, IgE)
What part of the Ab determines the isotype? (IgA, IgE, etc)
The Fc part
What are the 2 types of light chains?
kappa and lambda
(these are functionally the same)
What is the normal ratio of kappa to lambda light chains in humans? Why is it important?
2 kappa : 1 lambda
The ratio will be off in proliferative B cell dz like multiple myeloma
Using the heavy chain and light chain types, what are the possible ways to make an IgA
2 alpha regions (heavy) and 2 lambda regions (light)
2 alpha regions (heavy) and 2 kappa regions (light)
What are the 3 jobs of Ab?
Opsonization (promote phagocytosis)
Neutralization (prevents bacterial adherence)
Complement activation (which enhances opsonization and lysis)
The TCR is an Ab
Another name for Ab is Ag receptor. Same thing.
VDJ recombination: what are the DNA segements?
V = variable
D = diversity
J = joining
They are flanked by RSS (recombination signal sequences) on either side.
How is VDJ recombination initiated?
RAG 1 and 2 (recombination activating gene complex). RAG1 and RAG2 recognize the RSS flanking the VDJ.
What happens when there is a mutation in RAG1 or RAG2 (in mice)?
They can't initiate VDJ rearrangement, so there is arrest of B cell and T cell devt.
What enzyme is responsible for recombination?
Terminal deoxynucelotidyl transferase. It adds nucleotides to DNA during recombination.
How is Ab diversity generated?
1. Random recombination of VJ (light chain) or VDJ (heavy chain) genes
2. Random combo of heavy chains with light chains
3. Somatic hypermutation (after Ag stimulation)
4. Addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase
Which Ab are on the surface of Bcells?
IgM and IgD
How can Bcells which express IgM and IgD on their surfaces differentiate in plasma cells that secrete IgA, IgG, or IgE?
By isotype switching- alternative splicing of mRNA. Mediated by cytokines and CD40L
Main Ab in secondary (delayed) Ag response.
Most abundant Ab
Crosses placenta (infants get passive immunity)
Opsonizes bacteria, neutralizes bacterial toxins and viruses.
t1/2 = 21 days
Prevents attachment of bacteria and viruses to mucus membranes.
Monomer in circulation, Dimer when secreted.
In secretions (tears, saliva, mucus)
In breastmilk ("colostrum")
Picks up secretory component from epithelial cells before secretion.
Md in primary (immediate) response to Ag.
Ag receptor on the surface of Bcells
If on B cells- monomer
Otherwise, pentamer- which allows it to trap free Ag outside of the tsu while humoral response is working
On surface of Bcells, also in serum
Binds mast cells and basophils
Cross-links when exposed to allergen, mediates Type I HPS thru rls of inflam mediators (histamine)
Mediates immunity to works by activating Eosinophils
Lowest conc in serum
To see if a pt has a recent west nile virus infection, what Ab would you look for?
IgM- this will tell you if pt has a NEW infection. Pt may have IgG Ab which would suggest previous infection.
What are thymus-independent Ag?
Ag lacking a peptide component- the can't be presented to Tcells on MHC. They stimulate rls of IgM only, and don't result in immune memory
Ex: LPS from gram-neg; polysaccharide capsular Ag
What are the thymus-dependent Ag?
Ag that contain a protein component and there for do induce immune cell memory. Class switching (IgM --> IgG) occurs as a result of direct contact of Bcells w/ Thelper cells (CD40-CD40L interaction) and rls of IL-4, IL-5, and IL-6
Ex: Conjugated H. inflz vaccine
What are the two pathways of the complement system?
Classic- activated by Ag-Ab complexes (IgG or IgM with Ag)
Alternative- activated by microbial surfaces (nonspecific activators like endotoxin/LPS)
3rd pathway- Lectin is activated by microbial surfaces; enters classic pathway
What are the two primary opsonins in bacterial defense?
C3b- aids in clearance of immune complexes
How is complement activation of self inhibited?
DAF (decay accelerating factor) (DAF = CD55 + CD59)
C1 esterase inhibitor
Complement: what do C1, C2, C3, C4 do?
Complement: what does C3b do?
Opsonization. B Binds Bacteria.
Also clears immune complexes
Complement: what do C3a, C5a do?
Anaphylaxis (A= anaphylaxis)
Also, C5a is a neutrophil chemotactic factor
What molecules induce neutrophil chemotaxis?
Complement: what do C5b-C9 do?
Cytolysis by MAC
Deficiency of C1 esterase inhibitor
Causes hereditary angioedema.
No esterase inhibitor means increased bradykinin, which means angioedema
How does C3a cause anaphylaxis?
Stim's mast cells, basophils to rls histamine --> vasodilation and incrsd vasc permb --> fluid leaves vessels and goes to tsu --> decreased BP -->Anaphylaxis
the fluid mvmt also causes edema.
Rx for anaphylaxis?
Deficiency of C3
Severe recurrent pyogenic sinus and respi tract infections (esp w Strep pneumo and H.inflz)
Increased susceptibility to Type III HPS rxns, esp glomerulonephritis
Deficiency of C5-C9
No MAC --> Neisseria bacteremia (both gonococcal and meningiococcal)
Deficiency of DAF (GPI-anchored enz)
Complement-mediated lysis of RBC
PNH (paroxysmal nocturnal hemoglobinuria)
What is PNH
Paroxysmal Nocturnal Hemoglobinuria
No DAF (CD55&59) so RBCs are dmgd and iron spills out --> hemosiderinuria, plus iron-def anemia
Chronic intravascular hemolysis (this causes the hemosiderinuria)
How do you dx PNH?
Ham's Test: do RBCs lyse at low pH? If yes, it's PNH
Can also do flow cytometry- look for CD55 and CD59 (these are the DAF). If missing, it's PNH.
Rx for PNH
Iron and Anticoagulant (warfarin), but ultimately, bone marrow txplt
What are the granulomatous diseases? (12)
1. TB (only one with caseating granulomas)
2. Fungal infections (histoplasmosis, blastomycosis)
3. Syphilis (gummas)
5. Cat scratch fever (Bartonella)
7. Crohn's dz
10. Foreign bodies (body walls it off)
11. Wegener's granulomatosis
12. Chronic granulomatous dz (NADPH oxidase deficiency)
What is anergy?
Self-reactive Tcells become non-reactive without co-stim molecule.
Bcells can also become anergic, but tolerance is less complete than in Tcells.
Ex of antigenic variation in bacteria
Salmonella has 2 flagellar variants
Borrelia (relapsing fever)
N. gonorrhea (pilus protein)
Ex of antigenic variation in a virus
major = Ag shift
minor chg = Ag drift
Ex of antigenic variation in parasites
Trypanosomes have programmed rearrangement
What is active immunity?
Induced after exposure to foreign Ag.
Slow onset, long-lasting protection (Bcell memory).
Due to IgG.
What is passive immunity?
Immunity from Ab received from another host.
Rapid onset of immunity, but short life-span of Ab (t1/2 = 3 weeks)
Ex IgA in breastmilk.