Immunology Flashcards
What vaccines must be conjugated to be very effective? Why?
Vaccines directed against bacteria with polysaccharide capsule antigens as the target:
- Haemophilus influenzae b
- Streptococcus pneumoniae
- Neisseria meningitidis
Polysaccharide antigens cannot be presented to T-cells via MHC
-> need to conjugate to a immunogenic protein (i.e. tetanus toxoid) so that B cells which have B-cell receptor (antibodies) to the polysaccharide can process the toxoid protein and present it on MHC to get T cell activation
Why is T cell activation so important for vaccines? Why is this especially a big deal in children?
Activation by T cells allows antibody class switching (IgM -> IgG) and generation of memory B cells -> longer-lasting and more robust immune response
Furthermore, children have an underdeveloped humoral immunity -> administration of conjugated vaccines is the only way to generate an antibody response
What type of pneumococcal vaccine is generally given to adults vs children?
Adults - Mezzanine - IgM-generating vaccine of polysaccharide capsule not conjugated to anything -> no lasting memory B cell response
Kids - Ground - IgG vaccine conjugated to toxoid -> required for immunogenicity in children
How do you assess if hematuria / proteinuria in endocarditis is due to kidney infarct / abscess vs glomerulonephritis?
Infarct / abscess present with flank pain, while glomerulonephritis generally does not.
Which light chain type rearranges first, and what is the net result of this in terms of circulating Ig? Where does this occur?
Kappa locus rearranges first, and if successful, prevents lambda locus from rearranging (they are on separate chromosomes).
Result is there are about twice as many Kappa Ig molecules vs lambda
This all occurs in the bone marrow
What do V, D, J, and C stand for? Which are not present in light chains?
V = variable D = diversity J = joining C = constant
Diversity segments are not present in light chains
When and how does class switching occur?
After exposure to Ag, somatic rearrangement occurs non-reversibly at the DNA level in response to the cytokine environment (determines optimal Ig class).
What carries the signal that a successful heavy chain has been made, and light chain splicing should begin? What type of receptor is this?
Pre-B cell receptor shuts off surrogate light chain production and starts the light chain rearrangements, while also stopping heavy chain rearrangments.
This is a RTK which, if defective, will arrest all B cells in the pre-B stage (X-linked agammaglobinemia)
What is the main cell type involved in organizing lymphoid tissues?
Reticular cells - fibroblast-like cells which produce Type 3 collagen to provide the framework for spleen, lymph nodes, and lymph nodules
Give an example of a condition where only the cortex of the lymph node would be absent?
Bruton’s agammaglobulinemia -> B cells can never mature from bone marrow if they don’t move on from the pre-B cell stage
-> follicles will be absent
What is the mnemonic for the features of DiGeorge syndrome?
CATCH-22 Cardiac anomalies Abnormal facies Tetralogy of Fallot Cleft palate (not lip) Hypoparathyroidism / hypocalcemia
Explain internal hemorrhoids due to cirrhosis?
Portal HTN slows the drainage of the superior rectal vein, the final branch of the IMA
Superior rectal vein anastamoses with the middle and inferior rectal vein, which are branches of the internal iliac.
Explain the lymph drainage above and below the dentate line?
Above - superior rectal vein to IMA, and middle rectal vein to internal iliac nodes
Below - all lymph goes to superficial inguinal nodes.
What drains the lymph from the superior and inferior portions of the bladder?
Superior - External iliac nodes
Inferior - Internal iliac nodes
Where does the body of the uterus and cervix drain?
External iliac nodes, with the bladder
Where does the prostate, cervix, corpus cavernosum, and proximal vagina drain?
Internal iliac nodes
Where does the distal vagina, vulva, scrotum, and distal anus drain?
Superficial inguinal nodes
Where does the glans penis drain?
Deep inguinal nodes
Does the medial or lateral foot and posterior calf drain into the popliteal nodes?
Lateral tract -> follows the arteries. Ultimately this system drains into the deep inguinal nodes.
Remember the saphenous vein is medial so it drains the medial leg and foot into the superficial system
Where do the kidney lymph nodes drain?
Para-aortic nodes, since renal arteries branch directly from aorta
Where does lymph from the uterine fundus drain to?
Para-aortic nodes, along with the fallopian tubes and ovaries via the gonadal artery distribution
Where are the B and T cells found in the spleen?
T cells - periarteriolar lymphatic sheath - PALS
B cells - follicles within the white pulp
What are four changes seen in the blood post-splenectomy?
- Howell-Jolly bodies - nuclear remnants of RBCs remain in RBCs
- Target cells - lack of removal of excess membrane
- Thrombocytosis + 4. Lymphocytosis -> loss of sequestration in spleen
What are the histologic features of the thymic cortex / medulla on H&E stain?
Cortex - dark basophilic staining, with immature T cells
Medulla - pale staining, with mature T cells and epithelioreticular cells forming Hassall’s corpuscles
What is the pathway for antigen presentation on MHC Class 1? What proteins are involved in translocation to the ER?
Proteins are degraded by the proteasome. TAP-1 and TAP-2 transport the broken down proteins from the proteasome to the RER, where fragments become associated with the newly formed MHC Class 1. These peptides will be presented on the surface of the cell.
TAP1 = transporter associated with antigen processing
What is the mechanism of MHC Class 2 presentation?
MHC Class 2 is assembled in ER and stabilized by invariant change.
Invariant chain degrades to CLIP after vesicle ships from Golgi.
Phagocytosed and acid-digested vesicle (acidified endosome) fuses with MHC vesicle, and CLIP is removed.
The immunodominant protein fragment will bind
What chromosome is HLA found on and how do you remember this? This relates to hemochromatosis somehow.
Chromosome 6. Remember this because hemochromatosis is associated with HLA-A3, and must be in linkage disequilibrium since Chromosome 6 is also where the HFE gene is.
Which HLA’s are associated with Addison’s disease?
HLA-B8, DR-3, and DR-4
Think Graves + rheuatoid arthritis
Which HLA is associated with myasthenia gravis?
Sadly, same MHC class 1 as Graves disease
HLA-B8.
What HLA is associated with pernicious anemia?
Same as Hashimoto’s thyroiditis - HLA-DR5. High five luke!
How are NK cells and macrophages in a positive feedback loop?
Macrophages release IL-12 -> activates NK cells
NK cells release IFN-y (part of the lymphoid line, but still innate immunity) -> activates macrophages
How are natural killer cells activated in response to viral infection?
TLR-3 binds dsRNA -> upregulates local IFNalpha / IFNbeta synthesis
- > IFNalpha / IFNbeta activate NK cells
- > they also upregulate MHC class 1 to improve presentation of viral peptides to CD8 T cells.
How does ADCC occur?
CD16 (Fc receptor for IgG) binds to the base of immunoglobulin, activating NK cell to use perforin and granzymes to induce apoptosis of viral infected / tumor cells.
What is Stage 1 of T cell development? What takes place in the thymic cortex / medulla?
Bone marrow cells arrive at the thymus as double negative (CD4-CD8-).
Cortex - Positive selection, where TCRs capable of binding self-MHC survive
Medulla - Negative selection, mediated by AIRE. TCRs with high affinity for self antigens undergo appoptosis.
What selection takes place during the double positive stage (stage 2)? This follows the double negative stage where TCR rearrangement occurs and both CD4 / CD8 become expressed.
Positive selection - T cells bind with weak affinity to self MHC
Negative selection - T cell binding is too strong - recognition of self = apoptosis
Death by neglect - unreactive T cells to MHC die via apoptosis after neglect.
-> MHC type which they have the best affinity for determines if they will become CD4 or CD8 cell (other receptor is downregulated).
List the cytokines needed to induce formation of Th1 vs Th2 vs Th17 vs Treg cells? What cells are releasing these cytokines?
Th1 - IL-12 (macrophages), IFN-y
Th2 - IL-2, IL-4
Th17 - TGF-beta, IL-6
Treg - TGF-beta
Cytokines are released my antigen presenting cells to induce a specific subset differentation
List the cytokines which inhibit the formation of Th1 vs Th2 cells.
Th1 - IL-4, IL-10 (Th2 line)
Th2 - IFN-y (Th1 line)
What cytokines does the Th1 subset secrete and what does this do?
Secretes IFN-y -> activates macrophages, induces class switching to IgG3, suppresses Th2 response
Secretes IL-2 -> T cell growth factor and stimulator of CD8 cells (costimulator for cytotoxic cells which encounter their MHCI)
What cytokines does the Th2 subset secrete and what does this do?
Secretes IL-4, IL-5, IL-10 and IL-13
IL-4 - Class switching to IgE and IgG, inhibits Th1
IL-5 - Eosinophil chemotactic agent, class switching to IgA
IL-10 - Inhibits Th1
IL-13 - similar to IL-4
What is the function of Treg cells and what cytokines do they produce?
Suppress activation of immune response via production of TGFb and/or IL-10
They also express CTLA4 and bind B7, preventing the interaction betwen CD28 and B7 on CD4 cells.
What syndrome does Foxp3 mutation cause? Symptoms?
IPEX Immune dysregulation, Polyendocrinopathy - thyroiditis and pancreatitis -> destruction of pancreatic islets -> diabetes Enteropathy - diarrhea X-linked - (diabetes in males infants)
Also has dermatologic manifestations i.e. dermatitis / nail dystrophy
What is the process by which T cells are activated by antigen presenting cells?
- Signal 1 - APCs present peptides to TCRs via MHC Class 1 or 2
- Signal 2 - APCs send costimulatory signal by by having their B7 (CD80/86) bind CD28 of T cells.
What is the process by which T cells induce class switching in B cells?
- Signal 1 - B cell presents processed peptide via MHC Class 2 to CD4 T cell
- Signal 2 - CD40L of T cells bind CD40 receptor of B cells to induce class switching of B-cell as costimulation.
- Signal 3 - Cytokine released by T cell induces the class
IgE - IL-4
IgA - IL-5
IgG - IL-6
What portion of the heavy chain does complement vs macrophages bind?
Complement - side of Fc, closer to the hinge region (which is cleaved by papain)
Macrophage binding - Binds to the bottom of the segment. Makes sense because this is where FcR binds.
What generates the “insertional diversity” in the variable regions during VDJ splicing?
Random addition of nucletodies to DNA during recombination by the enzyme terminal deoxynucleotidyl transferase (TdT)
-> this is the marker we use to test for ALL
Where are the J chain and SC (secretory component) synthesized?
J chain = also in plasma cell. J chain catalyzes polymerization shortly before secretion
SC = epithelial cell
-> SC component made from Poly-Ig receptor which mediates trancytosis, then split off from epithelial cell which makes it the secretory component
What is the function of the secretory component?
Protects the Fc portion of IgA from luminal proteases
Which antibody has the lowest concentration in serum?
It’s actually IgE. IgD is there but has kind of an unknown function.
What is the structure of a thymus-independent vs dependent antigen?
Independent - lacks a peptide component, polysaccharide only (i.e. LPS)
-> weakly immunogenic, poor memory, IgM response only
Dependent - has a peptide component, thus can be presented on MHC to T cells, activation of T cells can occur, much stronger response.
Conjugated vaccines allow a thymus-dependent response to polysaccharide antigens.
What is the function of C-reactive protein? Is it a positive or negative APP?
+
Opsonization of damaged cells, activation of complement
-> fairly sensitive marker for inflammation
What is the erythrocyte sedimentation rate (ESR)? Does this increase or decrease in inflammation and why?
Distance that RBCs settle in a vertical column of anticoagulated blood in one hour
Increased in inflammation because of elevated fibrinogen levels (+APP), leading to increased thombosis risk.
Fibrinogen helps RBCs settle faster by making RBCs stick together and form Rouleaux stacks which are higher density and reach the bottom faster.
What are the functions of haptoglobin, ferritin, and hepcidin and are they positive or negative APPs?
Haptoglobin - binds free hemoglobin
Hepcidin - decreases iron absorption and transport (kills da iron). Degrades ferroportin on enterocytes.
Ferritin - binds free iron
- > decreases microbes ability to take up free iron
- > positive APPs
What are the steps up to C3 in the classical pathway?
- Ab binds the pathogen.
- C1 binds the Fc of the Ab.
- C1s cleaves C4 into C4a and C4b
- C4b is attached to pathogen, cleaves C2 to C2a and C2b.
- C4b2b complex is C3 convertase
What is the only change between classical and lectin pathway?
Lectin - MBL replaces the antibody as what ultimately binds the C1.
Mannose binding lectin binds the mannose residues of the pathogen
What is the alternative pathway up to C3?
C3 is spontaneously hydrolyzed and sticks to pathogen surface. C3b works with Factor B to be activated by factor D (activated factor B = Bb).
C3bBb = C3 convertase
What will C1, C2, and C4 deficiencies cause?
Poor clearing of immune complexes via C4 receptors on RBCs -> autoimmune or immune complex diseases (like SLE glomerulonephritis)
-> MBL and alternate pathway will still allow for MAC killing
What will C3 deficiency cause?
Frequent, serious pyogenic infections / respiratory infections (all pathways feed into this)
What complement component will be deficient in C1 esterase inhibitor deficiency?
C4, since it is the major substrate of C1 esterase (C1s) which cannot be inhibited.
What effect does IFN-y have on MHC?
Increases MHC expression (class 1 and 2) via all cells to increase antigen presentation -> best for cytotoxic response.
What secretes IL-10 and what is its function?
Secreted by Tregs and Th2 cells -> inhibits activated macrophages and dendritic cells
-> along with TGF-beta, IL-10 attenuates the immune response
How do patients with chronic granulomatous disease generate HOCl in catalase negative species?
They utilize the bacterial hydrogen peroxide (H2O2) to kill invading bacteria.
Thus, bacteria which produce catalase have much less free H2O2 for this conversion -> chronic granulomas.
What is lactoferrin / what is its purpose?
Protein found in secretory fluids (i.e. milk) / neutrophils, involved in the sequestration of iron / iron chelation. This inhibits microbial growth. (Part of innate immune system).
What are the functions of interferon alpha and beta? What triggers their release?
Released locally by infected cells to prime uninfected cells in viral infection.
Upregulates NK cells and downregulates viral mRNA production.
Release is triggered when viral dsRNA binds TLR3.
What is the differential expression of CXCR4 / CCR5 on T cells / macrophages?
CXCR4 - expressed on CD4+ T cells only, infective target of late HIV infection
CCR5 - expressed on CD4+ T cells AND macrophages, target of early HIV infection
What antigens are expressed on the surface of Tregs?
CD3, CD4, CD25 (IL-2 receptor subunit)
Also utilize FOXP3 transcription factor
What CD marker is TLR4?
CD14 -> receptor for LPS
What receptors do macrophages have on their surface which help with opsonization / phagocytosis?
- Fc receptor
2. C3b receptor
What CD marker is most suggestive for NK cells? You learned this in the heme unit.
CD56
What directly interacts for superantigens to work?
Superantigens of S pyogenes and S aureus cross-link the Beta region of the TCR to MHC Class 2 on APCs -> nonspecific activation and general release of cytokines
What louse-borne infection is a classic example of antigenic variation?
Borrelia recurrentis (Relapsing fever) -> due to constant antigenic variant via Variable Major Protein (VMP) gene
- > spirochete
- > transmitted by same vector of Rickettsia prowazekii.
What are the major live vaccines used in clinical practice today? What is their primary immune response advantage over inactivated / killed vaccines (mechanistically)?
MMR, Sabin polio, rotavirus, varicella (VZV), yellow fever
Main advantage: Induces cellular immunity due to CD8 T cells actually being recruited to kill infected cells.
Humoral immunity is achieved in both vaccine types.
What type of hypersensitivity is involved in the pathogenesis of polyarteritis nodosa?
Type III hypersensitivity - explains why hepatitis C immune complexes are a risk factor
What is an Arthus reaction? What causes it?
Local, subacute antibody-mediated hypersensitivity (type III hypersensitivity)
Due to intradermal injection of an antigen in an individual who already has circulating IgG -> i.e. previously vaccinated individual gets same vaccine.
-> Edema, necrosis, and activation of complement locally (due to antigen-antibody complexes in the skin)
What is meant by washing RBCs and what is this meant to prevent?
Remove donor plasma, wash RBCs, replace plasma with saline
Prevents allergic / anaphylactic transfusion reactions to a substance in donor plasma (i.e. IgA antibodies in IgA deficient individuals)
What are the symptoms of an anaphylactic transfusion reaction and how should it be treated? What type of hypersensitivity is it?
Shock, bronchospasm, and respiratory distress due to allergy to some component of donor plasma. Due to histamine release -> Type I hypersensitivity
Give epinephrine and IV fluids
What process is done to prevent transfusion reactions in immunocompetent hosts? What type of tranfusion reaction is this normally?
Leukoreduction
-> filter out WBCs
Usually a “febrile, non-hemolytic reaction” due to Abs against donor WBCs/platelets or cytokines present in donor plasma
What causes an acute hemolytic transfusion reaction? Is it intravascular hemolysis or extravascular hemolysis?
Type II hypersensitivity reaction -> ABO mismatch since IgM antibodies fix complement well -> intravascular
Extravascular hemolysis can also occur due to IgG antibodies against minor antigens on RBCs, which are well-opsonized by spleen
What are the symptoms of acute hemolytic transfusion reaction?
Just as you would expect:
Intravascular - hemoglobinuria, flank pain
Extravascular - jaundice
Along with fever, hypotension, tachypnea, tachycardia.
Treat with IV fluids / mannitol / furosemide to keep kidney excretion constant
What is tranfusion associated acute lung injury (TRALI) / what causes it? Treatment?
Noncardiogenic pulmonary edema due to donor antibodies against recipient neutrophils resulting in capillary leak
-> give supportive therapy and mechanical ventilation if needed
A patient was given several transfusions and now has dyspnea, cough, hypoxia, edema, and pulmonary congestion on CXR. What do they have and how do you treat them?
TACO - transfusion associated circulatory overload
Presents like CHF
Give diuretics to reduce blood volume
What condition is associated with anti-signal recognition peptide and anti-helicase antibody?
Polymyositis, Dermatomyositis
anti-Jo-1 = anti histidyl tRNA synthetase anti-SRP = anti signal recognition peptide anti-Mi-2 = anti helicase
What is anti-Ro antibody known for?
Ro-Ro-Rowing across the placenta and causing congenital heart block in neonatal lupus
Anti-Ro is also known as SS-A
What is the common variable in common variable immunodeficiency?
Lack of B cell differentiation
- > general there will be lymphadenopathy / lymphoid hyperplasia, but B cells fail to differentiate into mature cells
- > predispoes to autoimmune disease / lymphoma due to increased B cell proliferation but failure to make usable antibodies / plasma cells
What type of infections occur with IL-12/IFN-y receptor deficiencies?
Disseminated mycobacterial / fungal infections
What is the cause of Hyper-IgE syndrome and what is this also called?
Autosomal dominant mutation STAT3 cytokine-transducer.
Also caused Job syndrome
- > leads to a deficiency of Th17 cells, which are needed for neutrophil recruitment
- > causes impaired recruitment of neutrophils to the site of infection (similar to LAD)
What are the symptoms of hyper IgE syndrome?
FATED on the Job
coarse Facies staphylococcal Abscesses without pus (no neutrophils) Teeth - retained primary teeth igE -> elevated IgE Dermatologic problems - Eczema
Bone fractures occur from minor trauma (similar to osteogenesis imperfecta somehow)
What labs will be seen in hyper IgE syndrome?
Elevated IgE, decreased IFNy (impaired Th17 activation, increased eosinophils (correspondingly elevated allergic response)
What is the broad underlying cause of chronic mucocutaneous candidiasis?
T cell dysfunction
What is the most common cause of SCID?
X-linked - IL-2 receptor gamma chain deficiency
What are T cell receptor excision circles (TRECs) and how will they be affected in SCID?
They are episomal pieces of DNA found within T cell in the thymus during the differentiation / generation of new T cell receptors.
-> will be decreased in SCID because there are few T cells
What causes Ataxia-Telangectasia?
Autosomal recessive defect in ATM gene (Ataxia telangiectasia mutated)
-> unable to repair double-strand DNA breaks
What is the diagnostic quad of ataxia-telangectasia?
4 A’s
cerebellar Ataxia - with cerebellar atrophy
spider Angiomas (telangectasia)
IgA deficiency -> sinopulmonary infections. Also presents with IgG and IgE deficiency (AGE)
elevated Alpha-fetoprotein (impaired organ development)
What causes Hyper IgM syndrome and what lab values will be associated? What is the mode of inheritence?
X-linked Defect in CD40L required for class switching
Associated with normal or high IgM, and low IgA, IgG, and IgE (AGE)
What will be notably absent from the lymph nodes of those with hyper IgM syndrome?
Absence of germinal centers -> since class-switching and somatic hypermutation cannot be activated
What happens to antibody counts in Wiskott-Aldrich syndrome? Most common cause of death in these patients?
Decreased IgM, normal IgG, Increased IgE / IgA
Lack of IgM leads to recurrent pyogenic infections
Common cause of death: Bleeding (thrombocytopenia is the T in the mnemonic)
What causes Chediak-Higashi (CH) syndrome and what is the pattern of inheritance?
Autosomal recessive
Lysosomal trafficking regulator protein dysfunction
What happens to granular cells in CH?
They have giant granules due to fusion of cytoplasmic granules (defective lysosomes)
What happens to platelets in CH?
Abnormal dense bodies -> mild bleeding tendency
What is the inheritance pattern of chronic granulomatous disease? What is the treatment?
X-linked is most common -> deficiency in NADPH oxidase
Treatment is interferon-gamma
What bacteria and viruses are B cells needed against?
Bacteria - encapsulated, i.e. pseudomonas, Hib, Neisseria meningitidis, S. pneumonia, Salmonella, etc.
Viruses - primarily enteroviruses / Polio -> need IgA (reset are controlled by cell-mediated immunity)
What type of parasitic infections are B cells needed against?
Need IgA antibodies against Giardiasis
What types of infections do T cell deficiencies tend to cause?
Fungal (i.e. Candida, PCP, Crypto) / Viral infections
What is it called when you get a graft from an identical twin vs a non-identical individual of the same species?
Identical - Syngeneic graft
Non-identical - allograft
What are the two primary mechanisms of acute rejection, and which is more easily treatable?
- Cell-mediated - due to T-cell overactivity (primarily CD8 T cells being activated when donor MHCs present peptides to recipient CD8+ T cells)
- > easily treated by increasing immunosuppression (most immunosuppressives effective against T-cell proliferation) - Humoral - due to antibodies formed after transplantation. More difficult to treat.
What is the T cell response which leads to chronic graft rejection?
CD4+ T cells respond to recipient’s APCs presenting donor (graft) peptides -> activation of cellular / humoral components
Succinctly summarize the general damage you expect to hyperacute vs acute vs chronic rejection?
Hyperacute - type II hypersensitivity which looks like Type III -> fibrinoid necrosis of graft vessels
Acute - vasculitis of graft vessels with dense lymphocytic infiltrate
Chronic - atrophy and fibrosis with vascular smooth muscle proliferation. Accelerated arteriosclerosis.
What are manifestations of chronic graft rejection in the lung and heart?
Lung - Bronchiolitis obliterans -> lymphocytic destruction of small airways with progressive dyspnea
Heart - Accelerated atherosclerosis
What are manifestations of chronic graft rejection in the kidney and liver?
Kidney - Chronic graft nephropathy with vascular attack
Liver - Vanishing bile duct syndrome
What type of hypersensitivity reaction is graft-versus host disease? In what type of transplant is it most likely to happen?
Type IV hypersensitivity -> attacks skin, GI epithelium, and liver
Most likely to happen in liver transplants
