Immunity Flashcards Preview

M1 > Immunity > Flashcards

Flashcards in Immunity Deck (149):

1) Explain the importance of self-tolerance in immunity

2) Explain the types of tolerance - central and peripheral

1) The immune system must be tolerant to "self" and recognize it from non-self; loss of tolerance --> healthy cells are attacked by the immune system --> autoimmunity e.g. Type I Diabetes

2A) Central - occurs in thymus (T cells) and bone marrow (B cells); removal of self-reactive clones (cells with too high affinity) via apoptosis, receptor editing of B cells, or devlpt of tregs from CD4 T cells

2B) Peripheral tolerance - either apoptosis via Fas/FasL extrinsic pathway, hide the self-reactive clones/antigens (ignorance), shut them down (anergy), or suppression using tregs


Define the following:
1) Antigen
2) Epitope
3) Antibody (i.e. immunoglobulin)
4) Paratope
5) Idiotype
6) Adjuvant

1) Antigen = antibody generator; can be capsule, cell wall, etc.; also called immunogen since it elicits an immune response; can be part of pathogen or cancerous cells

2) Epitope = reactive portion of the antigen that reacts chemically with the paratope of an antibody to form the immune complex

3) Antibody = Y shaped protein that recognizes specific foreign antigen; secreted version of B cell antigen receptor

4) Paratope = portion of the antibody that binds to the epitope of an antigen; is sterically and chemically complementary and forms noncovalent bonds; is part of the Fab (fragment antigen-binding region)

5) Idiotype = set of epitopes on the variable region of an antibody molecule that are unique to an individual

6) Adjuvant = agent that stimulates immune system and enhances the response e.g. Toll-like receptors


Basic difference between B and T cells

Both part of adaptive immune response

B cells - defend body against antigens and pathogens in body fluids --> humoral immunity; recognize pathogens in native form; carry MHC Class I and II

T cells - defend body against pathogens in living cells --> cell-mediated immunity; recognize pathogens through MHC-peptide complex; only carry MHC Class I


Describe the following immunological techniques:
1) Flow cytometry - fluorescence activated cell sorting (FACS)

2) Monoclonal antibodies

1) FACS - cells with fluorescent tags funneled one at a time through nozzle --> hit by laser beam and produces energy/color --> can determine size and granularity of cells and quantitate levels of various proteins on cells

2) Monoclonal antibodies - generated from clones of single B cells; only hybridomas (myeloma cells fused with antibody-producing cells) survive in medium --> produce immortal fusion cells = single monoclonal antibody with single specificity against antigen; e.g. rituximab (anti-CD20 to treat NHL); produce side effects e.g. fever, chills, nausea


Describe innate immunity and key features

Innate immunity - initial response to pathogens and activates adaptive immune response; can eliminate damaged cells and repair tissue w/out inflammation; comes from long evolutionary history

Key features: functional at all times; immediately available, broadly specific = responds to CLASSES of microbes, no immune memory; multiple mechanisms to find and eliminate pathogens + infected cells

Includes: first line defense (physical barrier), PRRs, complement system, macrophages, DCs, NK cells, neutrophils, cytokines


1) PRR

1) PRR = Pattern Recognition Receptor = innate immunity molecules that recognize foreign molecules based on patterns not seeing in normal cells; can be on cell membrane, endosomal membrane, or cytoplasm

2) PAMP = Pathogen Associated Molecular Patterns = pathogen molecules recognized by PRRs; can immediately recognize these bc of evolution; can be part of intact pathogen, or shed by pathogen, or released following phagocytosis

3) DAMP = Damage Associated Molecular Patterns = subset of PAMPs; pathogen molecules recognized by PRRs that arise from unmasked/unusual host components due to infection, trauma, etc.


Describe at least 5 major molecular patterns that are recognized by PRRs and associate these molecular patterns with classes of pathogens

1) (PAMP) Nucleic acids --> ss or dsRNA --> viruses

2) (PAMP) Proteins --> pilin or flagellin --> bacteria

3) (PAMP) Cell wall lipids --> gram negative (LPS) or gram positive (lipoteichoic acid) bacteria

4) (PAMP) Carbs --> mannan or dectin glucans --> fungi

5) (DAMP) crystals e.g. monosodium urate, nuclear proteins


1) role of Toll-like receptors
2) 2 major cellular locations of TLRs
3) the physiological outcomes of TLR stimulation

1) Toll-Like receptors - family of PRRs conserved through evolution capable of recognizing wide variety of PAMPs from different classes of pathogens

2) A- Cell surface; B- endosomal membrane

3) PAMP binds to cognate TLR --> signal transduction cascade --> triggers inflammatory or antiviral response

A) NFkB transcription factor --> inflammatory response through cytokines TNF and interleukins IL-1 and IL-6, also stimulates adaptive immunity

B) IRF transcription factor--> antiviral response through Type I Interferons IFN (alpha and beta)


Describe the following types of cytoplasmic PRRs:
1) NLRs
2) RLRs

1) NLRs = NOD-like receptors - binding to peptidoglycan/bacterial PAMPs in cytoplasm triggers intracellular signaling cascade --> NFkb inflammatory response through cytokines; misregulation may lead to gut diseases e.g. IBD

2) RLRs = RIG-like receptors e.g. RIG1 - binds to nucleic acid PAMPs; senses RNA viruses bc there has to be a triphosphate on 5' end


Describe the role of neutrophils in innate immunity and response to interaction with bacteria

Neutrophil = PMN = granulocytes

Activation: predominant white cell type in blood (inactive); activated by TNF + IL-1 (inflammatory cytokines), fmet (1st AA terminal on N-terminus of bacterial proteins) --> first responders to acute inflammation

Function: Very phagocytic --> kill bacteria or fungi in circulation or tissues; short half-life (~5 hours) so require constant replenishment from bone marrow; old neutrophils phagocytosed by macrophages

neutropenia (e.g. during chemotherapy) --> high rate of bacterial and fungal infections


1) Differentiate between monocytes and macrophages
2) Differentiate between classical (M1) and alternatively activated (M2) macrophage - activation and function
3) What are add'l macrophage functions

1) Monocytes are immature macrophages that circulate in blood; mature into macrophages when they leave blood and go to site of injury/infection

2) Classical M1 macrophage matures due to binding of TLRs, IFNgamma --> secretes IL-1 + TNF, IL-12, ROS/NO --> inflammation, mobilization of NKCs/CD8T cells, phagocytosis/killing of pathogen

Alternatively activated M2 macrophage matures due to IL-4, IL-13, signals --> secretes IL-10 + TGFbeta, proline polyamines --> anti-inflammatory, wound repair + fibrosis

3) Add'l macrophage functions: surveillance, garbage collecting, antigen presentation to effector T cells (NOT naive T cells), more cell surface PRRs expressed upon activation


Describe function of NK cells in innate immunity in:
1) IDing targets
2) killing targets
3) protecting from viruses

Natural Killer (NK) cells - large lymphocytes with cytoplasmic granules; stimulated by IL-12 (released by macrophages) and Interferons alpha/beta, ALSO release IFNgamma which activates macrophages

1) IDing damaged/infected cells - NK cells have both inhibitory and activating receptors; healthy cells have MHC Class I molecules (e.g. HLA-E) which are recognized by inhibitory receptors; pathogens downregulate MHC Class I --> activate NK cell --> target killed

2) Killing IDed cells extracellulary - cytoplasmic granules contain substances that lead to target cell death via apoptosis

3) Can kill virus-infected cells in early stages of viral infection before there are cytotoxic T-lymphocytes


1) Describe functions of dendritic cells in innate immunity

2) Outline 2 types of dendritic cells and their specific functions:
A) Conventional (myeloid)
B) Plasmacytoid

1) Function of DCs: main type of APCs, most efficient ones that initiate most immune responses; immature DC does surveillance in epithelium --> migrate to lymph nodes and induce peripheral tolerance by inducing tregs, generating IgA

2A) Conventional DCs (bone marrow): immature DCs recognize and phagocytose antigens using TLRs 2/4 -> becomes mature DC and produce cytokines (i.e. IL-12 --> differentiation of Th1, enhancement of NKCs and CD8 T cells) + ROS/NO --> travel to nearby draining lymph node where they present antigen to naive T cells --> activate T cell to stimulate adaptive immune response--> increases antigen presentation + costimulatory molecules

2B) Plasmacytoid dendritic cell (periphery + spleen): high levels of TLRs 3/7/9 --> respond to ss/ds viral RNA/DNA --> Turn on Type I interferons TFN alpha and beta --> antiviral effects (block viral translation, inhibit replication via ribonuclease) + stimulate adaptive immunity


What is the complement system of innate immunity and the three major outcomes of activation?

Complement system - 20 soluble recognition molecules, produced in liver and found in the blood, that help tag or destroy antigens in serum

3 major outcomes:
1) opsonize (tagging) of microbes by C3b for phagocytosis and killing *most important function* - C3b receptor is on macrophages and neutrophils
2) mobilize and recruit phagocytes (neutrophils, macrophages, DCs, mast cells) to site of infection by C3a, C5a
3) recruit membrane attack complex --> directly lyse pathogens (only those with thin cell walls)


What are the three ways the complement system of innate immunity can be activated?

1) Classical pathway: Fc region of antigen+antibody complex (Only IgG or IgM) is bound by C1 to form protease --> activates C2 and C4 --> forms C3 convertase (C4bC2a)

2) Alternative pathway: spontaneous hydrolysis of complement protein C3 which is found in high concentration in serum and tissue; activated by high molecular weight bacterial polysaccharides and promoted by Properdin--> C3 breaks down into C3a and C3b --> C3b bound by Factor B (which is cleaved by Factor D) --> forms C3 convertase (C3bBb)

3) Lectin pathway: mannose binding lectin (MBL) protein recognizes terminal mannose residues found in bacteria/fungi but not humans --> recruits proteases to cleave complement proteins C4 and C2 --> form C3 convertase (C4bC2a)


Where do the three activation pathways of the complement system converge

Pathways converge at C3 convertase (C3bBb from alternative pathway or C4b2a from classical/lectin pathways)

C3 convertase cleaves C3 --> C3a and C3b --> C3b + C3 convertase --> C5 convertase (C3bBb3b or C4b2a3b) which cleaves C5 to C5a and C5b --> can form membrane attack complex

*factors H and I inhibit C3b*


What is the function of C3a and C5a soluble fragments in innate immunity?

1) bind to receptors on neutrophils and lead to chemotaxis (movement) towards infected site

2) recruitment and activation of other inflammatory cells e.g. monocytes, macrophages

3) activate and degranulate mast cells and basophils --> release of inflammatory mediators --> anaphylaxis


How are healthy cells protected from the complement system of innate immunity?

1) Regulatory proteins e.g. DAF, CD59

2) Protein I- serum/tissue inhibitor of C3b


Beyond complement proteins, what are examples of other soluble recognition molecules?

Pentraxins e.g. C-reactive protein CRP, SAP --> activate Complement C1 protein

Increased levels of CRP are systemic effect of acute inflammation --> serve as serum biomarkers for inflammation


Describe the forms of immunization against tetanus and when they should be used:
1) Tetanus toxoid
2) Tetanus antitoxin (Equine)
3) Tetanus immune globulin (human)

4) What is the ideal treatment for tetanus in non-immunized patients vs immunized patients?

1) Tetanus toxoid: stimulates active immunity --> production of protective antibodies in 3-5 days if previous vaccination was given (since memory lymphocytes exist); should get toxoid booster every 5 years

2) Tetanus antitoxin (Equine): should be used only if human immune globulin is not available and immediate passive immunization is required; can cause serum sickness if administered multiple times since it is a heterologous serum (from another species)

3) Tetanus immune globulin (human): passive immunization in patients with no prior history of active immunization; provides instant immunity but antibody half-life is 3 weeks; should not be used alone; should not be given to previously immunized patients bc expensive + unnecessary

4) Non-immunized: Administer tetanus immune globulin (human) + tetanus toxoid at same time in different sites

Immunized: N/A if they received booster w/in last 5 years, tetanus toxoid if they have not


Describe the steps in the response to an extracellular microbe

1) Activation --> C3 cleaved to C3b
2) C3b opsonizes pathogen to facilitate uptake
3) C3b binds other serum proteins to create complement complexes that increase C3 and also C5 breakdown --> can also form membrane attack complex
4) C3a and C5a attract phagocytes -- first neutrophils and then macrophages in tissues (then more come from circulation within 12+ hours(
5) Macrophages release IL-12 which activates pro-inflammatory NKCs, CD8 T cells
6) NKCs release IFNgamma which further activates macrophages
7) Macrophages release cytokines e.g. TNF alpha, IL 1,6,12
8) Dendritic cells recognize pathogen via PRR and mature --> act as APC and present antigen via MHC/TCR binding


What is the function of the Major histocompatability complex (MHC) molecules?

MHC = set of cell surface proteins that allow T cells (adaptive immune system) to recognize foreign molecules; bind pathogen peptide fragments after the pathogen has been ingested by macrophage or dendritic cell --> creates antigen-MHC complex "tag" on cell surface for recognition by T cells

MHC molecules do not discriminate between self and pathogen peptides --> present all of them bc peptides are the limiting factor --> it is T cells who mediate self vs non-self

*Major genetic association with MHC genes and devlpt of autoimmunity*


What are the differences between Class I and II MHC molecules in terms of:
A) Structure
B) Function
C) Locations expressed
D) Types of antigen peptides processed
E) Types of pathogens targeted

MHC I: A) Structure - heterodimer of heavy alpha chains and light beta2 chains; B) Function - attract CD8 killer T cells to kill infected cells; C) Expressed in all nucleated cells; D) Endogenous antigens - presents peptides synthesized in the cell; E) Targets mostly viruses

MHC II: A) Structure - heterodimer of heavy alpha and beta chains (alpha/beta binding domain); B) Function - attract CD4 helper T cells; C) Expressed in APCs (B lymphocytes, dendritic cells); D) Exogenous antigens - presents peptides from proteins phagocytosed and degraded in endosomes; E) Targets bacteria, parasites


1) Describe peptide binding by MHC molecules and motifs

2) Describe differences bw I and II in terms of:
A) binding domain
B) binding groove
C) length of peptides bound

1) MHC molecules unstable without bound peptide; binding restricted to anchor residues -- which remain constant; all the other peptide residues can vary; motif -- relationship between peptide sequence and MHC allele it binds --> helpful for predicting epitopes in Class I but not II

2A) Binding domain: alpha1/2 in Class I, alpha1/beta1 in Class II
B) Binding groove: Closed in Class I, open in Class II
C) Length: shorter (7-10 AA) peptides in Class I, longer (12-24 AA) in Class II


Describe the role of polygenicity and polymorphism in MHC molecules and its implication

HLA = MHC genetic locus in humans on Chromosome 6; contains >200 genes that encode proteins involved in antigen processing/presentation

Polygenic: contains several different MHC genes that together produce range of phenotypic variation; Class 1: A, B, C; Class II: DR, DP, DQ

Polymorphism: multiple alleles for each MHC gene e.g 195 alleles for Class 1 A gene --> binds peptides with different motifs

Implication: A) Diversifies immune response --> allows MHC binding to any peptide generated within in cell --> can alert immune system to every possible pathogen that enters body EVEN if pathogens mutate to avoid detection B) Every individual has unique haplotype (combination of MHC alleles) --> different set of MHC molecules with different binding specificities

*Do HLA typing to determine compatibility prior to transplant - given for A, B, and DR (since they have greatest # alleles)


Outline the MHC Class I pathway

1) Pathogen in cytoplasm (e.g. virus) produces protein
2) Protein eventually degraded
3) Transporters (TAP acts as membrane pore, Tapasin (makes sure only high affinity peptides presented) bring protein to the ER; ERAP trims peptides
4) MHC Class I binds peptide in the ER --> exocytosed out of cell and moves to cell surface
5) Antigen-MHC complex bound by CD8 T cell


Outline the MHC Class II pathway.

1) Protein antigens phagocytosed by APC into endocytic vesicle
2) Processed in endosome/lysosome
3) Class II MHC transported from ER into endosomes, facilitated via invariant chain (prevents premature binding)
4) HLA-DM removes CLIP from peptide binding groove (makes sure only high affinity peptides presented) --> Class II MHC binds peptide in the endosome
5) Antigen-MHC complex exocytosed out of cell to the cell surface
5) Complex recognized and bound by CD4 T cell


Describe MHC Class I cross-presentation and its implications

Dendritic cells endocytose viral infected cells and display these viral peptides to MHC Class I (even though Class I is usually for endogenously synthesized antigens)

Implication: essential for viral immunity --> way to signal to DCs there is a viral infection and initiate immune response through CD8 T cells, since most viruses do not infect DCs directly (e.g. are not intracellular pathogens)


Describe the function of the following Class 1b genes ("other") of the HLA genetic region:
1) H2-M3 (mouse)
2) MIC
3) HLA-G
4) HLA-E

Other/non-classical genes of HLA region have little polymorphism, many have unknown functions

1) H2-M3 (mouse): MHC Class 1b molecule that presents fmet peptides from bacteria

2) MIC: induced by cellular stress, important for areas where you need immune response but dont have DCs

3) HLA-G: expressed on fetus-derived placental cells that migrate into uterine wall; protect these cells from being killed by NKCs

4) HLA-E: inhibition of NKCs; if it is not there or downregulated--> cell is killed


1) Describe the main function of APCs

2) Describe function and expression of Class II MHC and costimulators of the following APCs:
A) Dendritic cells
B) Macrophages
C) B lymphocytes

1) Function of APCs: break down antigen peptides and display MHC-antigen complex to T cells --> initiate adaptive immune response through costimulation

2A) Dendritic cells: constitutive expression of Class II MHC; constitutive expression of B7 costimulators increased by maturation, induced by IFNgamma; activate naive T cells --> clonal expansion and differentiation into effector T cells

2B) Macrophages: low expression of Class II MHC; only interacts with effector T cells, NOT naive T cells --> kill phagocytosed pathogens (Cell-mediated immunity)

2C) B cells: constitutive expression of Class II MHC increased by IL-4; CD40 costimulators induced by T cells and antigen receptor cross-linking; only interacts with effector T cells, NOT naive T cells --> differentiates into plasma cells that produce antibodies (humoral immunity)


Describe the differentiation of naive T cells

Naive T cells see MHC-antigen peptide complex presented by DC and recognizes it as foreign --> clonal expansion and differentiation into either memory cells or effector cells --> effector T cells + antibodies persist for weeks after exposure (protective immunity)

immunological memory: on second exposure to antigen, memory T cells can rapidly differentiate into effector cells + more memory cells

*T cells recognize linear peptides only, only cell-associated (not soluble)*


Describe T cell activation and inactivation

1. Activation

Signal 1: TCR must recognize and bind to HLA-antigen complex on APC (ONLY Dendritic cell can activate naive T cell)

Signal 2: Costimulation; most important is CD28 on T cell binding to B7 1/2 (CD80/86) on DC; costimulatory molecules upregulated by activated APCs

2. Inactivation

CTLA-4 upregulated on T cells post activation --> binds with B7 on APC with higher affinity than CD28 --> inhibitory signals (dont know exact mechanism)


Explain peripheral T cell tolerance

T cell anergy (unresponsiveness) when T cells bind antigen in the absence of costimulatory signals (Signal 1 w/out Signal 2)

*one reason that tumors are hard to clear, since there is no upregulation of costimulatory molecules e.g. B7


Explain the therapeutic purposes of enhancing and blocking CTLA4

1) Enhancing CTLA4 through injected fusion protein CTLA-4-Ig (abatacept, beletacept)--> outcompetes CD28 to bind to B7 and blocks Signal 2 --> T cell becomes anergic --> prevents autoimmunity

2) Blocking CTLA4 activity through inhibition with antibody YERVOY --> prevented from binding B7 to inhibit the cell --> T cell remains active --> used to treat tumors (e.g. melanoma) though patients can experience autoimmunity


What are the components of the TCR complex?

Describe binding of MHC-antigen complex by T cell

1) Complex of proteins: T cell receptor (TCR) + CD3 co-receptors + zeta chain

signaling capacity is through ITAM motif on the intracellular tails of the CD3 molecules + zeta chain

2) TCR complex clusters within membrane lipid rafts upon peptide-MHC recognition--> TCR co-receptor CD4/CD8 binds to MHC and activates Lck protein --> Lck phosphorylates ITAMs --> ZAP-70 binds to the phosphorylated ITAMs --> stimulates multiple cascades including calcineurin --> calcineurin activates NFAT -- goes into nucleus and promotes production of IL-2 --> IL-2 promotes further differentiation of T cells


Describe the following subsets of CD4 T Cells including what pathogens induce them, signature cytokine, function, and role in diseases:
1) TH1
2) TH2
3) TH17

1) TH1: induced by intracellular microbes; produces IFNgamma (inhibits TH2) and IL-2 (T cell differentiation); involved in macrophage activation and IgG class-switching; role in autoimmune diseases

2) TH2: induced by extracellular helminths e.g. worms; produces IL-4 (B cell differentiation), IL-5 (B cell differentiation + induces eosinophils), IL-10 (inhibits TH1), IL-13 (alternative macrophage M2 activation); involved in mast cell activation and production by B cells; role in IgE class-switching /allergic response

3) TH17: induced by extracellular bacteria + fungi; IL-17A,17F,22 cytokines: involved in inflammation and neutrophil response; role in organ autoimmunity


1) What are tregs and how are they formed?
2) What is their function and mechanism of action?
3) How do tregs relate to IPEX?

1) treg = regulatory T lymphocytes, formed from CD4+ T cells in thymus that recognize self too well

Express FoxP3 transcription factor and require IL-7 (B and T cell survival signal), IL-2, TGFbeta

2) Functions: inhibit activation of naive T cells + inhibit T cell effectors --> used to prevent autoimmunity by shutting down T cell response when self antigen is recognized

Mechanism of action: potentially multiple, don't know how they actually work --> could release inhibitory cytokines, granzyme B, sequester IL-2, peripheral immune suppression of self-reactive cells

3) IPEX - autoimmune disease with DM1 and death by age 2 due to Foxp3 mutation; many autoimmune diseases could be due to treg mutation/resistance


Describe how T cell development allows TCRs to work with an individual's unique combination of MHC Class I and II molecules

T cell development (from hematopoietic stem cells in thymus): Of all TCRs --> positive selection (pick out T cells with useful TCRs that interact with your MHC molecules) --> negative selection i.e. central tolerance (eliminate the T cells that have too high MHC-peptide affinity and would cause disease)

complicated process of genetic rearrangements, differentiation, maturation, etc.

T cell recognition of self peptide-MHC complex necessary for selection


Describe the mechanism and function of bone marrow transplant.

Function: cure for leukemia and other cancers, doesnt require immunosuppressive rugs

Mechanism: Irradiate and kill all cells of the immune system --> replace with bone marrow from a donor to reconstitute the immune system --> mismatched genotype bw epithelial (host) and immune cells (donor)

age has major impact on survival -- decreases post 40 years


Describe the structure of the antibody/immunoglobulin molecules, including:
A) subunits
B) molecular domains in each subunit
C) the function of each domain

A) Subunits: 2 identical heavy chains and light chains (allelic exclusion) bound by disulfide bonds

B) Domains: Light chain has 2 (constant CL and variable VL) and heavy chain has 4 (constant CH1, CH2, CH3 and variable VH) + hinge domain H

C) Constant domains - identical in all molecules of the same class

Variable domains - N-terminal domains; each domain has 2 regions: 3 hypervariable complementarity determining regions CDR (antigen-binding site) and framework regions FR (hold CDRs in place)

Paratope = 6 CDRs (3 from VL and 3 from VH)


Define polyclonal response

Large, complex antigen has several epitopes

Each epitope is bound by specific antibody that is produced by clone of plasma cells -->

multiple clones required to produce population of antibodies that can bind to different epitopes

*these antibodies can be from different classes*


Describe the following mechanism underlying antibody/immunoglobulin diversity:
1) Combos of heavy and light chains

One type of heavy chain IGH found on chromosome 14

Two types of light chains: IGL-lamda on chromosome 22 and IGL-kappa on chromosome 2

--> two types of antibodies: IGH + IGL-lambda and IGH + IGL-kappa


Describe the following mechanism underlying antibody/immunoglobulin diversity:
2) V(D)J somatic recombination

V(D)J somatic recombination - happens in every B and T cell during devlpt (bone marrow and thymus); Antibody genes complex are in gene segments

E.g. Heavy chain IGH gene complex consists of regions VH, D, JH, and CH which each contain multiple gene segments; Light chain gene complexes contain VL, JL, and CL

Of these gene segments, one is chosen randomly from each region and spliced to form exon --> RAG1 and RAG2 proteins create double stranded breaks through the segments + random insertion/deletion of nucleotides --> huge diversity of possible antibodies

*since T cells also use V(D)J --> As many TCRs as there are antibodies


Describe the following mechanism underlying antibody/immunoglobulin diversity:
3) Junctional diversity

RSSs (recombination signal sequences) flank the V, D, J gene segments --> recognized by VDJ recombinase enzymes --> recombination occurs at junctional segments; not precise so leads to duplication, deletion, mutation, etc.


Describe the following mechanism underlying antibody/immunoglobulin diversity:
4) Class Switch Recombination

Class switching is irreversible, takes place in B cells during germinal center response, only affects constant regions of the heavy chain gene

First antibody made is always IgM

VDJ segment (and thus variable region) stays the same, but DNA fragment excised from constant region of heavy chain--> creates new antibody e.g. IgG --> new isotope/class, which is determined by identity of the heavy chain (each class has different Fc region)


Describe the following mechanism underlying antibody/immunoglobulin diversity:
5) Alternative RNA splicing

Post-transcriptional splicing of the constant gene region of the heavy chain --> yields different products (secreted antibody or membrane BCR, IgM or IgD)

*product retains same idiotype (VDJ rearrangement of variable chain) and isotype (e.g. IgM, based on type of heavy chain)


Describe the following mechanism underlying antibody/immunoglobulin diversity:
6) Somatic hypermutation

Takes place along with class switching during germinal center response (the two together are called "affinity maturation")

programmed process of mutations to the variable regions of Ig genes --> allows immune system to respond to new threats over course of lifetime

also the reason why secondary immune response produces antibodies with higher affinity

problems lead to B cell lymphomas or other cancers


Describe the following mechanism underlying antibody/immunoglobulin diversity:
7) Genetic variation

Maternal and paternal chromosomes can have different numbers of constant and variable gene segments due to deletions/mutations


What are the differences between primary and secondary B cell humoral immune response?

Primary: IgM>>IgG, low antibody affinity and takes 10-14 days before Ig appears and only small amount Ig made, requires high dose of antigen, short duration

germinal center response happens so memory B cells, affinity maturation, isotope switching, etc.

Secondary: IgG>>IgM, high antibody affinity and takes 2-3 days before Ig appears and large amount made; requires low dose of antigen and long duration --> Secondary immune response is "bigger, better, faster"


Describe the 4 functions of antibodies in the humoral immune response:
1) neutralization
2) opsonization
4) complement activation

Humoral immune response = antibody-mediated --> Destruction of extracellular pathogens and prevention of spread of intracellular infections

Function of antibodies:
1) neutralization - blocks binding of pathogen
2) opsonization - microbe tagged and bound to Fc receptor on phagocyte--> phagocytosed
3) ADCC - antibodies recruit cytotoxic NKCs via Fc receptors--> infected cell is killed
4) complement activation - activate through classical pathway --> more opsonization by C3b, inflammation via C3a and C5a, forms membrane attack complex that kills pathogen via osmotic lysis (poking holes)


Describe B cell development in the bone marrow including checkpoints and selection

Bone marrow (Stromal cells in marrow provide development signals): hematopoietic stem cell --> immature B cell

Checkpoint 1: after heavy chain is arranged, put preBCR on cell surface with surrogate light chain to see if there is tonic signal; otherwise, cell is killed via apoptosis

Checkpoint 2: real light chain binds to heavy chain --> see if there is tonic signaling from assembled BCR; otherwise, cell killed via apoptosis; If checkpoints passed --> immature B cells goes into the blood

Selection: via central tolerance in the bone marrow to remove self-reactive (v high affinity) B cells via apoptosis (Extrinsic Fas/FasL binding pathway); some cells get a second chance via receptor editing

Some self-reactive B cells that escape negative selection in the bone marrow are inhibited by Bregs (mechanism unknown)


Describe B cell activation via T-dependent vs T-independent antigens and the signals required

B cell activation takes place in secondary lymphoid organs e.g. spleen, lymph nodes (where they come into contact with antigens)

Signal 1 for both types is crosslinking of BCR, assisted by complement system

1) T-dependent antigens: protein antigens that cannot produce antibody responses in humans without T cells;

BCR binds TD antigen --> antigen take up and degraded --> presented on follicular B cells with MHC II --> recognized by CD4 T Cells --> Signal 2 = CD40 (B cell) + CD40L (T cell) linkage; results in high-affinity Ab and long-lived plasma cells

2) T-independent antigens: bacterial antigens that induce antibody response no matter what; usually contain repetitive patterns that crosslink BCRs on B1B or marginal zone B cells; Signal 2 = TLR activation; results in mainly IgM and short-lived plasma cells


Describe consequences of B cell activation

1) survival signals for increased survival and proliferation

2) Increased expression of B7 costimulatory molecule --> in order to activate more T cells

3) Secretion of cytokines e.g. IL-4 --> differentiation of B cells

4) Increased migration of B cells towards T cells --> in order to activate more T cells


After B cell activation, describe B cell maturation in the periphery and germinal center response

Immature B cell activated by antigen on CD4 T cell matures, travels through circulation to spleen/lymph node, and forms germinal centers --> clonal expansion

Germinal center response (in T dependent antigens):

-affinity maturation (somatic hypermutation of variable region via AID enzyme and then selection of B cells with higher affinity receptors, others die off) *unique to B cells* --> higher affinity antibodies

- isotype/class switching (isotype is based on constant region of heavy chains, also mediated by AID enzyme)

-differentiation into either memory B cells or long-lived plasma cell (churns out Ab)


Describe the B1 and B2 subsets of B cells

B1 in fetal liver --> matures into B1B cells --> mediate T-independent response, short-lived plasma cells that make IgM (natural antibodies) that act as first line of defense

B2 in bone marrow --> mature into B2B cells --> either follicular B2B (produce most antibodies, mediate T dependent response) or marginal zone B2B cells (facilitate T-independent response)

Other type of B cells: regulatory B cells, similar to tregs in that they shut down responses


Describe the sequence of events in acute inflammation, including:
1) Trigger
2) Recognition
3) Recruitment
4) Removal
5) Regulation
6) Repair/resolution

1) Trigger: trauma, immune reactions, anaphylatoxins (C3a, C5a), tissue necrosis, foreign bodies

2) Recognition: TLRs --> binding leads to transcription, production, activation, and release of inflammatory cytokines; Inflammasome --> activates caspase 1 --> activates IL-1B

3) Recruitment of neutrophils to extravascular space/site of tissue damage: Margination (accumulation on vascular surface) --> rolling (neutrophils roll on endothelial surface by binding/detaching to selectins- expression of which are upregulated by cytokines) --> adhesion mediated by integrins (ICAM/VCAM) - expression of which are upregulated by cytokines --> extravasation via diapedesis --> neutrophils move towards infection site via chemotaxis (chemical gradient)

4) Removal of agent: Activated neutrophils phagocytose particles (opsonization via Fc receptors on IgG, engulfment, and ROS killing) + secrete more cytokines

5) Regulation of response: Neutrophils dominate for first 24 hours then apoptose, replaced by monocytes/ macrophages, which phagocytose neutrophils that have broken apart

6) Repair: Ultimately, cells exit and tissue bed restored to original state


What are the 5 cardinal signs of acute inflammation?

1) Rubor - redness

2) Calor - heat

3) Tumor - swelling

4) Dolor - pain

5) Functio laesa - loss of function


What are the vascular changes that occur during acute inflammation? How does it connect to the cardinal signs?

Recognition of injury: Mast cells IgE receptor activated and release granules that contain various inflammatory agents (e.g. histamine), also release cytokines + eicosanoids

1) Histamine --> Arteriolar vasodilation --> increased blood flow --> leads to redness (erythema) and warmth

2) Histamine --> Increased vascular permeability (due to retraction of endothelial cells) --> protein + fluid moves into interstitial space (EXUDATE) --> Edema

3) Increased blood viscosity --> stasis (small vessels packed with RBCs) --> margination (neutrophils accumulate along vascular endothelial surface)


Describe the roles of the following cell-derived mediators of inflammation:
1) ROS
2) NO

1) ROS: synthesized via NADPH oxidase in lysosomes to kill ingested pathogens, but can also cause injury

2) NO: cytotoxic agent in activated macrophages; also leads to vasodilation


1) What is the pathology of chronic granulomatous disease CGD?
2) What is the difference between immune and foreign body granulomas?

1) Leukocytes lack NADPH oxidase --> no H202 generated --> decreased oxidative burst --> pathogens are not killed --> recurrent, life-threatening infections

see granulomas as a sign of chronic inflammation (contain giant cells due to macrophage fusion)

2) Immune granulomas: caused by insoluble particles inducing cell-mediated immune response

Foreign-body granulomas: e.g. splinter


Describe the features of chronic inflammation

Irreversible tissue changes initiated by parenchymal cell death due to prolonged inflammatory response

1) infiltration of mononuclear cells (mostly macrophages but also lymphocytes, plasma cells)

2) tissue destruction

3) attempts at healing: Angiogenesis (growth of new blood vessels) and fibrosis (production of new connective tissue) --> scarring


What are the systemic effects of inflammation i.e. acute phase response?

Mediators are TNF, IL-1, and IL-6 released by leukocytes in response to pathogen (e.g. bacterial LPS)

1) Fever due to prostaglandins e.g. PGE2 (give NSAIDs to reduce fever)

2) Increased levels of C-reactive protein CRP (track levels of CRP as biomarker of inflammation), fibrinogen

3) leukocytosis = increase in WBC (due to accelerated release from bone marrow --> immature cells enter blood --> "left shift")


Describe the two types of tissue repair:
1) Regeneration

2) Scar formation

Whether regeneration or scarring depends on whether cell tissues are labile, stable, or permanent and whether framework is intact or destroyed

1) Regeneration (labile/stable cells with framework intact): proliferation of uninjured cells and replacement of stem cells, induced by growth factors e.g. VEGF

2) Scar formation: EGF leads to specialized granulation tissue + VEGF leads to increased number of new bv --> fibroblasts migrating and laying down ECM (collagen) --> fibrosis


What are cytokines and their function

Cytokines: signal proteins that bind to membrane receptors to coordinate communication between cells; v potent molecules produced in v small amounts for v short periods of time

Immune functions:
1) formation of immune system --> proliferation, differentiation

2) Homeostasis --> targets cells to immune tissues

3) Response to infections/inflammation


Define pleiotropy and redundancy as it relates to cytokines

1) Pleiotropy: 1 cytokine can have multiple and different effects on a single cell type, depending on time of exposure and concentration of cytokine; different cell types respond differently to 1 cytokine

2) Redundancy: Different cytokines can have same/overlapping effects --> backup system so we do not rely on a single gene product


How do chemokines differ from other classes of cytokines?

What is the nomenclature for chemokines and significance of CCR5

1) Chemokines are a subset of cytokines and:

- are smaller
-signal through G protein coupled receptors (not kinase-coupled receptors as with other cytokines)
-are chemotactic --> attract cells to site of inflammation and attract circulating lymphocytes to secondary lymphoid organs (e.g. T cells to APCs, B cells to follicles)
-modulate cell adhesion

2) Nomenclature: based on pattern of cysteines in the structure; 1 or 2 cysteine bridges --> CCLx, and receptor is CCRx

3) Need CCR5 chemokine receptor binding WITH CD4 binding for HIV infection --> research into inhibiting CCR5 binding for HIV therapy


Describe Type 1 Interferons including activation and 3 antiviral effects

Type 1 Interferons: IFN alpha and beta (NOT gamma) -- generally co-expressed; Activation: IFN binds to IFNAR receptor --> stimulates Jak-STAT pathway

Effects: 1) Paracrine: bind to neighboring cells and induce protein synthesis --> cells become more resistant to viral infection (direct antiviral effect)

2) Autocrine: feedback onto viral infected cell to induce apoptosis

3) Stimulate cells of innate and adaptive immune system --> increased Class I MHC presentation; maturation of dendritic cells + Class II MHC/HLA upregulation; stimulate B cells to produce more antibodies


Describe the Jak-STAT signaling pathway and which cytokines use this pathway

Cytokine binds to receptor --> receptor dimerizes and activates Jak--> Jak phosphorylates tyrosine residues of receptor + STATs --> STATs dimerize and translocate to nucleus --> binds to promoter region --> induces transcription of proteins

Used by Type 1 interferons IFN alpha/beta, IL-10 (inhibits Th1), IL-2, and IL-4/5

*IL-2 (T cell differentiation) and IL-4 (B cell differentiation) both have gamma common chain subunits


1) Name major pro-inflammatory cytokines

2) Describe functions

3) Name potential deleterious effects

4) What is the major transcription factor in the pathway?

1) TNF, IL-1, and IL-6; produced by leukocytes (macrophages)

2) Functions: promote acute inflammations to fight infection (activate neutrophils, destroy harmful agents) and repair damage locally; initiate and coordinate defenses

3) High levels can cause fever, shock, death; chronic levels can cause weight loss, loss of connective tissue/bone

4) NFkB


1) Hypertrophy
2) Hyperplasia
3) Atrophy
4) Metaplasia
5) Autophagy

1) Hypertrophy: non-dividing permanent cells get bigger (e.g. CNS, muscle)

2) Hyperplasia: new cells from proliferating mature cells as well as stem cells

3) Atrophy: decrease in size (both in cell number and size) due to stress, disuse, decreased nutrients or hormones

4) Metaplasia: adverse environment leads to reversible change in cell type through reprogramming of stem cells e.g. Barrett's esophagus (SES --> simple columnar with goblet cells)

5) Autophagy: lysosomal digestion of cellular components due to nutrient depletion


Describe the cellular morphology of reversible vs irreversible injury

Reversible injury: cellular swelling (failure of ion pumps - due to hypoxia) and fatty change (lipid vacuoles in cytoplasm); mt swelling, plasma membrane blebbing, chromatin clumping

Irreversible injury (Necrosis): inability to reverse mt dysfunction, disturbance in membrane functions, karyolysis (nuclear fading), pyknosis (nuclear shrinkage), karyorhexis (nuclear fragmentation)

dead cells replaced by myelin figures --> degraded into fatty acids --> become calcified


List 6 mechanisms of cell injury

1) ATP depletion - due to hypoxia, mt damage, toxins

2) Mt damage --> necrosis (hypoxia, toxins) or apoptosis (leakage of pro-apoptotic proteins)

3) Release of Ca2+ from mt, SER, or extracellular--> mt damage, nuclear damage, ATP depletion

4) Increased ROS due to oxidative stress --> DNA mutations, membrane damage, protein misfolding

5) membrane damage - plasma, mt, or lysosome --> necrosis

6) protein misfolding/DNA damage --> ER stress --> apoptosis (e.g. Alzheimer's, Huntington's, Parkinson's)


List the differences between apoptosis and necrosis

What is necroptosis?

Apoptosis: requires ATP, often physiologic, plasma membrane intact, cell shrinks, no leakage --> no inflammation; leads to apoptotic body that is phagocytosed

Necrosis: passive (no ATP), always pathologic, plasma membrane disrupted, cell swells, no phagocytosis, leakage --> inflammation

Necroptosis: genetically programmed (like apoptosis) but no caspase activation --> TNFR1 recruits RIP1 and RIP3


Describe the two pathways of apoptosis:
1) Intrinsic

2) Extrinsic

1) Intrinsic: Cell injury (DNA damage, no growth signals, misfolded proteins)--> inhibits Bcl2 in mt membrane and activates BH3 sensors --> Activate Bak/Bax --> create pores in mt --> caspase cascade --> executioner caspases --> apoptosis

2) Extrinsic: Fas/TNFR ligand binding --> receptors cross linked --> bind adaptor proteins via death domain FADD --> recruit caspase 8 --> executioner caspases --> apoptosis


What are the 4 types of abnormal intracellular accumulations?

1) Abnormal metabolism --> fatty liver due to alcoholism, protein malnutrition

2) Antitrypsin mutation --> defect in protein folding --> abnormal protein accumulation

3) Enzyme mutation --> storage disease e.g. LSDs --> accumulation of endogenous material

4) Ingestion of indigestible materials --> accumulation of exogenous materials e.g. carbon, silica


Describe the following types of necrosis:
1) Coagulative
2) Liquefactive
3) Gangrenous
4) Caseous
5) Fat

1) Coagulative: underlying tissue architecture preserved; characteristic of infarcts

2) Liquefactive: CNS infarcts, bacterial/fungal infections destroy tissue and turn into liquid mass

3) Gangrenous: ischemic limb that undergoes coagulative necrosis through several tissue layers; "Wet" =liquefactive due to bacterial infection

4) Caseous: due to tuberculosis; tissue architecture obliterated, surrounded by granuloma inflammation

5) Fat: due to release of activated lipases, can see outlines of necrotic fat cells --> can see calcifications


Describe the ABO blood system including:
1) Antigens and production
2) Antibody, production, mechanism of action
3) Blood type (genotype) --> antigens on RBCs + Ab produced

1) Antigens are located on the RBC membrane; h antigen --> H --> A (if you add galNac) OR B (if you add galactose)

2) Antibodies are in the plasma; they are IgM, T-independent, natural Ab--> make antibodies to antigens we do not express, produced against similar structures in intestinal bacterial microbes (by 9 mos)--> destroy RBC in blood stream (intravascular hemolysis)

3) A (AA or AO) --> A antigen + Anti-B antibodies

B (BB or BO) --> B antigen + Anti-A antibodies

AB (AB) --> A and B antigens + No antibodies

O (OO) --> H antigen + Anti-A and Anti-B antibodies


Describe the genetic and immunological basis of the Bombay-O blood type

Explain how individuals of this blood type can be identified.

Bombay-O: do not have the enzyme to convert h --> H antigen --> RBCs have anti-H antibodies --> will have transfusion reaction if they receive Type O blood

Appears as Type O, recognize bc anti-H Ab in blood sample will agglutinate Type O RBCs


Describe rules of whole blood transfusion under non-emergency conditions

Describe transfusion under emergency conditions

Whole blood contains antigens and antibodies --> donor and recipient blood types should be identical

Under emergency conditions - can use O, Rh- RBCs (contain no antigens)


Describe Rh system including:
1) Antigen involved
2) Antibody production, mechanism of action
3) How Rh incompatibility relates to fetal hemolytic disease (i.e. hydrops fetalis)
4) Treatment for fetal hemolytic disease

1) Rh0/D antigen --> Rh+ (DD or Dd) have it, Rh- do not (dd)

2) Antibody produced by Rh- on exposure to Rh+ blood; Ab are IgG and can cross placenta, opsonize RBCs and stimulate phagocytosis (Extravascular hemolysis via Fc gamma receptors)

3) Rh- mother exposed to Rh+ positive cells during first birth --> makes Anti-Rh+ antibodies

subsequent Rh+ fetus --> secondary immune response --> anti-Rh+ IgG crosses placenta and kills fetal RBCs --> fatal hemolytic disease

4) Mother given Rhogam antibody (anti-Rh+ immune globulin) before/after birth --> destroys fetal RBCs before they can trigger maternal immune response; high Ab levels lead to feedback immunosuppression of B cells


Describe agglutination. Which antibodies can be detected via agglutination?

If RBC has antigen on surface --> IgM antibody can bind several RBCs at once --> forms latticework = agglutination

IgM (ABO) can agglutinate bc they are pentamers --> big enough to bridge zone of repulsion between large, (-) RBCs

IgG (Rh, other minor blood groups) are not big enough


Describe the two tests for non-agglutinating antibodies incl when you would use them:

1) Direct Coombs' test (DAT)

2) Indirect Coombs' test (IDAT)

1) DAT: detects antibodies that are bound to RBCs but cannot agglutinate them; used to test for bound IgG, diagnose autoimmune hemolytic anemia

Add Coombs reagent (anti-IgG antibody) --> these antibodies bind to the Fc portion of the RBC antibody --> link RBC antibodies together --> RBCs agglutinate

2) IDAT: detects antibodies in patients plasma that have not yet been bound; use to detect anti-Rh+ ab in mother's serum (maternal-fetal Rh incompatibility)

Add RBCs with antigen of interest (e.g. Rh+) to patient's plasma serum --> if there are anti-D antibodies, they will bind to the RBCs but not agglutinate --> then add Coombs reagent (anti-IgG antibody) --> RBCs will agglutinate

*Coombs reagent produced by immunizing animals with human antibodies and isolating the anti-human antibodies*


1) Describe multiple myeloma.
2) How is it detected on electrophoresis?
3) How do you determine which isotype (IgG, IgA, IgM, etc) is elevated?

1) Multiple myeloma - malignancy of antibody-producing plasma B cells; most common lymphoid malignancy and usually happens in older patients

multiple=multiple tumor cells by the time condition is detected; myeloma=tumors formed in bone marrow where plasma B cells live

2) spike in gamma band which represents the excess of one type of antibody --> monoclonal gammopathy; does NOT show which particular class is elevated

can be heavy chain secretion or light chain secretion (bence-jones proteins in urine)

3) Immunofixation : separate proteins on strips and flood strip with antibodies specific for particular class e.g. IgA --> if antibody binds, precipitate forms and electrophoresis band widens


Differentiate pharmacodynamics and pharmacokinetics

Pharmacodynamics: effect of a drug on the body-- interactions between receptors and inhibitors/activators

Pharmacokinetics: effect of the body on a drug --> in terms of absorption, metabolism, elimination; determines therapeutic efficacy and duration of action


Describe the limitations of pharmacological uses of biologic cytokine inhibitors compared to traditional DMARDS e.g. methotrexate

Biologics = engineered antibodies
-injection site reactions - cant be given orally; need to be given subcutaneously, via IV
-cytopenias with anti-TNF therapy --> monitor CBCs
-cost --> biologics (large proteins) are v expensive bc they are tailored

On the other hand, methotrexate and leflunomide are DMARDs (Disease modifying anti-rheumatic drug): inhibit DHFR --> less targeted immunosuppression by preventing lymphocyte proliferation --> oral pill, less expensive


What is the difference between chimeric and humanized antibodies?

Chimeric - part of the variable region of the antiobdy is from another species e.g. mouse; "xi" in generic name

Humanized - as many portions of the mouse variable region have been converted to human sequence to minimize immune response; "mu" in generic name


List clinical use and mechanisms of the following:
1) anti-TNF alpha agents (biologic)
-etanercept (ENBREL)
-infliximab (Remicade)
-adalimumab (Humira)

Anti-cytokine therapy used to treat autoimmune diseases of chronic inflammation (RA, IBD, lupus)

1) Anti-TNF alpha agents used to treat RA

etanercept (ENBREL) - binds TNF via TNF receptors attached to Fc portion of IgG1 --> neutralizes biological activity

infliximab (Remicade) - chimeric monoclonal antibody --> reduces blood levels of TNF alpha; also treats Crohn's

adalimumab (Humira) - humanized monoclonal antibody --> complexes with soluble TNF alpha and inhibits


List clinical use and mechanisms of the following:
2) IL-1 inhibitors
-anakinra (Kineret)

2) IL-1 inhibitor used to treat RA

anakinra (Kineret) - IL-1 receptor antagonist, endogenous protein --> blocks cellular effects of IL-1

Not widely used bc has to be injected daily; can be given with methotrexate but not the anti-TNF agents


List clinical use and mechanisms of the following:
3) B cell inhibitors
-belimumab (Benylsta)

3) B cell inhibitor used to treat lupus

belimumab (Benylsta) - monoclonal antibody to BAFF (B cell activating factor/survival signal) --> reduces excess levels of BAFF that lead to inflammation


List the following lymphoid tissues and what happens there:
1) Primary
2) Secondary
3) Tertiary

1) Primary (where lymphocytes are produced): bone marrow, thymus

2) Secondary (where B and T cells are found together and interact with APCs): Peyer's patches - defends mucosa, spleen-- defends blood, lymph nodes- defends tissue fluids

3) Tertiary: transient aggregations, can occur anywhere


Describe the histology of the bone marrow and role of hematopoietic stem cells

Bone marrow: B and T cells born in the stromal cords, get into circulation via vascular sinuses; both arise fro hematopoietic stem cell --> B cells mature in marrow and are sent straight to secondary lymphoid tissues; T cells mature in the thymus


Describe structure and function of thymus

Describe process of T cell maturation

1) Thymus: bilobed, distinct cortex and medulla, NO B nodules or reticular fibers

Contains endodermally derived epithelial reticular cells (ERCs, found ONLY in thymus, aggregate into Hassell's corpuscles in the medulla) --> promote maturation of T cells along with macrophages (which remove failed recruits) and DCs --> maturation occurs as the T cells migrate through the thymus

2) T cells enter through HEV, start in subcapsular zone (CD4-/CD8-) and migrate through cortex (CD4+/CD8+) --> learn self from non/self and mature --> become either CD8+ or CD4+ by the time they reach the medulla and exit --> secondary lymphoid tissues

*need 5 layer blood:thymus barrier to keep antigens out of cortex and getting into contact with maturing cells (medulla doesnt need specialized barrier bc T cells are already mature)


Describe the structure of the lymph node and where immune cells are located. How do lymphocytes get into the nodes?

Lymph node: macrophages and DCs attach to Type II collagen reticular fibers and monitor lymph

B and T cells are both in the cortex: T cells are in paracortex; B cells segregate into primary follicles in the cortex near the subcapsule--> become secondary and develop germinal center when exposed to antigen

Lymphocytes carried in through afferents; majority squeeze through epithelium of high endothelial venules (HEVs) --> then hop onto reticular fibers to travel throughout node


Outline flow of lymph through the lymph node

Flow: afferent lymphatics pierce lymph node capsule to deliver lymph -->

subcapsular sinus (unique to lymph node) -->

lymph passes through cortex and then medulla (opportunities for interactions bw antigens in lymph and immune cells in the node!) -->

lymph exits from hilus via efferent lymphatic -->

returns to circulation via thoracic duct or right lymphatic duct


Describe the histology of the following secondary lymphoid tissues:
1) palatine tonsil
2) Peyer's patches
3) spleen

B and T cells segregated

1) Palatine tonsil: antigen exposure through SSE epithelial crypts that extend through the tonsil; starry night appearance due to macrophages

2) Peyer's patches: in ileum, covered by specialized follicular epithelial incl M cells which take up antigen via transcytosis and deliver to immune cells

3) Spleen: has capsule but no cortex, medulla, afferent lyphatics; white pulp --> immune surveillance (T cells assemble into PALs that cover the artery, B cells are in follicles nearby); red pulp --> remove old RBCs that are slow moving from cord to splenic sinus


Describe how papain and pepsin proteases cleave antibodies and the fragments produced

1) Papain --> 2 Fab segments and 1 Fc segment

2) Pepsin --> 1 (Fab')2 segment + fragments of heavy chain

Fab = fragment antigen-binding region, composed of complete light chain and amino terminal of heavy chain, linked by disulfide bond

Fc = terminal parts of heavy chain constant region; responsible for antibody effector functions e.g. complement fixation, binding to cell membrane Fc receptors

(Fab')2 = 2 Fab fragments + additional hinge region


MHC Fun Fact

Women are most attracted to men whose MHC genes are very different from her own


T Cell Fun Fact

Doherty and Zinkernagal won the Nobel Prize for discovering how T cells recognise their target antigens through MHC proteins

Doherty was nonconformist and outsider

Zinkernagal failed at surgery before discovering interest


Antibodies Fun Fact

Paul Erhlich coined chemotherapy and magic bullet; co-win Nobel Prize for theory on body producing antibodies to combat pathogens


Histamines Fun Fact

Daniel Bovet won Nobel Prize for discovery of histamines


Interferon (cytokine) Fun Fact

Interferon was the subject of Flash Gordon comic in the 60s


Blood Fun Fact

In some Asian cultures, blood type is considered to be predictive of personality

A: creative and earnest

B: wild and selfish

AB: rational and indecisive

O: sociable and vain


What is AIRE and its function in regulating autoimmunity?

AIRE = autoimmune regulator gene that encodes TF (transcription factor) expressed in the thymus

Function: mediates transcription of ectopic genes --> turns on expression of peripheral antigens not normally expressed in thymus --> expands T cell repertoire --> key for mediating self/non-self and preventing autoimmunity

Mutations lead to autoimmune disease APS (failure of parathyroid, adrenal glands)


1) How do autoimmune diseases develop?
2) How does infection trigger autoimmunity?
3) How do drugs trigger autoimmunity?

1) We don't actually know -- usually arise spontaneously; tend to be chronic since trigger cannot be eliminated

Potential mechanisms: loss/resistance to tregs; normal self-antigens modified by drugs, environment, mutations; molecular mimicry

2) How infection triggers autoimmunity: A) molecular mimicry = exposure to pathogen v similar to self-antigen --> immune response against pathogen --> activated T cells and B cell antibodies cross-react with self-antigen

B) infection provides environment that promotes lymphocyte activation --> release of previously sequestered antigens which react with self-reactive T cells

3) How drugs trigger autoimmunity: A) Drug hypersensitivity= drug metabolite complexed with host protein, is reversible; B) drug interferes with peptide binding to MHC --> T cells see cell as non-self


What is the model for the development of rheumatoid arthritis?

What are treatment options?

RA = systemic autoimmune disease

Citrullination: Altered self due to enzymatic chemical conversion of arginine --> citrulline (has =0 instead of =NH)

T cell sees as non-self --> IgM and IgA autoantibodies directed against citrullinated peptides --> T cells and antibodies enter joints and cause tissue injury via cytokine production /inflammation --> destruction of tissue and bone

Treatment options: TNF inhibitors (etanercept), IL-1 antagonist (anakinra), anti-IL-17 antibodies, anti-B cell monoclonal antibody (rituximab)


Define the types of transplants:
1) Autologous
2) Syngeneic
3) Allogeneic
4) Xenogeneic

1) Autologous: transplant between locations in same individual

2) Syngeneic: transplant between genetically identical individuals e.g. identical twins

3) Allogeneic: transplant between different individuals of same species

4) Xenogeneic: transplant between different species


Which part of the immune system mediates transplant rejection? By which antigens?

Adaptive immune system --> graft rejection mediated by T cells; shows memory + specificity (cardinal features of adaptive system)

Major histocompatibility complex locus (HLA in humans)--> encodes the antigens that dominate transplant rejection

Each individual has a unique set of MHC I (ABC) and II (DR DP DQ) alleles inherited from parents --> donor MHC can appear to be self-MHC + foreign peptide complex--> direct allorecognition by host TCR via cross-reaction


Describe the direct and indirect pathways by which the immune response against transplants is initiated

1) Direct recognition: transplanted tissue contains DCs --> migrate out of graft into lymph nodes --> present alloantigens to CD8 T cells --> generation of alloreactive T cells that attack donor cells

2) Indirect recognition: donor MHC ingested by host DCs --> donor MHC processed and presented by self-MHC molecule --> recognized by CD4 T cells --> secretion of cytokines --> inflammation

In both pathways, DCs provide costimulation via B7


Describe the 3 immune mechanisms of graft rejection including timeline and which cells mediate the rejection:
1) Hyperacute
2) Acute
3) Chronic

1) Hyperacute: rejection occurs in minutes, mediated by circulating antibodies specific for donor antigens that are already present before transplantation (IgM Abs for ABO, MHC due to pregnancy, previous transfusion, etc.); not common bc of cross-matching

2) Acute: rejection occurs in days to weeks; mediated by T cells and Ab specific for alloantigens; use immunosuppressive therapy to block activation of alloreactive T cells

3) Chronic: rejection occurs over months to years; mediated by T cells that react against alloantigens --> secrete cytokines --> fibroblast and vascular SM proliferation --> fibrosis + arteriosclerosis; principal cause of graft failure


Discuss hematopoietic stem cell transplantation and what disease can result if it goes wrong

Hematopoietic stem cell (HSC) transplantation: Ablate recipient bone marrow --> injected HSCs

If mature allogenic T cells are transplanted along with the HSCs --> T cells can attack the recipient tissue --> Graft versus host disease (GvHD) --> scaling rash, jaundice, keratinocyte apoptosis

in most cases, host can recognize the donor T cells and kill them; BUT if host is immunosuppressed --> cannot destroy donor T cells --> death

SOLUTION: irradiate donor tissue to kill donor T cells


Type I Hypersensitivity:
1) Time course + examples
2) Important classes of Ab involved (if any)
3) Mechanism of damage
4) Symptoms e.g. skin lesion characteristics

Type I Hypersensitivity:
1) Time course: immediate (minutes); Atopy = allergic reaction- heightened immune response to allergen

2) Sensitization: TH2 activation --> IgE antibody --> binds to Fc receptor on mast cells and basophils

3) Mechanism: On secondary exposure: multivalent allergen binds to IgE and crosslinks (cannot be hapten/univalent antigen)--> degranulation of mast cells + production of eicosanoids --> release of inflammatory mediators (e.g. histamine) + chemoattractant for eosinophils

4) Symptoms: sneezing, coughing, itching, anaphylaxis (need epi pen); skin lesions have wheal (Swelling) and flare (Redness)


Type II Hypersensitivity:
1) Time course + examples
2) Important classes of Ab involved (if any)
3) Mechanism of damage
4) Symptoms e.g. skin lesion characteristics

Type II Hypersensitivity:
1) Time course: hours; transfusion rxns (ABO mismatch), fetal hemolytic disease

2) IgM or IgG binds to antigens on cell surface

3) Mechanisms: Opsonization (via IgG) and phagocytosis (via neutrophils or macrophages); activation of classical complement pathway; antibody-dependent cell-mediated cytotoxicity (ADCC) where NKCs recognize Ab bound to antigen and kill the cell (but do NOT phagocytize)

4) N/A


Type III Hypersensitivity:
1) Time course + examples
2) Important classes of Ab involved (if any)
3) Mechanism of damage
4) Symptoms e.g. skin lesion characteristics

Type III Hypersensitivity:
1) Time course: hours (like Type II); farmer's lung (localized), RA + lupus + serum sickness (Systemic)

2) IgG reacts with antigen to form immune complexes (Defective clearance of apoptotic nuclei)

3) Mechanism: Large insoluble complexes are phagocytosed, but small soluble complexes lodge in vessels and organs --> complement activation + mast cell degranulation --> C3a and C5a release inflammatory mediators and lytic enzymes and attract neutrophils --> inflammation and tissue necrosis

4) Arthus reaction (experimental rxn): localized vasculitis (wheal + flare) that takes hours to form due to deposition of immune complexes


Type IV Hypersensitivity:
1) Time course + examples
2) Important classes of Ab involved (if any)
3) Mechanism of damage
4) Symptoms e.g. skin lesion characteristics

Type IV Hypersensitivity (Delayed-type hypersensitivity):
1) Time course: 48-72 hours; contact hypersensitivity dermatitis (e.g. poison ivy), allergy to metals or other haptens, acute/chronic transplant rejection

2) N/A - mediated by antigen-specific TH1 cells

3) Mechanism: Secondary exposure: CD4 TH1 cells activated --> Secrete cytokines --> recruit macrophages

4) Symptoms: firm, red bump (induration + erythema) e.g. positive Mantoux test


Fun Fact: Poison Ivy

First European to describe poison ivy was Captain John Smith


Fun Fact: Serum Sickness

Clemens von Pirquet coined the term allergy, devised tuberculin skin test


Fun Fact: Bee Sting

Bee stings have been used in traditional Chinese medicine to cure disease; investigating now use in therapy for MS


How is histamine synthesized?

Where is it stored in the body?

How is it degraded

Histidine + (Decarboxylase) --> Histamine

Produced/stored in:
A) cytoplasmic granules in mast cells,
B) cytoplasmic granules in basophils (circulate in blood),
C) vesicles in enterochromaffin-like (ECL) cells (gastric mucosa),
D) vesicles in CNS neurons (use histamine as a neurotransmitter)

Degraded within 1 minute; primary pathway uses imidazole-N-methyltransferase and monoamine oxidase enzmes


Different mechanisms of histamine release:
1) Immunological release
2) Mast cell injury
3) Endocrine/neuronal stimulation
4) Chemical displacement

1) Immunological release (i.e. Type I Hypersensitivity): allergens bind to IgE Ab on surface of pre-sensitized mast cells --> crosslinking of Fc receptors --> degranulation

2) Mast cell injury: local release of histamine e.g. scratching your arm leads to redness/swelling

3) Endocrine/neuronal stimulation: rapid histamine exocytosis from the cytoplasmic vesicles in ECL cells or histaminergic neurons

4) Chemical displacement: Drugs that stimulate release of histamine without prior sensitization --> peptides displace histamine from granules


Describe the 4 types of histamine receptors including distribution and functions

1) H1: smooth muscle, endothelium, peripheral neurons; increases IP3 and DAG --> increased itching, pain, edema, bronchoconstriction, vasodilation via NO

2) H2: gastric mucosa, cardiac and vascular smooth muscle; increases cAMP --> increased gastric acid secretion, HR, vasodilation via cAMP

3) H3: presynaptic histaminergic neurons; decreases cAMP --> negative feedback on histamine release

4) H4: hematopoietic cells e.g. neutrophils, DCs, basophils, monocytes, T cells ; decreases cAMP --> differentiation of cells, chemotaxis, cytokine secretion


What are the systemic effects of histamine on the following systems:
1) Nervous
2) Cardiovascular
3) Respiratory
4) Digestive

1) Nervous: (peripheral) H1 induces depolarization of nerve endings in the skin --> itching/pain; (CNS) H1 and H3 involved in increased wakefulness, satiety, homeostasis

2) Cardiovascular: Vasodilation via H1 on endothelial cells (NO) and H2 on vascular smooth muscle (cAMP) --> "flare" (redness); H1 induces increased capillary permeability --> "wheal" (edema) and decreased BP --> reflex tachycardia

3) Respiratory: H1 induces contraction of bronchial smooth muscle

4) Digestive: H2 facilitates gastric acid secretion, H1 stimulates contraction of intestinal smooth muscle --> diarrhea


Describe pathophysiologic actions of histamine based on different routes of exposure to allergens:
1) Allergen inhaled through nose
2) Allergen inhaled into lungs
3) Allergen on skin
4) Allergen distributed systematically

1) Allergen inhaled through nose--> Allergic rhinitis (nasal congestion, runny nose, itchy eyes, sneezing); affects upper respiratory tract

2) Allergen inhaled into lungs --> allergic bronchospasm

3) Allergen on skin (topical or ingestion) --> urticaria (hives)

4) Allergen distributed systematically --> Anaphylaxis (severe bronchoconstriction, systemic vasodilation --> decreased BP and pulse) *antihistamines not effective in treating anaphylaxis bc many mediators, not just histamine, are released* USE EPI PEN


Describe the mechanism of action and uses of the following non-histamine receptor targeting drugs:
1) Cromolyn and nedocromil
2) Epinephrine
3) sensitization shots

1) cromolyn sodium and nedocromil block Ca2+ entry --> stabilize mast cell membranes and prevent mast cell degranulation --> reduce release of histamine; used to prevent asthma attacks (not helpful once attack is happening)

2) epinephrine --> agonist of beta and alpha adrenergic receptors --> bronchodilation and vasoconstriction --> counteracts bronchoconstriction and vasodilation

3) Sensitization shots: add blocking antibody (IgG) --> binds allergen and prevents IgE from binding to it and causing allergic reaction


Describe the general mechanism of histamine receptor blockers (antihistamines)

Differentiate between 1st, 2nd, and 3rd generation of H1 antihistamines incl therapeutic uses and side effects

Mechanism: inverse agonists --> bind to the inactive
conformation of histamine receptor --> used to treat hives, pink eye, itching (NOT asthma, anaphylaxis)

1) First Generation eg Benadryl, PBZ, promethazine, hyroxyzine + cyclizine (all OTC): neutral so readily enter CNS --> highly sedative and anti-vomiting, also used for treating insomnia, motion sickness; short acting - metabolized in liver via cyt p450; side effects: anticholinergic (dry mouth, blurred vision), drowsiness

2) Second generation e.g. cetirizine (Zyrtec), loratidine (Claritin), fexofenadine (Allegra): ionized so do not enter CNS --> no sedative effect; selective and longer acting (12-24 hrs); formulated with pseudoephidrine --> side effects include insomnia, increased HR

3) Third generation e.g. Xyzal, Clarinex: active versions purified for greater potency


Describe mechanism of action and effects of H2 antihistamines

H2 antihistamines e.g. famotidine (Pepcid *most potent*), cimetidine (Tagamet), ranitidine (Zantac)= treatment of gastric hyperacidity e.g. gastric ulcers, GERD

Blocks histamine release from ECL cell --> parietal cell not stimulated to release H+

Characteristics: hydrophilic so do not enter CNS, highly specific, work best at night; less effective than PPIs


Fun Fact: Cortisone

Cortisone discovered by Edward Calvin Kendall while at Mayo Clinic, received Nobel prize in 1950


Fun Fact: Aspirin

Aspirin was the first drug to be sold with child safety caps


Describe the biosynthesis and function of the eicosanoids derived from arachidonic acid

Eicosanoids: Arachidonic acid metabolites, located in every tissue

Membrane phospholipid --> phosphate group clipped off, released as omega 6FA arachidonic acid

if cyclo-oxygenase (COX) acts on arachidonic acid --> prostaglandins PGs (vasodilation) + thromboxanes TXs (vasoconstriction) *PGs + TXs are called prostanoids*

If lipoxygenase acts on arachidonic acid --> leukotrienes LTs (chemotaxis) + lipoxins LXs (inhibit chemotaxis)


Differentiate between cyclo-oxygenase I and II (COX1 and COX2)

COX1 and COX2 are isozymes

COX1 -- produces prostaglandins involved in homeostasis (housekeeping), expressed constitutively

COX2 -- expression induced by inflammation, produces PGE2 (main prostaglandin involved in inflammation)


Describe the effects of the following prostanoids:
1) PGE2
2) PGI2 aka prostacyclin
3) TXA2
4) PGF2alpha

1) PGE2: main prostaglandin involved in inflammation (via COX2) --> vasodilation, increased vascular permeability, promotes pain signal conduction through bradykinin; also protects stomach lining by promoting mucous secretion and inhibiting acid secretion (via COX1)

2) PGI2: produced by vascular endothelium; anti-platelet clotting, bv vasodilation

3) TXA2: produced by activated platelets; pro-platelet aggregation, bv vasoconstriction

4) PGF2alpha: protects stomach lining by promoting mucous secretion and inhibiting acid secretion


Describe the role of leukotrienes (LTs) in the inflammatory response and therapeutic strategies for controlling their effects

Leukotrienes: associated with allergic reactions, anaphylactic shock, dermatitis, asthma --> promote bronchospasm, vasoconstriction, edema, inflammation

Antileukotrienes are non-steroidal drugs that inhibit 5-lipoxygenase or act as receptor antagonists (e.g. Montelukast - Singulair) --> less effective than corticosteroids in treating asthma, more effective in treating mast cell disorders


Compare the actions of the following as anti-inflammatory drugs and list their side effects:
1) Non-selective NSAIDs
2) Selective (COX-2) NSAIDS
3) baby aspirin
4) acetaminophen

1) NSAID: e.g. aspirin, ibuprofen, naproxen (OTC); Action - inhibit COX2 --> reduce levels of PGE2 --> reduce inflammation, fever; Side effects - also inhibits COX1 --> reduced PGE2 --> GI discomfort + increased risk ulcers

2) Selective NSAIDs: e.g. Vioxx, Celebrex; Action - selective for COX2 >> COX1; Side effects - no GI upset but TXAs >>PGI2 --> increased risk cardiovascular events --> drugs withdrawn

3) Baby aspirin: type of NSAID; Action - inhibits TXA2 production in platelets >> inhibits COX2 irreversibly via acetylation--> PGI2 >> TXA2 --> reduces ability to coagulate with fibrin --> used as anti-clotting to prevent strokes, MI; Side effects - asthma (shifts arachidonic acid towards leukotriene pathway)

4) Acetaminophen: e.g. Tylenol; Action - reduces prostaglandin synthesis but we do not know mechanism --> reduces inflammation, fever; Side effects - hepatotoxicity due to toxic metabolite NAPQI (antidote = NAC --> increases glutathione)


Difference between endogenous and synthetic glucocorticoids

Functions, Indication for treatment and side effects

Glucocorticoids are a class of corticosteroids that inhibit phospholipase (production of arachidonic acid)

Endogenous corticosteroids e.g. cortisol (produced in adrenal cortex); Synthetic corticosteroids e.g. prednisone, dexamethasone, hydrocortisone

Functions: (1) downregulate production of COX2 --> reduce PGE2 --> reduce inflammation; (2) reduce activity of immune cells e.g. mast cells, macrophages --> reduces production of histamine --> anti-inflammation but pro-infection; (3) inhibits transcription of IL-2 in T cells

Indications: treatment of allergies (e.g. asthma, which affects lower respiratory tract); treatment of autoimmune disorders (e.g. lupus, IBD, arthritis); prevention of transplant rejection

Side effects: shuts down immune response --> infections and poor wound healing, muscle wasting + osteoporosis, Cushing symptoms (fat redistribution, moon face), weight gain and hyperglycemia, depression, peptic ulcers


Fun Fact: Immunosuppression

Joseph Murray performed first successful organ transplant and received Nobel Prize in 1990


Biologics (antibodies) in organ transplant:
1) Mechanism of action
2) Clinical uses
3) Side effects/drug interactions

Biologics (antibodies) e.g. antithymocytes, daclizumab, muromonab

1) Mechanism: Specific Ab against lymphocyte cell surface receptors --> prevent lymphocyte activation --> immunosuppression

2) Uses: Induction therapy --> administered before other drugs e.g. calcineurin inhibitors; (daclizumab) used against acute rejection by competitively inhibiting IL-2 receptor; (muromonab + antithymocyte globulin) depleting agents that destroy CD3-bearing T cells

3) Side effects: inflammation, increased infections, acute hypersensitivity


Calcineurin inhibitors in organ transplant (cyclosporine, tacrolimus):
1) Mechanism of action
2) Clinical uses
3) Side effects/drug interactions

Calcineurin inhibitors e.g. cyclosporine (older), tacrolimus (newer)

1) Mechanism: inhibits calcineurin phosphatase activity --> inhibits dephosphorylation/activation of NFAT --> blocks T cell production of IL-2 --> blocks T cell activation

2) Clinical uses: Prevention of transplant rejection, autoimmune disorders

3) Side effects: renal toxicity/kidney failure, toxicity enhanced by sirolimus; avoid drugs that affect p450 action


mTOR inhibitors in organ transplant (sirolimus, everolimus):
1) Mechanism of action
2) Clinical uses
3) Side effects/drug interactions

mTOR inhibitors e.g. sirolimus (Rapamycin), everolimus

1) Mechanism: Inhibits mTOR pathway --> inhibits IL-2 production --> blocks T cell activation

2) Clinical uses: prevention of transplant rejection, advanced renal cancer

3) Side effects: increase in cholesterol and TAGs, enhances renal toxicity from calcineurin inhibitors; avoid drugs that affect CYP3A4 or P-glycoprotein actions


Cytotoxic drugs in organ transplant (azathioprine, mycophenolate):
1) Mechanism of action
2) Clinical uses
3) Side effects/drug interactions

Cytotoxic drugs e.g Azathioprine, Mycophenolate

1) Mechanism: Azathioprine contains purine analog and Mycophenolate inhibits IMP enzyme --> inhibits de novo purine biosynthesis --> inhibits DNA synthesis/transcription --> inhibits cell proliferation esp in B and T cells (which DO NOT have purine salvage pathway)

2) Clinical uses: preventing kidney rejection; autoimmune diseases

3) Side effects: (Azathioprine) bone marrow suppression; avoid allopurinol (inhibits xanthine oxidase, which metabolizes the drug);

(Mycophenolate) GI upset, myelosuppression


Describe the development and structure of mucosal tissues

Development: all mucosal surface cells come from stem cells in the crypt --> Wnt signaling tells the stem cells to migrate up, Notch signaling tells them how to differentiate

Structure: Antigens pass by luminal side and mucosal microbiota --> outer mucus layer --> inner mucus layer --> epithelial layer with goblet and paneth cells and mucosal leukocytes


Describe the barrier components of mucosal tissues

1) Mucus: viscous secretion with glycoproteins, permeable to some molecules that are conjugated to Igs

2) Paracellular pathway/ intracellular junctions: tight junctions (claudins + occludins), adherens junctions (cadherins), + desmosomes

3) Antimicrobial peptides: released upon stimulation by pathogens (cathelicidins, defensins)


Describe cellular components of the mucosal system:
1) Intraepithelial lymphocytes
2) T cells
3) B cells
4) Dendritic cells
5) Macrophages

1) Intraepithelial lymphocytes (IEL): small mononuclear T cells, both natural and induced; express NK receptors and integrin (to attach to cadherins on epithelial cells), signal to thymus to learn self/non-self

2) T cells: in lamina propria; predominately CD4; receive signals from IELs + epithelial cells and interact with microbiota to induce cytokine responses in mucosal T cells

3) B cells: antibodies in mucus (tears, saliva, etc); most common IgA and IgM --> produced by mucosal plasma cells --> Secreted out of cell, and brought back in when they bind to antigen

4) DCs: Phagocytose self-antigens e.g. food, commensal bacteria and migrate to lymph nodes to induce peripheral tolerance (this is how tregs are tolerant to gut bacteria); also imprint lymphocytes with homing receptors so they circulate back to intestine

5) Macrophages: continuously populate uninflamed intestinal mucosa, scavenge + phagocytose + repair tissue but do NOT present antigens


Describe 3 ways antigen can be taken up from the lumen into mucosal tissue

1) By M cells in FAE (follicle associated epithelium)

2) By DCs - antigens presented via costimulation (tells DCs these are pathogens) or w/out (tells DCs those are safe)

3) Igs in lumen bind to antigen --> taken up by immunoglobulin receptor


List the steps of cell trafficking and homing to mucosal tissue

1) M cells deliver antigens to DCs

2) Lymphocytes activated by specialized DCs and acquire gut homing receptors e.g. CCR9

3) Lymphocytes go to mesenteric lymph nodes --> downregulate systemic homing receptor and induce proliferation of different cells

4) Lymphocytes go through blood stream to mucosa and home to effector site where local action takes place


1) What is primary immunodeficiency?
2) What are the parts of the immune system that can be dysfunctional?
3) What are the warning signs

1) Chronic disorder where immune system does not function properly

2) Most common is B cell defect (antibodies), then combined, then phagocytic system, then cellular, then complement system

3) Warning signs: multiple occurrences of pneumonia, ear/sinus infections; recurrent abscesses (central necrotic area surrounded by neutrophils), persistent thrush in mouth or fungal infection in skin


T-cell deficiency:
1) Examples
2) Types of infections
3) Tests in workup

T-cell deficiency:

1) Examples: SCID (no T cells), ADA, PNP, DiGeorge (thymus atrophies --> low T cells, cleft palate, hypocalcemia), Ataxia telangectasia (IgA/IgE deficiency), Wiskott-Aldrich (low platelet count --> eczema, lymphoid malignancy - combined immunodeficiency)

2) Infections: fungal pneumonia or meningitis; herpes infections

3) Tests: CBC, B and T cell counts, HIV test, hypersensitivity skin tests


B-cell deficiency:
1) Examples
2) Types of infections
3) Tests in workup

B-cell deficiency:

1) Examples: Burton's X-linked agammaglobulinemia (all Igs are low), IgA deficiency (most common, usually asymptomatic), Common Variable Immunodeficiency CVA (Ig low, most common symptomatic)

2) Infections: otitis media, streptococcus pneumonia, GI infections (pneumococcus or campylobacter), parasitic infections (Giardia), enterovirus infections

3) Tests: CBC, IG levels, B and T cell counts, vaccination titers (to see if there is a response)


Phagocytic system deficiency:
1) Examples
2) Types of infections
3) Tests in workup

Phagocytic system deficiency:

1) Examples: Chronic granulomatous disease (CGD - mutation in NADPH oxidase), Neutropenia, Chediak-Higashi (mutation in lysosomal trafficking protein --> decreased phagocytosis --> large abnormal granules, albinism + retardation)

2) Infections: bacterial infections (staphylococcus), burkholderia pneumonia, fungal infections (aspergillus)

3) Tests: CBC, peripheral smear, neutrophil oxidative bursts


Complement system deficiency:
1) Examples
2) Types of infections
3) Tests in workup

Complement system deficiency:

1) Examples: Neisseria infections of late component of classical Complement pathway

2) Infections: bacterial (Neisseria --> meningitis or gonorrhea)

3) Tests: Total complement level (CH50) + individual component levels


Differentiate healing by first vs second intention

First intention: healing occurs through direct union of skin edges by fibrous adhesion and epithelial regeneration, without granulation tissue --> small scar e.g. small wounds (surgical incisions)

Second intention: healing occurs through granulation tissue formation and wound contraction by fibroblasts --> larger scar e.g. large wounds (abscesses, ulcers)