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Immunology

Terms in this set (296)

______________________ immunity is the early line of defense, mediated by cells and molecules that are always present and ready to eliminate infections microbes.
Innate immunity
_______________________ immunity is mediated by lymphocytes stimulated by microbial antigens, requires clonal expansion and differentiation of the lymphocytes before it is effective; responds more effectively against each successive exposure to a microbe.
Adaptive immunity
_________________________ are the cells of adaptive immunity and are the only cells with clonally distributed receptors with fine specificities for different antigens.
Lymphocytes
Adaptive immunity consists of ______________________ immunity, in which antibodies neutralize and eradicate extracellular microbes and toxins.
Humoral
Adaptive immunity also consists of ____________________________ immunity in which T lymphocytes eradicate intracellular microbes.
Cell-mediated
Adaptive immune responses consist of what sequential phases?
1. Antigen recognition by lymphocytes.
2. Activation of lymphocytes to proliferate & differentiate
3. Elimination of microbes
4. Decline of immune response
4. Long-lived memory
_________________________________ are the only cells that produce antibodies
B lymphocytes
___________________________ recognize peptide fragments of protein antigens displayed on other cells.
T lymphocytes
What cells kill other infected cells harboring microbes in the cytoplasm?
Cytotoxic T Lymphocytes (CTLs)
_____________________________________ capture antigens of microbes that enter through epithelia, concentrate these antigens in lymphoid organs, and display the antigens for recognition by T cells
Antigen-presenting cells (APCs)
Toll-like receptors (TLRs)
Expressed on plasma membranes and in endosomes of many cell types; major class of innate immune system receptors that recognize different microbial products, including bacterial cell wall constituents and viral nucleic acids.
The principal components of innate immunity are epithelia, phagocytes, _____________________________, ____________________________, cytokines, and plasma proteins.
Dendritic cells, natural killer cells
_______________________ provides a physical barrier against microbes; it also produces antibiotics and contains lymphocytes that may prevent infections.
Epithelium
Innate Lymphoid Cells (ILCs)
Secrete various cytokines that induce inflammation; NK cells kill host cells infected by intracellular micromes and produce the cytokine interferon gamma, which activates macrophages to kill phagocytosed microbes.
What cytokine, produced by NK cells, activates the macrophages to kill phagocytosed microbes?
Interferon gamma
The ________________________ system is a family of proteins that are activated on encounter with some microbes (innate immunity) and by antibodies (humoral arm of adaptive immunity).
Complement
Role of complement system
Opsonization and phagocytosis of microbes, stimulation of inflammation, and lysis of microbes
Cytokines of innate immunity function to stimulate inflammation (TNF, IL-1, chemokines), activate _______________ cells (IL-12), activate macrophages (IFN-gamma), and prevent viral infections( type 1 IFNs)
NK
Antiviral defense is mediated by _______________________, which inhibit viral replication; and NK cells, which kill infected cells.
Type 1 IFN
Paneth cells
secrete enzymes that kill bacteria: alpha-defensins, lysozyme, and phospholipase A
Cells of the Innate Immunity
Epithelial cells, Phagocytes: Macrophages, Neutrophils, Dendritic Cells; NK cells, Intraepithelial lymphocytes
Type I and Type III IFNs have very similar functions and are primarily involved in:
Antiviral defense
Cardinal Signs of Inflammation
Pain (Dolor), Warmth (Calor), Erythema (Redness/Rubor), Swelling (Tumor/ Edema)
Margination
the sticking of phagocytes to blood vessels in response to cytokines at the site of inflammation
Pavementing
The adherence of white blood cells to blood vessel walls during inflammation
Diapedesis
the passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.
Leukocyte adhesion deficiency
results from loss of CD18/ICAM-1. This leads to inability to synthesize integrins and thus lekocytes can't get out of blood stream.

Manifestaions: infection without pus formation, delayed detachment of the umbilical cord and poor wound healing.
CD18 binds to ___________________ in the process of margination/ pavementing
ICAM-1
Chemotaxis
Cell movement that occurs in response to chemical stimulus
IL-8
Secreted by macrophages. Major chemotactic factor for neutrophils.
Pavementing is due to the expression of
Selectins, integrins, CD18 on the phagocyte and ICAM-1 on the endothelium
Disease resulting from the loss of CD18
Leukocyte Adhesion Deficiency (LAD)
No CD18 = No interaction with ICAM-1; results in what loss of function of phagocytes?
Ability to move into extracellular space towards the site of infection/ damage.
The complement system can be activated by what three pathways?
1. Alternative Pathway (Innate)
2. Classical Pathway (Adaptive)
3. Lectin Pathway (Innate)
What is the end/ final effect of the compliment system?
Membrane attack complex formation and Lysis of microbe
When the phagocyte ingests a pathogen, it shifts from glycolysis to the pentose-phosphate pathway and utilizes which enzyme?
Glucose-6-phosphate dehydrogenase
G6PDH
Required for phagocyte to shift its metabolism from glycolysis to the pentose phosphate pathway
G6PDH deficiency
- most common human enzyme defect
- X linked recessive disease
- hemolysis induced by oxidative stresses
NADPH Oxidase
- generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce superoxide anion, a reactive free-radical.
Superoxide dismutase (SOD)
An enzyme that destroys superoxide: O2- + O2- + 2H+ --> H2O2 + O2
NADPH Oxidase Deficiency
-Chronic granulomatous disease
-Phagocytes of patients with CGD can utilize H2O2 generated by invading organisms and convert it to ROS.
-Patients are at increased risk for infection by catalase ⊕ species (e.g., S. aureus, Aspergillus) capable of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections.
What enzyme is critical for use in phagocyte destruction of pathogens?
NADPH Oxidase
What test measures the killing capacity by ROS?
NBT Nitro Blue Tetrazolium
Nitro Blue Tetrazolium
Immunocompetant neutrophil breakdown bacteria and phagosize when stain it will turn blue; if it does not metabolize it will remain colorless.

Chronic granulomatous disease stains colorless (lack of NADPH Oxidase/ lack of killing capacity of phagocyte)
Myeloperoxidase
enzyme that combines peroxide + Cl to form bleach (HOCl)
Is myeloperoxidase absolutely necessary for function of phagocyte?
No. NADPH Oxidase is efficient in producing ROS to kill
Myeloperoxidase Deficiency
respiratory burst is present, but no bleach is produced; NOT CLINICALLY SIGNIFICANT.
Chronic Granulomatosus Disease
Deficiency in NADPH Oxidase
Intraepithelial lymphocytes (IELs)
Innate lymphocytes; found within the epithelium, mostly CD8 cells.
Natural Killer Cells
-Large, granular, cytotoxic lymphocytes
-Express CD56
-Absence of TCRs (T-cells without TCRs)
-Express KAR (Killer Activation Receptor) and KIR (Killer Inhibition Receptor)
-Release perforin/granzyme (cell cytotoxicity)
-Inducible expression of FasL (cell cytotoxicity)
CD56
Unique marker for NK cells
CD2
T cells and NK cells
MHC-1 binds to _______________ on NK cells, inhibiting killing.
KIR (Killer Inhibition Receptor)
NK cells are activated by what cytokines?
IL-12, IFN-alpha, TNF-alpha, IL-15....
NK cells release ____ and granzymes, which together trigger ______ in the target cell
perforins; apoptosis
NK cells release ___________ in response to IL-12 stimulation
IFN-gamma
When the NK cell is bound to MHC I via KIR will the NK cell kill?
No; KIR = Killer Inhibitory Receptor
Antibody Dependent Cellular Cytotoxicity (ADCC)
Adaptive killing function by NK cells

-Due to function of CD16 on NK cell
-CD16 binds to IgG, which is also bound to the microorganism
-This anchors the NK cell to the pathogen for killing of antibody-coated cell.
FasL
Fas Ligand delivers "death signal" —> Fas is the death receptor.

Binding of FasL to Fas induces cell death in Fas-expressing cells
Binding of __________ to Fas induces cell death in Fas-expressing cells.
FasL; this turns on the death domain/ activates apoptosis via caspase cascade.
Antigens
-A molecule that is recognized by the immune system that can induce an immune response

-Usually foreign, 6-10 kd in size, and soluble
What makes the best antigen?
Large, Complex, Foreign, Protein
What is the typical size of an antigen?
6-10 kD
Antigens vs. Immunogens
Antigens that provoke an immune response are called immunogens

-All immunogens are antigens; but not all antigens are immunogens.
_______________________ are antigens that provoke an immune response
Immunogens
Factors influencing immunogenicity
-Dose (small quantities get rapidly cleared/ large quantities may inhibit response)
-Route (best route is bloodstream)
Adjuvants
Chemical substances that enhance the immune response to an antigen; thought to prolong the persistence of the antigen, stimulate or modulate immune cells, and/or enhance macrophage function.
Haptens
Small molecules that are not immunogenic; can bind antibodies; generally only have one epitope
How can a hapten become immunogenic?
By binding to a protein carrier molecule to form a conjugate
What happens when a hapten binds to a carrier protein?
It becomes a conjugate and can drive an immune response.
Epitopes
Antigenic determinants; part of the antigen that is active/ binds the antigen recognition molecule.

-Number of epitopes = valence of the antigen
Phases of Antigen Elimination
-Equilibrium Phase
-Catabolic Delay Phase
-Immune Elimination Phase
-Detectable Antigen-Specific Antibody
Equilibrium phase
Distribution of antigen between vascular and extravascular compartments
Catabolic Phase
Elimination of antigen by innate cells; processing and presentation of antigen
Immune Elimination Phase
Formation of antigen-antibody immune complex and removal of complex
Antigen Elimination Curve
At point C antibodies are produced, but free antibodies cannot be detected until point D

Innate Immunity: A-D
After D: antibody can be used to help kill more
Antibody Basic Structure
2 heavy chains; 2 light chains

Fab on the amino end —> Binds antigen/ variable region

Fc on the c-terminal —> constant region
Fab
The variable region of an antibody
Antibody Functions
1. Neutralization
2. Opsonization & Phagocytosis
3. Complement activation & Lysis
CD16
Fc gamma receptor that marks: NK cells, macrophages, and neutrophils
CDC 16 of a macrophage binding to Fc of antibody results in _____________________formation
ADCC (Antibody dependent cell-mediated cytotoxicity)
ADCC
Antibody-dependent cell-mediated cytotoxicity
Two types of light chains
κ and λ . B cells express one or the other but not both at the same time.

V, J
Heavy Chains
V, D, and J combinations
What determines the type of heavy chain?
The constant region
Antigen recognition site is created through gene segment rearrangements/ recombinations; mediated by __________ and __________.
RAG-1 and RAG-2
RAG-1 and RAG-2
They recognize recombination signal sequences, specifically heptamer-nonamer, and make dsDNA breaks.

Function temporarily ceases during proliferation.
No RAG-1/ RAG-2 =
No Antibody & No TCR, No BCR
Junctional Diversity
The heterogeneity that results from either the removal or addition of bases at the junction of DNA segments V, D, J

Random addition by TdT or random deletion by exonuclease
Junctional Diversity is mediated by
terminal deoxynucleotidyl transferase TdT
TdT
terminal deoxynucleotidyl transferase-enzyme that transfers DNA nucleotides onto the cut end of DNA. Random addition that allows junctional diversity
Complementarity determinant region, CDR is also called:
HV Regions/ Hypervariable regions
Diverse specificity is reflected in the degree of amino acid variability in the _________________ regions and framework regions, FR, within the variable region.
Hypervariable Hv
Hypervariable regions
loops in protein structure of variable region at antigen binding site, HV1, HV2, HV3

Also called CDR (Complementarity determinant region)
IgG crossing the placenta is (active/passive)
Active process; Fc fragment can cross and bind to Fc gamma receptor
Significance of Enzymatic Cleavage of IgG
Role of Fc(gamma)R

Fc(gamma) can cross and bind to Fc(gamma)R
Characteristics of the Constant Region (Fc) of Immunoglobulin
-Constant sequence
-Crystalizable
-Carboxyl terminal
-Cell binding
-Complement binding and activation
Isotypic difference
Antibody class: Determined by the heavy chain (Ex: IgG, IgM, IgE...etc.)

-Defines the Function
Idiotype Difference
Refers to the antigen binding site variations, particularly hypervariable region

-Determines specificity (Which antigen will bind)
-Variable domains
Isotypes of antibodies
IgM, IgD, IgG, IgE, IgA
IgM
-First antibody secreted in immune response
-Found on surface of naive B cells
-Has 10 antigen binding sites
-Readily activates classical complement
_________ is a strong activator of classical complement pathway
IgM
IgG
-Second antibody to be secreted, secreted in large amounts
-Most abundant isotype in blood and lymph
-Secreted as monomer
-Activates classical complement
-Opsonization of pathogens (Triggering phagocytosis and ADCC)
-Neutralization
IgA
Secreted as a monomer and dimer
-Dimeric form contains J chain and secretory component
-Facilitates transport across epithelium into secretions of the mucosal system
-Most predominant isotype produced in the gut
-Mainly functions in neutralization
This immunoglobulin is the predominant isotype found in the gut and mainly functions in neutralization
IgA
IgE
Binds with high affinity to Fc(epsilon) receptors on mast cells, eosinophils and basophils

Efficienty triggers degranulation; important in allergy and response to helminthes
IgD
Expressed on the surface of naive B cells
-Secreted form has no known function
-Part of BCR receptor
What immunoglobulin is part of the BCR
IgD
Antibody isotype tissue distribution
IgM = only in blood
IgG = blood, tissues & can cross placenta
IgA = Gut lumen, secretions (saliva, tears, milk), mucous membranes (resp/ GI/GU).
IgE = found in Fc(epsilon) receptors on mast cells in tissues
___________ is found bound to Fc(epsilon) receptors on mast cells in tissues
IgE
Why do lymphocytes continually recirculate through peripheral lymphoid tissue
To encounter specific antigen
_______________________ immunity is acquired passively by receiving serum from someone who has recovered form an infection
Humoral
The alternate pathway of complement activation requires which complement protein?
C3
(True/False) Complement participates both in innate and adaptive immune response
True
What term is used to describe two or more cytokines that have the same effect on the cells they bind?
Redundancy
Which cytokine stimulates hepatocytes to produce acute phase proteins that function as early indicators of inflammation?
IL-6
Where would an antigen entering the body in a subcutaneous injection most likely activate its specific lymphocytes?
Draining lymph nodes
What is the primary purpose of the adaptive immune system?
To protect from disease upon re-infection
What type of immunity is stimulated by the flu vaccine?
Artificial active
The greatest concentration of T lymphocytes is found in which part of the lymph node?
In the paracortical zone
What Natural Killer (NK) cell receptor is responsible for initiating the lysis of virus-infected cells?
(KAR) Killer Activating Receptor
A 4-year-old child presents with hypopigmentation of the skin, alopecia, hypodontia, and dystrophic nails; the child also presents with delayed cognitive development. Genetic testing reveals a mutation in a gene required for the phosphorylation of IkB(alpha), thereby confirming a diagnosis of incontinentia pigmenti. What gene is affected by this mutation?
IKK
Which of the following is determined by the constant regions of the five major types of immunoglobulin heavy chains?

A. Epitope
B. Idiotope
C. Allotype
D. Isotype
Isotype
Which of the following is a characteristic of the region of antibody that binds antigen?

A. Forms covalent bonds with antigen
B. Varies between antibodies binding different antigens
C. Found on the Fc portion of antibody
D. Binds to Fc-receptors regardless of the specificity of the antibody
E. Directly activates complement
Antibody-antigen interactions are non-covalent bonds and easily irreversible.

B. Correct; the antibody binding sites for antigens are very unique.
In which of the following cells do V(D)J recombination events take place?

A. NK cells, B cells and neutrophils
B. Eosinophils, T cells and B cells
C. B cells, dendritic cells, and T cells
D. Plasma cells, mast cells and B cells
E. CD4+ T cells, CD8+ T Cells, and B cells
E. CD4+ T Cells, CD8+ T Cells, and B Cells
What drives V(D)J recombination?
RAG-1 and RAG-2
What would happen if RAG-1 and RAG-2 were absent?
No VDJ recombination; No antibody; No TCRs or BCRs

Clinical Correlate: Omenn Syndrome
A toddler presents with recurrent infections and failure to thrive. Further investigation reveals mutations in the transcription factors involved in the expression of MHC-II genes. What result would be consistent with this condition on a CBC with diff?
A very low number of CD4 T Lymphocytes

This patient has APCs that cannot express MHC-II; when T-cells go to mature in the thymus, no selection will occur and no CD4 cells will "pass" through the thymus school.
Which of the following is an essential property of somatically generated receptors found on B and T cells?

A. They bind only MCH-1 molecules
B. They are identical among individuals
C. They are generated after an encounter with non-self
D. They are randomly generated during development
E. Encoded in the germline to recognize pathogen-associated molecular patterns.
D. They are randomly generated during development.
What cytokines are responsible for the activation and clonal expansion of the main cell type involved in the immune response to a bacterial pneumonia?
IL-2, IL-6, IL-23, and TGF-B
Professional antigen presenting cells (pAPCs) capture _______________________
Antigen (Ag)
pAPC PRRs are stimulated by pathogenic _____________________ in the cognition phase.
PAMPs
In the cognition phase, PRRs transduce the stimulation in the form of intracellular signaling, mainly through the canonical ___________________ pathway.
NF-kB
All signals from all PRRs stimulated are integrated by the pAPC and the resulting transcription factors bind the promoters of genes encoding _______________________________. What is then secreted by the pAPC?
Proinflammatory cytokines; cytokines
As part of the innate response, pAPC uptake of antigen results in the secretion of proinflammatory cytokines by the pAPC. What are the main cytokines released?
IL-1B, IL-6, TNF-alpha, IL-12, CXCL-8 (IL-8) chemokine.
CXCL-8 can be described as a _____________________. What is the other name for it?
Chemokine; IL-8
Anaphylotoxins
C3a & C5a (mediate Histamine release from Basophils & Mast cells)
C3a and C5a are anaphylotoxins which are chemotactic for leukocytes and trigger the release of ___________________ and other vasoactive mediators by mast cells.
Histamine
TNF-alpha, IL-1B, histamine, and other mast cell-derived vasoactive mediators activate the endothelium near the site of infection to induce:
Vascular leakage to facilitate complement and other acute phase proteins, as well as leukocyte infiltration in the site of infection.
What are the major chemotactic cytokines that recruit leukocytes to the site of infection following their extravasation?
CXCL-8 (IL-8), C3a, C5a
The first cells to be recruited to the site of infection
Monocytes and neutrophils
During the innate phase of the immune response, bacteria are primarily killed by:
Lysis or phagocytosis
During the innate phase of the immune response, pathogens can be killed by lysis as a result of the membrane attack complex (MAC). What pathways of complement will activate the MAC in innate response?
Both the alternative and lectin pathways of complement
Phagocytosis is primarily mediated by______________________ but also by macrophages, through CR1 binding of C3b that has opsonized the bacteria.
Neutrophils
When dealing with viruses and other intracellular pathogens, the main mediators of innate defenses against intracellular parasites are the ________________________________
Natural Killer Cells
Cellular cytotoxicity is mediated mainly by ___________________________ and perforin/granzyme killing
Fas/FasL
FasL and granzymes lead to which kind of cellular death?
Apoptotic death
When pAPCs enter secondary lymphoid tissue, in the T cell-rich area, they interact with ____________ cells until they find one that has the TCR specific for the MHC-II/Ag peptide complex they carry.
TH0
Transcription factors will trigger the differentiation of the TH-0 cells into TH-1 cells that will secrete the following TH-1 cytokines:
IL-12, IFN-gamma (major ones to remember)

TNF-alpha, IL-18, IL-2, IL-1 and IL-6
For parasitic worms, if antigen presentation is done in an environment rich in IL-4, then this cytokine will trigger signals that culminate in the expression of what transcription factors? These TF's will trigger the differentiation of TH-0 cells in to Th-2 cells.
STAT6 and GATA-3
TH-2 cells secrete which cytokines?
IL-4, IL-5, IL-13, IL-10, IL-2, IL-1, IL-6
For extracellular bacteria and fungi, if antigen presentation is done in an environment rich in IL-6, IL-23, and TGF-beta, then these cytokines will trigger a release of transcription factors STAT3 and ROR-gamma-t which in turn trigger the differentiation of TH-0 cells into _____________ cells.
TH-17
TH-17 cells secrete what cytokines?
IL-17 and IL-22 (major)

Also IL-2, IL-1, IL-6
For intracellular pathogens, TH-1 cells express what to help pAPCs increase their expression of co-stimulatory molecules (CD-80, CD-86) or (B7.1-B7.2) to activate cytotoxic T lymphocytes
CD40L, IL-2, IL-12, and IFN-gamma
IFN-gamma and TNF-alpha increase the intracellular killing of _________________________, with the help of CD40L
Macrophages
____________ cells activate B-cells (CD40L, IL-21, and IFN-gamma) and generate germinal centers (secondary follicles) leading to the secretion of immunoglobulin (IgG) by plasma cells.
T-FH
What type of immunoglobulins are the main antibodies involved in the neutralization of intracellular pathogens?
IgG
How do IgG's exert their effects?
They bind to the outside of pathogens to prevent their attachment to host cells

They generate immune complexes that can be cleared by splenic macrophages

They opsonize infected cells to trigger antibody-dependent cellular cytotoxicity by NK cells (Fc-gamma receptor III (CD16) mediated).
Once an infection is cleared how are individuals protected from further infection?
Protective immunoglobulin antibodies remain in the serum and memory TH-1 cells and B cells remain to prevent disease in case of future exposure to the same pathogen.
For extracellular bacteria and fungi, TH-17 cells leave the secondary lymphoid tissues and migrate to the bone marrow and the site of infection where they stimulate cells to secrete ________________________________________, stimulating the bone marrow to increase neutrophil and monocyte production
IL-6, G-CSF, and GM-CSF
IL-6, CXCL8 and CXCL2 expression at the site of infection function to
Recruit newly formed neutrophils to the site of infection .
IgG and _________ are the main antibodies involved in the elimination of bacteria and fungi
IgA
IgA antibodies mainly exert their effects by:
1. Preventing pathogen attachment to host cells by neutralizing pathogen adhesins

2. Neutralizing soluble pathogen toxins
In the case of parasitic worms, TH-2 cells secrete IL-4, IL5, as well as IL-13 and IL-10. IL-5 functions to:
Stimulate the production of eosinophils
_________ are the main antibodies involved in the elimination of worms.
IgE
What cytokine stimulates isotype-switching to IgE antibodies which sensitizes eosinophils and mast cells, that then bind to parasites en masse and degranulate towards the surface of the worm to destroy it?
IL-4
IL-4, IL-13, and ________________ stimulate goblet cells to secrete more mucus as well as promote peristalsis to facilitate parasite expulsion.
Histamine
TH-2 responses are involved in what type of hypersensitivity responses involved in allergies and asthma, associated with eosinophilia?
Type 1 hypersensitivity
Type I and Type II Cytokine Receptors only differ slightly in structure, but they respond similarly and generally activate a __________________ signaling pathway.
Jak/STAT
Type I Cytokine (Hemopoietin) Receptors have the following ligands:
IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, GM-CSF, G-CSF
The two principal types of reactions of the innate immune system are ____________________________ and ___________________________ defense.
Inflammation & antiviral defense
Innate immune defense against intracellular viruses is mediated by __________________________, which kill virus-infected cells, and by cytokines called Type I Interferons which block viral replication within host cells.
Natural Killer Cells
Type I Interferons
The antiviral interferons IFN-α and IFN-β; block viral replication within host cells
The microbial molecules that stimulate innate immunity are often called ________________________________ to indicate they are present in infectious agents and shared by microbes of the same type.
PAMPs : Pathogen-associated molecular patterns
The receptors of the innate immunity that recognize PAMPs are called:
PRRs : Pattern Recognition Receptors
The innate immune system recognizes molecules that are released from damaged or necrotic host cells. Such molecules are called:
DAMPs: Damage-associated molecular patterns
(T/F) Receptors of the innate immune system are encoded by inherited genes that are identical in all cells
True; the PRRs of the innate immune system are nonclonally distributed and identical receptors are expressed on all cells of a particular type
TLR-2
recognizes several bacterial and parasitic glycolipids and peptidoglycans
TLR-3, 7, 8
specific for viral single-stranded and double-stranded RNAs
TLR-4
specific for bacterial LPS (endotoxin)
TLR-5
Specific for flagellin
TLR-9
recognizes unmethylated CpG DNA that is abundant in microbial genomes
RIG-like receptors (RLRs)
found in cytoplasm, detect viral RNA indicating infection, produce interferons
Cytosolic DNA sensor (CDS)
Detects microbial DNA
Signals generated by engagement of TLRs activate transcription factors that stimulate the expression of genes encoding cytokines, enzymes, and other proteins involved in the antimicrobial functions of activated phagocytes. Among the most important transcription factor activated is:
NF-kB
NF-kB
Transcription factor; promotes expression of cytokines, endothelial adhesion molecules, and type I interferons
What large family of receptors detect DAMPs and PAMPs in the cytoplasm?
NOD-like receptors (NLRs)
NOD-1 & NOD-2
Cytosolic proteins containing a caspase related domain; specific for bacterial peptidoglycans

-Activate NF-kB
What intracellular receptors are specific for bacterial peptidoglycans?
NOD-1 and NOD-2
NOD-1 and NOD-2 receptors activate what transcription factor?
NF-kB
NLRP-3
Cytosolic NLR that acts as a "sensor" on the inflammasome.

-recognizes many microbial products
-enhances the production of IL-1B
IL-1
Induces fever and acute inflammation
The cytosolic complex of NLRP-3, an adaptor protein, and caspase-1 is known as the ________________________
Inflammasome
Gain of function mutations in NLRP-3 are the cause of ____________________________________
Rare auto-inflammatory syndromes (can be treated with IL-1 antagonists)
The ______________________ receptors recognize RNA produced by viruses in the cytosol and activates signaling pathways that lead to the production of type I IFN
RIG-like receptors
__________________ receptors in the plasma membrane are specific for fungal glycans and for terminal mannose residues
Lectin receptors
Epithelial cells produce peptide antibiotics called _______________________ and ______________________ which kill bacteria as a means of chemical barrier against infection
Defensins and cathelicidins
The two types of circulating phagocytes, _________________________ and ____________________________, are blood cells that are recruited to sites of infection, where they recognize and ingest microbes for intracellular killing.
Neutrophils and monocytes
____________________________ are the most abundant leukocytes in the blood
Neutrophils
The production of neutrophils is stimulated by cytokines, known as _________________________________, which are secreted by many cell types in response to infections and act on hematopoietic stem cells to stimulate proliferation and maturation of neutrophil precursors.
Colony-stimulating factors (CSFs)
Neutrophils express receptors for:
Products of complement activation and for antibodies that coat microbes
During inflammatory reactions, monocytes enter extravascular tissues and differentiate into cells called _________________________, which can survive for long periods of time.
Macrophages
Macrophage Function
Production of cytokines that induce and regulate inflammation, ingestion and destruction of microbes, and clearing of dead tissues and debris and initiation of tissue repair
Macrophages can be activated by what two pathways?
1. Classical: induced by innate immune signals
2. Alternative: occurs in the absence of strong TLR signals
Classical macrophage activation
Induced by innate immune signals such as from TLRs, and by IFN-gamma

-produce M1 macrophages
Alternative macrophage activation
Induced by IL-4 and IL-13 in the absence of strong TLR signals

-M2 Macrophages

Function in tissue repair and termination of inflammation
M2 Macrophages
decrease inflammation and encourage tissue repair

Stimulated by IL-4 and IL-13
Dendritic Cells
Respond to microbes by producing cytokines to initiate inflammation

-stimulate adaptive immune responses by acting as APCs
Mast cells
Activated by microbial products binding to TLRs; granules contain histamine that cause vasodilation and increased capillary permeability, as well as proteolytic enzymes that kill bacteria or inactivate toxins

-also secrete prostaglandins and cytokins
Innate lymphoid cells (ILCs)
Lymphocyte-like cells that produce cytokines and perform functions similar to T cells, but do not express T cell antigen receptors (TCRs)

Th1, Th2, Th17
Natural Killer Cells
Recognize infected and stressed cells and respond by killing these cells and by secreting the macrophage-activating cytokine IFN-gamma

-contain abundant cytoplasmic granules

-NK cells empty the contents of their granules into the extracellular space at the point of contact with infected cells

-granule proteins enter infected cells and activate apoptosis
NK cell-activating cytokines
IL-15 (development & maturation)
type I IFNs
IL-12

Type I IFNs and IL-12 enhance killing functions.
What cells are the principal mediators of antibody-dependent cellular cytotoxicity?
NK Cells
ITAMS
Immunoreceptor Tyrosine Activation Motifs

Become phosphorylated on tyrosine residues when the receptors recognize their activating ligands
Phosphorylated ITAMs bind and promote the activation of cytosolic ________________________
Protein kinases
Inhibitory receptors of NK cells
Block signaling by activating receptors

Specific for class I MHC molecules, which are expressed on all healthy nucleated cells
How do NK cells recognize self cells (i.e. how do they not kill healthy cells).
inhibitory receptors on NK cells are specific for Class I MHC expression which is common to all healthy cells
Killer Cell Immunoglobulin-like Receptors (KIRs)
Share structural homology with Ig molecules

When KIRs are bound to Class 1 MHC molecules on normal cells, the killing activity of NK cells is shut off.
The complement cascade may be activated by what three pathways?
1. Alternative pathway
2. Classical Pathway
3. Lectin pathway
What pathway of complement activation is triggered when some complement proteins are activated on microbial surfaces and cannot be controlled
Alternatiive pathway
What two pathways of complement activation are part of the innate immunity?
Alternative and lectin pathways
The classical pathway of complement activation is a component of ___________________ immunity
Adaptive; it requires antibodies
Antigens must possess the following characteristics to provoke an immune response:
Size: 10,000 Da minimum
Complexity: Proteins are the most antigenic
Foreignness
Soluble
Not all antigens recognized by immune cells induce an immune response. Those that can are referred to as __________________________
Immunogens
What factors contribute to the immunogenicity of an antigen?
Dose:
Route
Host factors
Adjuvant effects
Adjuvants act through what three basic mechanisms?
1. Prolonging the persistence of the antigen
2. Stimulating or modulating immune cells
3. Enhancing macrophage function
The portions of an antigen that bind the recognition molecules of the immune system are referred to as _____________________
Epitopes or antigenic determinants
Epitopes that comprise amino acids on the same chain are called ____________________________ epitopes.
Linear or continuous
Epitopes formed by three-dimensional conformations are nonlinear or ____________________epitopes.
Conformational
The number of epitopes on an antigen molecule is called the ______________________.
Valence
Haptens
Small molecules that are non-immunogenic; can be recognized by antibodies but the binding is below the threshold required for immune response.
Haptens may become immunogenic when they become linked to larger molecules called ___________________________, which bring the total mass above threshold.
Carrier proteins
Equilibrium Phase
Represents the time required for equilibrium of the antigen with tissues and fluids.
Catabolic Decay Phase
Second phase; antigen removal proceeding over the following 4-7 days.
Immune Elimination Phoase
3rd phase; phase of accelerated removal due to binding of newly formed antibody with antigen.

Antigen specific antibodies are not yet detectable because they are all bound to antigen.
At the end of which phase is it possible to detect free circulating antibody?
At the end of the 3rd phase; immune elimination.
Recognition of antigen through the BCR results in:
Clonal expansion and differentiation of B cells into plasma cells
Somatic hypermutation
Results in additional diversity in the BCR; addition of random nucleotides into the antigen-binding region (V-region) of the BCR and further modifies the avidity and affinity of antibody molecules.

Occurs during the late state of B cell differentiation, after contact with the antigen.
There are three regions within both the VH and VL chains that have particular variability; these hypervariable regions are separated by ____________________________________ that provide the structural framework.
Framework regions
When the antibody molecule assembles into its 3D structure, the hypervariable regions form loops at the surface of the molecule that will interact with antigen; these loops are often called ____________________________________.
The complementarity-determining regions (CDRs)
Papain cleaves the antibody into what 3 fragments?
2 identical Fab (Fragment antigen binding) fragments and one Fc (Fragment crystallizable) fragment.

Fab Fragments —> contain variable regions

Fc Fragment —> constant sequence, determines the effector function.
Fc Fragment
Constant sequence, crystallizable, complement binding, complement activating, carboxyl terminal end and cell binding via the FcR
The Fc domain can bind to other cells via what receptor?
FcR
Can IgG cross the placenta?
Yes; it is an active process involving the binding of the Fc-gamma domain
Enzymatic cleavage of IgG with papain yields what three fragments?
Two monomeric Fab fragments and one Fc fragment
Digestion of IgG with pepsin yields what results?
One large dimeric fragment and a truncated Fc fragment
Allotypic variation
Refers to genetic differences between individuals within a species involving different alleles at a given locus.

No functional significance.

Occur mostly as variations of heavy chain constant regions.
Idiotypic variation
Refers to the variations in the variable domain, particularly in the hyervariable region.

Determine antigen binding specificity for an antibody.
Isotypic variation
Achieved through the linking of different constant region genes with the same variable region.

Effector function is defined by its isotype

Antibody isotypes possess different C regions, but have identical Fab regions.
Isotypic variation results in antibodies with same specificity, but different
Biological function
An antibodies ___________________ chain determines its tissue distribution and effector function.
Heavy
__________ is the first antibody secreted in an immune response.
IgM
IgM
-first antibody secreted in an immune response
-secreted as a pentamer with 5 identical subunits bound by a J chain.
-(10 binding sites)

-Found mainly in blood and lymph
-Powerful activator of complement cascade due to its size and the formation of immune complexes.
__________ is the second antibody to be secreted
IgG
IgG
-second antibody to be secreted
-secreted in large amounts and has a longer half-life than IgM
-most abundant antibody in blood and lymph
-can cross the placenta
-can activate the classical complement pathway
-important role in opsinization
-IgG1 and IgG3 can bind to CD16 to trigger NK cell antibody dependent cell-mediated cytotoxicity.
IgA
Monomer in serum; dimer in secretions
13% of serum antibodies
Common in mucous membranes, saliva, tears, and breast milk
Prevent microbial attachment to mucous membranes
What is the most common Ig in the gut?
IgA
Main function of IgA antibodies?
To neutralize pathogens
IgE
Binds to high affinity receptors on mast cells
-trigger mast cell degranulation
-trigger elimination of helminthic parasites
-role in allergic reactions
IgD
Secreted IgD has no known fuction.

-expressed on B cells; with IgM, acts as the BCR
Antigen-inexperienced B cells only express surface-bound antibodies that are of what isotypes?
IgM and IgD
Only after naive B cell encounters and receives help from CD4 T cells can the B cell switch their heavy chain isotype. Help from CD4 T cells comes in the form of ___________________
Cytokines
Fc Receptors
Specialized receptors expressed by immune cells that bind Fc portions of antibodies to trigger a variety of effector functions.
What cells regulate isotype switching?
Helper T Cells

-Cytokines produced by CD4 T cells can induce activated B cells to switch to a particular isotype.
IL-4 induces the expression of which Ig?
IgG1 & IgE

Inhibits: IgM and IgG3
IL-5 augments the production of which Ig?
IgA
IFN-gamma induces the formation of which Ig?
IgG3 and IgG2a
TGF-B induces the formation of which Ig:
IgG2b and IgA
The immunoglobulin isotype is determined by
The H chain constant region
What process is taking place during the lag period between antigen contact and detection of adaptive immunity?
Innate immune effectors are eliminating antigen
If VDJ recombination events cannot take place due to the absence of RAG1 and/or RAG2 genes, which cells would be most affected?
B and T cells
Antibody-dependent cell-mediated cytotoxicity (ADCC) is a process in which antibody-coated cells are killed by cells with ______________________________
Fc receptors for IgG3
When do lymphocytes acquire their antigen specificity?
Before they encounter antigen
Name some effector functions of antibody
1. Activation of complement on bacterial surfaces to promote phagocytosis by neutrophils

2. Binding extracellular viruses to block entry into host cells

3. Blocking uptake of bacterial toxins by host cells

4. Coating bacteria to promote their phagocytosis by neutrophils
The gene segments needed to encode the variable region of a lambda chain are:
One V and one J
Humoral immunity is mediated by _______________ that bind to extracellular microbes and their toxins, which are neutralized or targeted for destruction by phagocytes and the complement system
Antibodies
Isotype switching is stimulated by the combination of ____________________ and _______________ expressed by helper T cells
CD40L and cytokines
__________________________ is the process by which the affinity of antibodies for protein antigens increases with prolonged or repeated exposure to the antigens. It is initiated by signals from Tfh cells and results in the migration of the B cells into follicles and the formation of germinal centers.
Affinity maturation
Where does affinity maturation take place?
germinal centers
Which of the following is involved in the humoral immune response to T-independent antigen?

A. Memory B Cells
B. Memory T Cells
C. CD40/CD40L Interaction
D. IgG production
E. IgM production
IgM production
What B Cells have the longest life span?
Memory B Cells
Why is B cell isotype switching important for an effective immune response?
To produce antibodies that can perform different functions
What immunoglobulin regions/domains determines affinity, specificity, and idiotype of a molecule?
The light and heavy chain hypervariable domains
What property is exhibited by the fact that each B cell productively rearranges a single H and L chain allele?
Allelic exclusion
What is expressed first during B cell development?

A. Membrane u chain & Surrogate L chain
B. Membrane IgD
C. Membrane IgM
D. Germline IgM
E. Rag-1, Rag-2, and TdT
E. Rag-2, Rag-2, TdT
B Cell development occurs in a step-wise fashion, each step characterized by specific events. Which occurs first?
Rearrangement of immunoglobulin heavy chain genes
What marker could be used to identify a B cell?
CD19
CD19 is a marker for what type of lymphocyte
B cells
The complement system is responsible for the augmentation of a number of immunological functions. The engagement of which complement receptor is most likely to result in enhanced B lymphocyte activation?
CR2
What B cell surface protein undergoes rearrangement during B cell development and can serve as a receptor for antigens?
Ig; Immunoglobulins are also known as antibodies and are rearranged during B cell development
What B cell surface protein presents foreign antigens to T cells and induces antibody production?
MCH II

The MHCII proteins are part of the HLA system (HLA-DP, HLA-DQ, HLA-DR) are all present on antigen presenting cells including B cells, macrophages, and dendritic cells
What B cell protein provides the costimulatory signal for isotype class switch?
CD40; it is a costimulatory protein that binds to CD40L
What protein is a co-receptor to CD19 and is known as the Epstein-Barr receptor?
CD21
What protein is a co-receptor to CD21 and present on all non-plasma B cells?
CD19 is expressed on B cells and acts as a co-receptor with CD21; it is lost if the B cell undergoes transformation to a plasma cell
What B cell surface protein facilitates T cell activation?
B7 (CD80/CD86)
What B cell protein is involved in optimizing immune responses; it is present after pro-B but lost in plasma cells
CD20
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