Exam 1: Learning Objectives Flashcards
What are the major functions of the immune system
-distinguishes self vs non-self vs altered self
-wound healing and resolution of infection
-retain information in case of secondary exposure
-tissue homeostasis
-support commensal microbiota
3 major lines of defense
Physical barriers
Innate immunity
Adaptive Immunity
Inflammation
-Normal immune response to infection or damage
-immune cells activated, recruitment of additional cells and secretion of cytokines
4 cardinal signs of inflammation
heat, pain, redness, swelling
Cytokines
Proteins secreted by immune cells to communicate and signal with other cells
Two arms of the adaptive immune response
B cells: make and secrete antibodies to protect against extracellular pathogens before they invade
T cells: kill intracellular pathogens and produce cytokines
Hematopoiesis
Development of immune cells
-occurs in bone barrow
Erythroid
Leads to red blood cells (erythrocytes) and platelets
Myeloid
Leads to erythroid progenitor cells and white blood cells (neutrophils, eosinophils, basophils, macrophages, dendritic cells, mast cells)
Lymphoid
Leads to B cells, T cells, NK cells, and ILCs (innate lymphoid cells)
Two major types of adaptive immune receptors and what they recognize
B cells (immunoglobulin/antibody): surface bound and soluble forms, recognizes macromolecules
T cells: only surface bound, recognize peptides
Antigen
Any foreign molecule that can be bound by a lymphocyte receptor and initiate an immune response
Two types of T cells
CD4+ : helper T cells, produce cytokines, binds peptide-MHC II
CD8+ : cytotoxic T cells, kills target cells, binds peptide-MHC I
Antibodies
Soluble form of B cells
Immune-privileged
Organs that are excluded from the immune system: brain and eyes
Primary lymphoid organs
-Thymus, bursa, peyer’s patches, bone marrow
-Where lymphocytes mature and self-reactive cells are elimated
Secondary lymphoid organs
-Tonsils, spleen, lymph nodes, peyer’s patches, bone marrow
-Where lymphocytes encounter and respond to antigens
Entrance for microbial products (antigens) in lymph nodes
Afferent lymphatic vessels (via dendritic cells)
Lymphocyte entrance in lymph nodes
Blood capillaries to high endothelial venules
T cell zone in lymph nodes
T cell area, germinal center
B cell zone in lymph nodes
Lymphoid follicle, germinal center
Lymphocyte exit in lymph nodes
efferent lymphatic vessels
Entrance for microbial products in spleen
Blood via central arteriole
Lymphocyte entrance in spleen
Blood via central arteriole
T cell zone in spleen
Periarteriolar lymphoid sheath
B cell zone in spleen
B cell corona
Lymphocyte exit in spleen
Blood via veins
Entrance for microbial products in MALTs
Gut lumen via M cells
T cell zone in MALTs
Blood capillaries and HEVs
Lymphocyte entrance in MALTs
Blood capillaries & HEVs
B cell zone in MALTs
B cell follicle
Lymphocyte exit in MALTs
Efferent lymphatics
Asplenia
-Absence of a spleen
-Can be congenital or acquired
-Highly susceptible to certain infections
Mechanical barriers of the skin, lung, gut, and oral cavities
epithelial cells joined by tight junctions
skin & gut: longitudinal flow of air/fluid
lungs: movement of mucus by cilia
eyes/nose/oral cavities: tears, nasal cilia
Autonomic mechanical strategies for expelling pathogens
blinking, tears, swallowing, peristalsis, mucociliary escalator
Energetic mechanical strategies for expelling pathogens
coughing, sneezing, urination
Violent mechanical strategies for expelling pathogens
vomiting, diarrhea
Examples of chemical barriers
skin: fatty acids
gut: low pH, antimicrobial enzymes
lungs: pulmonary surfactant
cavities: antimicrobial enzymes
all: antimicrobial peptides
How do defensins function as antimicrobial peptides
defensins are amphipathic which allow them to disrupt membrane integrity of pathogens
promote protein unfolding, denaturation of bacterial toxins
How to pentraxins bridge pathogen and immune cells
promote engulfment of pathogens by phagocytes
Benefits of commensal microbiota
presence of microbiome makes it harder for pathogenic microbes to invade by competing for nutrients and space
required for immune homeostasis and proper barrier function
Complement system
complex system of 30+ proteins: kill invading microbes, trigger inflammation, regulate immunity
Complement fixation
irreversible attachment of C3b to pathogens
C3 activation
C3 cleaved unto C3a and C3b
thioester bond exposed
most C3b hydrolyzed by water
some C3b binds to surface of pathogens
3 pathways of complement activation
Alternative pathway
Lectin pathway
Classical pathway
Soluble alternative C3 convertase
80-90% complement activation
initiated by spontaneous hydrolysis of thioester bond of C3 to iC3 “tickover”
iC3 binds to B. Bb remains bound, Ba cleaved
resulting complex, iC3Bb functions as soluble C3 convertase
Alternative C3 convertase
80-90% complement activation
iC3Bb cleaves other C3s into C3a & C3b
C3b fragments bind to pathogen surface
C3b bind to B, produces C3bBb
Lectin pathway
triggered when MBL or other lectind binds to carbohydrates on microbial surface
MBL binds and activates MASP
MASP activates C4 and C2 to generate classical C3 convertase C4bC2a
Classical pathway
triggered when antibodies of C-reactive protein bind to bacterial surface and recruits C1 complex
activates C4 and C2 to generate C4bC2a
3 downstream outcomes of the complement system
Recruitment of inflammatory cells, opsonization of pathogens, perforation of pathogen cell membranes (MAC)
Opsonization
= engulfment
C3b coated pathogens bound by complement receptor 1 to promote phagocytosis
Anaphylotoxin production
= inflammatory cells
C3a, C4a, C5a
recruits neutrophils and monocytes to site of infection
also trigger contraction of smooth muscle, mast cell & basophil degranulation leading to histamine release and vascular permeability
Membrane attack complex
= lyse
perforation of pathogen cell membranes causes assembly of membrane attack complex
forms a pore in the membrane
Why are complement regulatory proteins necessary
could lead to immune mediated pathology and collateral damage
soluble factors prevent amplification
membrane bound factors prevent formation of C3 convertase & inactivates C3b
What are pattern recognition receptors (PRRs)
recognized pathogen-associated molecular patterns (PAMPs) presented by microbes
Major classes of Pattern Recognition Receptors
Membrane bounds receptors:
TLRs- toll like receptors, surface and endosomal
SRs’ scavenger receptors, surface
Cytoplasmic receptors
NLRs- NOD like receptors
RLRs- RIG-I-like receptors
TLR1:2 and TLR2:6 heterodimers
peptidoglycans
lipoproteins
(surface)
TLR3
double stranded RNA
(endosomal)
TLR4
lipopolysaccharide
TLR5
flagellin
TLR7 and TLR8
single stranded RNA
(endosomal)
TLR9
unmethylated CpG DNA
(endosomal)
How does assembly of adaptor components lead to intracellular signaling
engagement of PRRs leads to intracellular signaling cascade
oligomeric assembly brings weak interactions together quickly
Outcome of TLRs
NF-kB activation and cytokine production
Outcome of SRs
phagocytosis of microbes
Outcome of NLRs
NF-kB activation or cytokine (inflammasome/IL-1beta) production
Outcome of RLRs
production of type 1 Interferons
Difference in response between extracellular and intracellular LPS
Intracellular LPS induces death
Extracellular LPS ?
What are DAMPs
Damage-associated molecular patterns
Products of broken cells
Released by damaged or stressed tissues
How do Type 1 interferons amplify the innate response
Produce anti-viral proteins
Amplify the response through paracrine action
What are the main effector functions of tissue-resident macrophages
Sentinels for invasion by pathogens
Produce cytokines
Tissues maintenance
What is phagocytosis?
Process by which cells ingest or engulf particles or microorganisms
Stages of phagocytosis
1) binding to pathogen
2) ingestion
3) degradation in endosome/phagosome
4) further degradation in phagolysosome
Main effector functions of neutrophils
Phagocytosis
Respiratory burst
Production of NETs (neutrophil extracellular trap: capture & kill pathogens w/o ingesting them)
Extravasation
Leakage of fluid from blood vessel into tissue
4 stages of extravasation
1) rolling adhesion
2) tight binding
3) diapedesis
4) migration
Main effector functions of NK cells
Highly cytotoxic
Produce cytokine IFN-gamma
How do NK cells recognize altered self
NK cells are inhibited by target cell expression of MHC I
Loss of MHC I will lead to killing of infected host cell or tumor cell
Difference between mature B cell and plasma cell
B cell: antibodies bound to surface
Plasma: secrete antibodies
B cells turn into plasma cells when they encounter an antigen
Parts of an immunoglobulin
heavy chains, light chains, constant regions, variable regions, hinge region
Hypervariable regions
Form the antigen binding pocket
Epitope
Part of the antigen which the antibody binds
Found at end of variable region
Affinity
Measurement of binding strength of the antibody
4 mechanisms to generate antibody diversity
Before antigen encounter
1. somatic recombination
2. junctional diversity
3. heavy chain & light chain pairing
After antigen encounter
4. somatic hypermutation
Purpose of somatic recombination (VDJ recombination)
Produces high diversity in antibody specificity using only a limited number of genes
Overall outcome of somatic recombination
Variable region sequences constructed from random recombination of a light chain (V+J) and a heavy chain (V+D+J)
Steps of somatic recombination
1) recombinational signal sequences (RSS) mediate V/J and V/D/J rearrangements
2) recombination-activating genes (RAG-1 & RAG-2) mediate DNA rearrangements
? idk if this is right ?
How is recombination regulated
12/23 rule: recombination only occurs between a 12 bp spacer and a 23 bp spacer
RAG-1/2 only expressed by B & T cells
Junctional diversity
Created during DNA rearrangements
Diversity in the hypervariable regions of H & L chains
Consist of P N P nucleotides
Somatic hypermuation
After contact with an antigen, the rearranged gene segments encoding the variable region undergo many mutations with the goal of increasing affinity to the antibody
5 main isotype classes
IgG, IgM, IgD, IgA, IgE
Isotype switching
Antibody changing classes
Involves gene rearrangement between specific switch regions
how are monoclonal antibodies generated
1) immunized B cells fused with myeloma cells
2) grown in a medium that selects for only hybrid cells to survive
3) select for antigen-specific hybridoma
4) clone selected hybridomas (aka monoclonal antibody)
What are monoclonal antibodies used for
1) as therapies for large number of diseases (ex. organ transplants, non Hodgkin’s lymphoma, plaque psoriasis, rheumatoid arthritis, covid)
2) detect proteins on cell surface through flow cytometry
T cell receptor
Membrane bound glycoprotein
Consists of 2 polypeptide chains: TCRalpha & beta or TCRgamma & delta
Two regions: variable and constant
How is TCR diversity generated
VDJ areas undergo recombination using RAG1/2
Junctional diversity
Compare and contrast features of BCRs & TCRs
TCR:
Do not undergo somatic hypermutation, isotype switching
Only have 1 antigen binding site
Are not secreted
beta and delta have VDJ, alpha and gamma have VJ
BCR:
Have 2, 4, or 10 binding sites
Do not bind with MHC
Are secreted
Heavy chain has VDJ, light chain has VJ
Components of TCR complex
cytoplasmic tail, transmembrane region, constant (C) region, variable (V) region, antigen binding site
Steps of antigen processing and presentation
1 peptide degradation & peptide formation
2) peptide loading onto MHC molecules
3) peptide-MHC complex transport to the cell surface
4) presentation of antigen to T cells
Compare and contrast CD4+ and CD8+ T cell recognition
CD8+: recognize antigen from infected cells, associated with killer T cells
CD4+: recognize antigens from antigen presenting cells (APCs), associated with helper T cells, make cytokines
How are endogenous vs exogenous antigens processed for presentation
Endogenous: made by virus infected cells, fragmented by proteasomes, bind to MHC class I, presented to CD8+
Exogenous: captured by antigen presenting cells, fragmented by proteases, bind to MHC class II, presented to CD4+
Components of peptide loading complexes for MHC I and MHC II
Class I: alpha 1,2,3, beta2m
Class II: beta 1,2 and alpha 1,2
Cross presentation
Allows CD8+ T cells to recognize antigens presented by non infected dendritic cells
Prevents immune evasion by viruses
How is MHC diversity generated
genetic polymorphism, many different forms of the gene exist within the human population
MHC haplotype
Combination of MHC genes on a single chromosome, each individual inherits two parental haplotypes
Why is diversity at the MHC locus so important for immunity
The more unique MHCs you have, the more antigens you can respond to
Too many loci can lead to autoimmunity
What is Devil Facial Tumor Disease and why is it impacted by lack of diversity
An infectious tumor found in the tasmanian devil, which are all highly inbred and thus have low MHC diversity. This allowed for the disease to spread to virtually every single tasmanian devi
