1. Overview of the Immune System Flashcards
Where did the field of immunology grow from?
- observations that those who recovered from certain infectious diseases were then protected from the disease
What is immunity?
- state of protection from infectious disease
What was the earliest reference to immunity?
- those who recovered from plague could safely nurse the currently ill
What was the first recorded attempt to induce immunity?
- dried crusts from smallpox pustules were inhaled/ inserted into small cuts in the skin (variolation) > to prevent smallpox
How was the first vaccine developed?
- Edward Jenner observed that milkmaids who contracted cowpox were then immune to smallpox
- He reasoned that introducing fluid from a cowpox pustule could protect people from smallpox
- Inoculated 8 yr old boy with cowpox (to protect against smallpox)/ intentionally infected with cowpox > child did not develop smallpox
How was the induction of immunity to cholera developed?
- Pasteur grew the bacteria that causes fatal fowl cholera in culture
- Injected chickens with old bacterial culture > became ill but recovered
- Tested fresh bacterial culture on both previously exposed/ unexposed chickens > chickens with past exposure to old bacterial culture protected from disease/ only previously unexposed chickens died
What was the significance of Pasteur’s work with fowl cholera?
- aging had weakened the virulence of the bacterial pathogen
- this attenuated strain could be administered to provide immunity against the disease > called it a vaccine
What other vaccines did Pasteur develop?
- vaccinated sheep with anthrax bacteria attenuated by heat treatment
- first human vaccine with a series of attenuated rabies virus
What is the goal of vaccination?
- to expose individuals to a pathogen in a safe way > allowing immune cells to respond/ develop strategy to fight the pathogen
What infectious disease was successfully eradicated?
- smallpox was eradicated by universal vaccination
- problem: end of universal vaccination (↑ # of people with no immunity over time) > smallpox is now considered a potential bioterrorism threat
What are some goals of immunology research?
- not only the eradication of infectious disease through vaccination
- manipulate immune response > treatments to boost/ inhibit/ redirect immune cells (autoimmune disease/ cancer/ allergies)
What does the humoral branch of the immune system involve?
- B cells interact with foreign proteins (antigens) via BCRs
- differentiate into antibody-secreting (plasma) cells
- secreted antibodies bind to antigen > help clear from body
What does the cell-mediated (cellular) branch of the immune system involve?
- CD4+ T-helper cells interact with antigen > cytokine secretion (soluble messengers that direct cells of immune system)
- CD8+ Cytotoxic-T cells interact with antigen > killing of infected cells
What was the first evidence of the humoral response?
- serum from animals immunized with diphtheria can transfer immune state to unimmunized animals
What was the first evidence of the cellular/ cell-mediated response?
- certain WBCs termed “phagocytes” ingested foreign material
- more active in immunized animals > major effectors of immunity
Who won the 2018 nobel prize in physiology/ medicine?
- James Allison/ Tasuku Honjo > cancer therapy by inhibition of negative immune regulation
- PD-1/ CTLA-4 = T-cell breaks that inhibit T-cell activation
- antibodies against PD-1/ CTLA-4 block the breaks > T cell activation
What are the 4 main differences between innate/ adaptive immunity?
- response time: minutes/ hours vs days
- specificity: limited/ fixed vs highly diverse/ adapts to improve
- response to repeat infection: same vs more rapid/ effective
- major components: barriers/ phagocytes/ PRRs vs T/B cells
How do the innate/ adaptive responses work cooperatively?
- activation of innate response > produces signals required to stimulate/ direct behaviour of adaptive immunity
What is hematopoiesis?
- process by which HSCs differentiate into mature blood cells
What is the site of hematopoiesis?
- site shifts during fetal development (starts in yolk sac)
- ultimately seed in bone marrow at late stages of fetal development
What are 4 major properties of HSCs?
- give rise to all types of blood cells
- rare > less than 1/ 50,000 of cells in bone marrow
- most are quiescent under normal homeostatic conditions (only a few divide)
- self-renewing (some daughter cells retain stem cell characteristics)
What is the fate of dividing HSCs?
- self renew > some daughter cells retain stem cell characteristics
- daughter cells can differentiate into progenitor cells
- progenitor cells lose their self-renewal capacity > become progressively more committed to a particular blood cell lineage
What do self-renewing HSCs differentiate into?
- CMP = Myeloid Progenitor Cell
> gives rise to RBCs/ platelets/ granulocytes/ monocytes/ macrophages/ some DCs - CLP = Lymphoid Progenitor Cell
> gives rise to B and T lymphocytes/ ILCs/ some DCs
What is the role of RBCs? (erythrocytes)
- main function is gas exchange
- bind antibody complexes for clearance by macrophages
- can generate compounds like nitric oxide that damage microbes
What is the role of platelets?
- derived from megakaryocytes that reside in bone marrow
- circulate in blood > participate in blood clot formation
- clots prevent blood loss/ provide barrier against pathogen invasion
What are the members of the innate immune system?
- granulocytes (neutrophils/ eosinophils/ basophils/ mast cells)
- monocytes/ macrophages/ some DCs
What are the granulocytes named after?
- named for the densely staining granules in their cytoplasm
- Neutrophils/ Eosinophils/ Basophils/ Mast cells
How can the granulocytes be distinguished under the microscope?
- different staining properties of granules in standard H&E staining
> neutrophil granules stain neutral pink
> eosinophil granules stain brilliant pink
> basophil granules stain blue - neutrophils have multilobed nucleus
What is the most abundant blood cell?
RBCs
What are the majority of circulating leukocytes (WBCs)?
Neutrophils (50-70%)
What is the main cellular component of pus?
Neutrophils
What is used medically as an indication of infection?
Leukocytosis
- transient increase in # of circulating neutrophils
What is the role of neutrophils?
- swarm to infection site in response to inflammatory molecules
- phagocytosis
- secrete antimicrobial and tissue-remodeling molecules
What is the role of eosinophils?
- coordinate defence against parasitic organisms, including helminths (parasitic worms)
> cluster around worms/ damage membranes by releasing granule contents
What is the role of basophils?
- non-phagocytic
- Histamine in basophil granules ↑ blood vessel permeability/ ↑ smooth muscle activity > allows immune cells to access infection site
- response to parasites (helminths)
- allergy symptoms
What are the 3 main functions of proteins in granulocyte granules?
- damage pathogens directly
> defensins (antimicrobial protein in neutrophils) - regulate trafficking and activity of other WBCs
> RANTES (chemokine in eosinophils)
> IL-4 (cytokine in basophils/ mast cells) - contribute to tissue remodelling at infection site
> collagenase (protease in neutrophils)
What are the professional APCs?
monocytes/ macrophages/ DCs
What happens when pAPCs encounter pathogens? (3x)
- secrete proteins that attract/ activate other immune cells
- internalize pathogens via phagocytosis > digest pathogenic proteins into peptides > present them to T cells via MHC II = antigen presentation
- upregulate costimulatory molecules required for T cell activation
What are the 2 broad categories of monocytes?
- Inflammatory monocytes
> enter tissues in response to infection - Patrolling monocytes
> crawl along blood vessels monitoring repair
> provide reservoir for tissue-resident monocytes
What is the role of macrophages?
- monocytes that migrate to tissues can differentiate > macrophages
- dual role in immune response
> contribute directly to clearance of pathogens via phagocytosis
> act as pAPCs
Where do most tissue-resident macrophages arise from?
- most arise early in life from embryonic cells rather than from circulating monocytes
> these can self-renew/ assume tissue-specific functions
What are some examples of tissue-specific macrophages?
- all macrophages so phagocytic cells
- microglia in brain
- kupffer cell in liver
- langerhans cell in skin
- subcapsular sinus macrophage in lymph nodes
What is the role of DCs?
- arise from both myeloid and lymphoid lineages of HSCs
- immature DCs capture antigens > process them > migrate to lymph nodes for antigen presentation to naive T cells
Since B/T lymphocytes appear identical under a microscope, how can they be differentiated?
- lymphocytes express different CD surface proteins
> markers used to differentiate lymphocyte subpopulations (B cell/ Th cell/ Tc cell/ ILC-includes NK cells)
Why do plasma cells have a large cytoplasm/ lots of ER/ golgi?
- make antibodies (need organelles to make protein)
What is the role of activated B cells? (3x)
- can act as pAPCs
- differentiate into plasma/ memory cells
- express costimulatory molecules required to activate T cells
How many BCRs does each B cell express?
- each B cell expresses a BCR (surface immunoglobulin) with unique specificity
- each of 150,000- 300,000 BCRs on B cell has identical binding sites for antigen
What is the role of plasma cells?
- lose expression of surface immunoglobulin (BCR)
- become highly specialized for antibody secretion
> each plasma cell secretes 100’s-1000’s of antibodies per second
What are the 2 major types of T cells?
Th cell- CD4+ T cells recognize antigen in complex with MHC II
Tc cell- CD8+ T cells recognize antigen in complex with MHC I
What happens when naive CD8+ Tc cells bind to MHC peptide complex?
- become activated/ proliferate/ differentiate into CTLs
- CTLs kill cells that display non-self antigen complexed with MHC I
What happens when naive CD4+ Th cells bind to MHC II peptide complex?
- become activated/ proliferate/ differentiate into effector T cell subset
> Th1/ Th17 > response to intracellular pathogens
> Th2/ Tfh > response to extracellular pathogens
> Treg > quell autoreactive responses/ limit normal T cell responses
How do NK cells work?
- express receptors for self MHC I > inhibits ability to kill
> when encounter cells that lost their MHC I > inhibiting receptor no longer engaged > release cytotoxic granules killing target cell - express FcRs > link to antibodies specific for pathogenic proteins
> brings NK cell in contact with target cell > releases granules to kill
Where do immune cells develop?
- Primary lymphoid organs
> Bone marrow/ Thymus
Where is the immune response initiated?
- Secondary lymphoid organs
> LNs/ Spleen/ MALT (tonsils/ appendix/ peyers patches ext)
How does the stem cell niche in the bone marrow support hematopoiesis?
- Perivascular niche > lines the blood vessels
> quiescent long-lived HSCs nurtured by perivascular/ endothelial cells
> some HSCs divide/ differentiate > myeloid/ lymphoid lineages - Endosteal niche > lines the bone
> osteoblasts regulate the differentiation of lymphoid cells
What are the most active sites of hematopoiesis?
- Femur/ Humerus/ Ileum/ Sternum (flat bones)
Where do B cells develop?
- B cell progenitors in endosteal niche in association with osteoblasts
- more mature B cells in central sinuses of bone marrow
> exit to complete maturation in the spleen
Where do T cells develop?
- initially develop in bone marrow
- migrate to thymus to achieve full maturity
How do T cells develop?
- T cell progenitors exit bone marrow at very immature stage > complete development in thymus
- enter thymus in blood vessels at the corticomedullary junction
> double negative DN (neither CD4/ CD8 markers) - DN cells travel to subcapsular cortex > proliferate
- travel to cortex > where first express mature TCRs/ interact with cTECs
> upregulate both CD4/ CD8 > become double positive DP - DP cells tested for ability of TCRs to bind MHC-peptide complexes on cTECs > positive/ negative selection
- positively selected DP thymocytes mature/ lose a marker > become single positive SP
> migrate to thymic medulla where they encounter mTECs - mature SP cells exit thymus via blood vessel of corticomedullary junction (as entered)
What is positive/ negative selection?
- DP cells in cortex tested for ability of TCRs to bind MHC-peptide complexes on cTECs (cortical thymic epithelial cells)
> negative selection > bind with too high affinity (self-reactive) > induced to die
> positive selection > bind with intermediate affinity > survive
What happens in the thymic medulla?
- SP thymocytes encounter mTECs (medullary thymic epithelial cells)
- mTECs express proteins otherwise exclusively found in other organs
> negatively select autoreactive T cells not deleted in cortex
What happens in secondary lymphoid organs?
- lymphocytes encounter antigen > become activated > undergo clonal expansion/ differentiate into effector cells
What are 3 key features of SLOs? (secondary lymphoid organs)
- have anatomically distinct regions of B/ T cell activity
- develop lymphoid follicles
- connected via blood/ lymphatic circulatory systems
What are lymphoid follicles?
- areas in SLOs for selection of B cells that produce high-affinity antibodies
What is the lymphatic system?
- network of vessels with a major role in immune cell trafficking
- lymphatic vessels filled with lymph derived from blood plasma that seeps through capillaries into surrounding tissue)
- most of this interstitial fluid returns to blood through venule walls
> remainder enters the lymphatic vessels
How is lymph returned to blood circulation?
- thoracic duct > collects lymph from whole body except right arm/ right side of head > empties into left subclavian vein
- lymph from right arm/ right side of head collected > right lymphatic duct > drains into right subclavian vein
What are the divisions of the lymph nodes?
- Cortex > B cells/ macrophages/ follicular DCs
- Paracortex > T cells/ DCs
- Medulla > sparsely populated lymphoid cells/ plasma cells
How does antigen enter lymph nodes?
- antigen enters cortex via afferent lymphatic vessels
> either in particulate from/ presented on surface of migrating APCs - particulate antigen can be presented on surface of resident DCs in paracortex
How do T cells enter lymph nodes?
- T cells enter cortex through HEVs (high endothelial venules)
- browse MHC-peptide complexes on DCs in the paracortex
What happens to T cells in lymph nodes?
- T cells browse MHC-peptide complexes on DCs in the paracortex
- if bind MHC-peptide complex > proliferate/ differentiate > effector cells
- if do not bind MHC-peptide complex > exit lymph node via efferent lymphatics in medulla (not via blood)
What allows T cells to browse APC surfaces in lymph nodes?
- APCs wrap themselves around long processes of FRCs
> gives T cells ample opportunity to browse MHC-peptide complexes - fibroblastic reticular cells (FRCs) in paracortex guide T cell movements
What happens to B cells in lymph nodes?
- like T cells enter via HEVs (high endothelial venules)
- migrate to follicles > bind/ process antigen > present on surface > partially activated
- moves to paracortex > binds to Th cell that recognizes its antigen-MHC surface > becomes fully activated
What regulates the activation of B cells in lymph nodes?
- FDCs (follicular dendritic cells) in follicles
> FDCs are not pAPCs/ do not activate naive T cells
What are the different types of B cell follicles?
- Primary follicle > follicle without a germinal center
- Secondary follicle > follicle that develops a germinal center
Where does antigen affinity of B cells increase?
- affinity maturation in germinal centers of follicles
> somatic hypermutation of BCR genes of a proliferating B cell clone - cells with highest affinity receptors survive/ differentiate > plasma cells
Where are plasma cells located?
- some stay in medulla (lymph node)
- some exit LN via efferent lymphatics > bone marrow
- whether in LN/ bone marrow > release antibodies > bloodstream
What is the main role of the spleen?
- filters blood > first line of defence against blood-borne antigens
What are the 2 main compartments of the spleen?
- Red pulp > where old/ defective RBCs are removed
- White pulp > where immune response initiated
How do antigens enter spleen?
- blood-borne antigens enter spleen through splenic artery
> spleen is not supplied by lymphatic vessels - antigens interact with cells at marginal zone
> antigen trapped/ processed by DCs > travel to PALS
