APPP Quiz: Hematopoietic System and Body Defence Systems Flashcards
What are the 3 major functions of blood?
- transportation and distribution (O2, CO2, nutrients, hormones, wastes)
- regulation and homeostasis (pH, body temperature, water content of cells)
- protection and repair (blood loss, inflammation, wound healing)
What are the components of plasma? (6)
- electrolytes
- water
- proteins (albumins, globulins, fibrinogen/blood coagulation components, complement proteins and cytokines)
- wastes
- nutrients/vitamins/hormones
- gases (N2, O2, CO2)
What are the 3 different types of globulins and what are their functions?
- alpha – transport of lipids/metals
- beta – transport of hormones/vitamins
- gamma – immunoglobulins/antibodies
Rank formed components by number, from most to least. (8)
- erythrocytes
- platelets
- reticulocytes
- neutrophils
- lymphocytes
- monocytes
- eosinophils
- basophils
Rank formed components by size, from largest to smallest. (8)
- monocytes – largest WBCs
- granulocytes (WBC) – all considered to have comparable sizes
- lymphocytes – smallest WBCs
- erythrocytes (RBC)
- platelets
What are reticulocytes?
immature RBCs released by bone marrow
- mature into final RBC after 1-2 days in peripheral circulation
Lifespan of Formed Components
- erythrocytes: 100-120 days
- platelets: 5-10 days
- monocyte: months
- lymphocyte: hours to years
- neutrophil: 6 hours to few days
- eosinophil: 5-10 days
- basophil: few hours to few days
What is hematocrit?
% erythrocytes in whole blood
Describe the structure of hemoglobin.
- 4 protein helixes: 2 alpha and 2 beta globin chains
- heme molecule (porphyrin ring and Fe2+ core)
- 4 sites for cooperative binding of O2
- O2 binds to heme molecule in one monomer, which induces conformational change in the other three molecules, leading to increased O2 affinity
What are the 3 factors that affect O2 binding capacity?
- hematocrit
- other gases (CO2 and CO)
- RBC diseases
What are the 4 factors that affect O2 binding affinity?
- pH and temperature
- 2,3-biphosphoglycerate
- fetal hemoglobin (δ chain instead of β chain)
- RBC diseases
How does erythropoeisis occur?
initiated by low O2 (reduced oxygen-carrying capacity of blood)
- kidney senses drop in O2 and releases erythropoietin (hormone)
- erythropoietin stimulates RBC production in bone marrow
- increased O2 reduces erythropoietin production in kidney – NEGATIVE FEEDBACK
What is polycythemia?
overproduction of RBCs (high hematocrit)
What is secondary polycythemia?
caused by factors other than RBC production such as hypoxia, sleep apnea, certain tumours
What are alpha and beta thalassemias?
defects in production of the respective hemoglobins
What is sickle cell anemia?
HbS instead of HbA
- sickle shape in hypoxic conditions
What are the 2 causes of anemia?
- decrease production of RBC
- increase turnover of RBC – abnormal hemoglobins
Granulocytes
- polynucleated
- activated through binding of ligands to cell surface receptors (toll-like, cytokines, immunoglobulins)
- contain cytoplasmic granules of inflammatory cytokines that are released upon activation
Neutrophils
- most abundant WBC
- short lifespan (1-5 days)
- mobile first responders – follow chemokine gradients
- amplify response – secrete cytokines, recruit/activate other immune cells
- kill invaders via phagocytosis (activation of PAMPs), degranulation (release soluble anti-microbials and lytic enzymes), neutrophil extracellular traps (NETs)
- eliminated through apoptosis
Eosinophils
- attack organisms that are too big for phagocytosis
- role in asthma and allergies
- counts increase with rheumatoid arthritis, Hodgkin’s disease, and Addison’s disease
- release granule contents such as enzymes and cytokines to damage infectious organisms while creating localized tissue damages
- release granule contents such as interleukins, leukotrienes, and PGE2 to amplify immune response
Basophils
- histamine
- serotonin
- heparin
- several proteases
- degranulation induce by IgE or IgG – FceRI is receptor for IgE
Agranulocytes
- no granules
- single-lobe nucleus
Monocytes
- migrate out of blood into tissue for local patrol
- responsible for presenting foreign materials to immune systems
- types include macrophages and dendritic cells
Lymphocytes – Natural Killer Cells
- contain large granules
- lack antigen-specific receptors
- roles in tumour surveillance
Lymphocytes – T- and B-Lymphocytes
- cellular mediators of adaptive/acquired immunity
- activate and respond to innate immunity – cytotoxic, specificity (specific antigen receptor), generates memory
- specialized and adaptable
- eliminates pathogens and infected cells
When are neutrophil counts higher?
- bacterial infection
- fungal infection
When are lymphocyte counts higher?
viral infection
When are monocyte counts higher?
fungal/viral infection
When are eosinophil counts higher?
- viral infection
- parasite infection
- allergic reaction
When are basophil counts higher?
- allergic reaction
- thyroid disease
What are the 2 functions of thrombocytes (platelets)?
- hemostasis, coagulation, and wound healing
- participation in innate and acquired immune functions – ie. serotonin storage and release
Platelet Morphology
- originate in bone marrow as fragments of megakaryocytes
- no nucleus
- different types of cytoplasmic granules in which contents are released by surface receptor binding – dense (serotonin, ADP), alpha (clotting factors)
How does thrombopoiesis occur?
negative feedback pathway in bone marrow
- hormonally regulated by thrombopoietin (TPO) produced by liver (main), kidney and bone marrow
- TPO is bound to surface of platelets and destroyed, then free circulating TPO concentration increases with low platelet counts to induce production by megakaryocytes in bone marrow – NEGATIVE FEEDBACK
- myeloid stem cell, megakaryoblast, megakaryocyte with platelet precursor extensions, platelets
Explain the process of the hematopoietic system renewal.
- mature blood cells have short lifespan and constant renewal is necessary
- hematopoiesis starts in bone marrow
- hematopoiesis is regulated by vast network of cytokines and growth factors
- synthetic versions of growth factors used as clinical therapies
What are the 5 properties of the immune system?
- mobility – systemic protection against localized insults through rapid cell migration to infected area
- replication – immune response is amplified through clonal expansion and signaling cascade
-specificity – prevent recognition of non-cross-reacting antigens and identify self vs. non-self - memory – faster and stronger response to (similar) subsequent infection
- diversity – combinatorial library of antigen receptors to recognize innumerable pathogens
What are the 4 areas of a lymph node?
- cortex – unactivated mature T cells
- germinal centre – activated B cell development (plasma cell development and antibody affinity maturation)
- para-cortex – mix of unactivated and activated mature T cells
- medulla – funnels to outgoing vessels to collect mature immune cells and antibodies for distribution to lymphatic/blood circulation
What are the cellular mediators of the innate response and what are their functions? (8)
blood:
- neutrophils – ingest (phagocytotic) and destroy
- eosinophils – release toxic molecules and destroy
- monocytes – ingest, destroy and antigen presentation
- natural killer cells – kills cancer or viral infected host cells
- basophils – release first chemicals that start inflammation
peripheral tissues:
- macrophage – ingest, destroy and antigen presentation
- dendritic cells – ingest, recruit others and antigen presentation
- mast cells – release first chemicals that start inflammation
How are pathogens detected in the innate response?
recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors such as toll-like receptors (TLR)
- recognize PAMPs essential to microorganism survival or pathogenecity
Tissue Monocyte Derivatives
Macrophages
- located in every tissue
- some circulate in blood and migrate with rapid response to insults in tissues
- inactive lifespan: months to years
- active lifespan: day to weeks
- phagocytosis
- antigen presentation (APC)
- initiation of tissue repair
Monocyte Derivatives
Dendritic Cells
- immature: in blood and tissues interfacing the outside (skin, nose, lungs, stomach)
- mature: move to lump nodes and interact with T cells and B cells
- phagocytes
- antigen-presenting cells
- activate adaptive immune response
- regulate T cell activation
B cells vs. T cells
- function
- development
- B: attack invaders outside cells, can act as antigen-presenting cells (only one type of antigen receptor) to activate helper T cells, can induce differentiation into plasma cells for antibody production, can induce differentiation into memory B cells
- T: attack invaders inside cells (inaccessible to antibodies), no antigen-presenting properties
- B: mature and negatively selected in bone marrow
- T: mature in thymus (but produced in bone marrow)
Helper T cell
assist other immune cells with maturation/activation
- CD4+ co-receptor (activates cytotoxic T cells and B cells)
- binds to MHCII (antigen-presenting cell)
- 70% of all T cells
Cytotoxic T cell
virally infected cells and tumour cells
- CD8+ co-receptor (induces release of cytotoxic molecules)
- binds to MHCI (infected cells)
- 25% of all T cells
T Regulatory cell
suppress and regulate auto-reactive T cells
- CD4 and CD25
Memory T cell
proliferate when reintroduced to antigen
- CD4+ or CD8+
What are the 4 things that innate and acquired immunity overlap in?
- co-activation of B cells through BCR and TLR
- antigen-presentation by macrophage
- complement proteins
- cytokines (interferons, TNF, IL-1)
What can occur if there is a reduction or dysfunction in the adaptive immune response?
- over-activity of innate system
- exaggerated cytokine response
- compromised normal immune functions
- coagulation dysfunctions and other organ system failures
How does inflammation occur?
cross-talk and signaling through release of cytokines and inflammatory chemicals/hormones
What are the 2 types of mediators of the inflammatory response?
- pre-formed mediators
- newly synthesized mediators
Protein Mediators of the Immune Response
What are the 5 types of cytokines (protein signaling molecules) and their functions?
- interferons (type 1 alpha and beta, type II gamma) – innate antiviral response
- chemokines (MCP-I, IL-8, etc.) – chemotaxis proinflammatory
- interleukins (IL-6, IL-10, etc.) – leukocyte development, responsible for cross-talk between RBCs
- TNF-a – acute phase response, coagulation/stop inflammation and call for help
- growth factors( VEGF, GM-CSF, TGF beta, etc.) – growth differentiation/proliferation of immune cells
Chemical and Hormonal Mediators of Immune Response
signaling molecules activated or released by immune cells and injured cells
- mediate inflammatory responses
- amino acid derivatives: histamine, serotonin
- lipid derivatives: prostaglandins, leukotrienes (both eicosanoids)
- hormones and other neurotransmitters: bradykinin, substance P
Amino Acid Mediators of Humoral Immune Response
Histamine
- derived from amino acid histidine
- produce, store, and release, mainly from mast cells
- serves important roles in immune responses and inflammation process
- binds to and activates GPCRs (H1 to H4 tissue-specific subtypes)
- vasodilation, increase permeability
Amino Acid Mediators of Humoral Immune Response
Serotonin
- derived from amino acid tryptophan
- produced by enterochromaffin cells and stored mainly in platelets
- neurotransmitter serves multiple functions in homeostasis (GI, CNS, body defence)
- binds to and activates GPCRs (5HT1 to 7 tissue- and function-specific subtypes)
- vasodilation, increase permeability, pain, fever
Lipid Mediators of Humoral Immune Response
Eicosanoids (Prostaglandins and Leukotrienes)
- synthesized with arachidonic acids
- made by oxidation of omega-6 fatty acids
- 20 carbons, 4 double bonds
- biosynthesis by cyclo-oxygenase (prostglandins) and lipo-oxygenase (leukotrienes)
Lipid Mediators of Humoral Immune Response
Prostaglandins
vasodilation, pain, fever
Lipid Mediators of Humoral Immune Response
Leukotrienes
increase permeability, leukocyte adhesion, and chemotaxis
Lipid Mediators of Humoral Immune Response
Platelet Activating Factor
vasodilation, increase permeability, leukocyte adhesion, and chemotaxis
What are the functions of eicosanoids?
- essential control of inflammation and immunity
- synthesized upon activation signals
- specific inhibition of major biosynthesis enzymes is a major mechanism to control inflammation
- role in systemic inflammatory response and cellular defense functions
Eicosanoid
Prostacyclin and Prostaglandin D/E
vasodilation
Eicosanoid
Thromboxane A2 and Leukotrienes C/D/E
vasoconstriction
Eicosanoid
Leukotrienes C/D/E and Prostaglandin D
vascular permeability
Eicosanoid
Leukotriene B and HETE
chemotaxis and leukocyte adhesion
Eicosanoid
Leukotrienes C/D/E
bronchoconstriction
Explain how the immune system distinguishes self from non-self.
major histocompatibility complex (MHC) – I and II
- cell surface molecules
- present as peptide epitope on surface of cell
- normal functions include playing essential roles in immune system engagement
- known as the human leukocyte antigen (HLA)
- unique to each of us – highly polymorphic
MHC I
- present on all nucleated cells and platelets
- display infectious epitopes – from hijacked cells’ synthesis of infectious agent (non-self), and recognized by cytotoxic T cells (CD8+ receptor)
- special breaks to ensure a regulated immune activation (CTLA4 and PD1 receptors)
MHC II
- present on antigen-presenting immune cells (macrophages, dendritic cells, and B cells)
- display degraded/digested pathogen epitopes that are recognized by helper T cells (CD4+ receptor)
- special breaks to ensure a regulated immune activation (CTLA4 and PD1 receptors)
Genetic Recombination of T cell Receptors (TCR)
- receptor has alpha and beta chain subunits
- each subunit is generated through recombination of 1 segment each from the V and J loci (alpha), and D and J loci (beta)
- generates immunological diversity, as each mature T cell will have a different combination of subunits that recognize different antigens
Positive and Negative Selection of T cells in Thymus
- occurs during development/maturation
- positive selection of affinity for MHC I or MHC II (antigen presentation cell surface molecules) with either CD4 or CD8 receptors
- negative selection of cells that recognize self-antigens cannot be autoreactive
- 2% survival
Diversity of B cell Receptors (BCR)
- each mature B cell is covered with a single type of BCR
- BCRs are predecessors of antibody that recognized one antigen
- two identical binding sites on each fork of the Y
- BCR can bind antigen directly in absence of co-receptors
- B cells with BCR that recognizes self-antigens are destroyed (central and peripheral tolerance)
Explain how B cells are activated via the T-cell dependent pathway.
- antigen binds to BCR
- internalization and MHC II presentation to helper T cells
- helper T cell releases cytokines
- activated B cell differentiates into plasma cells for antibody production and memory B cells
What are immunoglobulins?
family of globular proteins (Ig)
- bind with specificity and affinity to antigen
- produced and secreted by activated B- lymphocytes following earlier encounter with the infectious materials
Describe the structure of immunoglobulins.
- Y-shaped molecule made of 4 protein chains – 2 identical light, 2 identical heavy
- constant region
- variable region
What is the constant region of immunoglobulins?
stem of monomer and lower part of Y
- Fc region: recognized by Fc receptor on leukocytes/complement factors
What is the variable region of immunoglobulins?
gives specificity and affinity to singular antigen
- two identical regions on Y arms (mirror images)
- Fab-binding sites – antigen-binding region
- identical on same antibody, but highly variable across antibodies
What is second recombination?
switching the Fc region and the class switching mechanism
- constant (Fc) region of BCR can go through a second recombination after the activation of a mature B-cell (CLASS SWITCHING)
- generates antibodies with the same antigen recognition region (Fab), but different constant region (Fc)
- creates functional diversity by increasing the numbers of effector processes Ab-binding can engage
What are the 5 immunoglobulin classes and what is classification based on?
based on which heavy chain is present
- IgA – alpha
- IgD – delta
- IgE - e
- IgG - gamma
- IgM – mu
What is the function of IgM?
- main antibody of primary responses
- best at fixing complement
- the monomer form of IgM serves as the B cell receptor
What is the function of IgG?
- main blood antibody of secondary responses
- neutralizes toxins
- opsonization
- Fc binds to phagocytes
What is the function of IgA?
secreted into mucus, tears, saliva, colostrum
What is the function of IgE?
- antibody of allergy and antiparasitic activity
- Fc binds to mast cells and basophils
What is the function of IgD?
B cell receptor
What are the functional outcomes of antibody binding? (6)
recruit cytotoxic immune cells and complement proteins by providing recognition and destruction signals – protective mechanism of binding antibodies to antigens
- agglutination
- neutralization
- opsonization
- antibody-mediated cytotoxicity (ADCC)
- inflammation
- complement activation
What is agglutination?
clumping of antigen-containing pathogens
- enhances phagocytosis
- reduces number of infectious units to be dealt with
What is neutralization?
blocking active sites
- blocks toxins from binding
- blocks adhesion of pathogens to host cells
What is opsonization?
coating pathogens with antibody for recognition/to enhance phagocytosis
What is antibody-mediated cytotoxicity (ADCC)?
antibodies attached to target cell cause destruction by non-specific immune system cells
- NKC, macrophages, neutrophils, and eosiniphils
- antibodies assist in detection of virus- and bacteria-infected host cells
- cytotoxic immune-cell-surface Fc receptor binds immunoglobulin motif (Ig) on antibody
- binding causes degranulation leading to cell apoptosis
What is inflammation?
amplification of the immune response and attract other immune effectors
- disruption of cell by complement/reactive protein attracts phagocytic and other defensive immune system eclls
What is complement activation?
opsonization and membrane attack complex
- cell lysis
Complement System
What are complement factors?
protein and glycoprotein components
- around 30 small peptides (‘C’ designation– ie. C1)
- synthesized primarily in liver
- represent 5% of globulin content in blood
- activated through cascade of proteolytic activities
Complement System
What are the 3 activation pathways?
- classical
- alternative
- lectin
(C3b is deposited on microbe)
Complement System
What is the classical pathway?
antigen:antibody complexes for activation (adaptive/specific)
Complement System
What is the alternative pathway?
non-specific (antibody-independent, C3 autolysis)
Complement System
What is the lectin pathway?
binding of specific carbohydrates on pathogens, aided by C-reactive proteins
Complement System
What are the 3 functional outcomes of complement system activation? What mediates all 3 processes?
C3b binding mediates all 3 processes
- opsonization: coats infected cells for recognition by phagocytes
- chemotaxis: directs immune cells to infection (inflammation)
- infected-cell lysis: formation of membrane attack complex (MAC)
Direct Cell Lysis from Complement Activation
What is the membrane-attack complex (MAC)?
- result of classical, alternative, and lectin pathways
- forms on membrane of bacteria – multiple complement factors come together, interact to insert into/through lipid bilayer
- forms transmembrane channels – non-specific (free diffusion of molecules and water), cell death occurs if sufficient MAC complexes form
Acquired Immune System
What is the primary response?
after 1st exposure to antigen
- response 5-10 days
- after contact with Ag
- IgM secretion
- low IgG production
- lower antibody affinity
Acquired Immune System
What is the secondary response?
after 2nd exposure to antigen
- fast response (1-3 days after contact)
- IgG secretion
- heavy chain class switching
- higher antibody affinity
What is immune memory?
- conferred by the acquired immune system through generation of memory T cells and B cells from the first encounter
- second encounter with same pathogen will lead to a response with greater magnitude and with faster kinetics
- basis of vaccination – first encounter is deliberately introduced through injected materials
- immunocompromised individuals generate weaker or shorter-lived immune responses to infections and vaccination compared to those who are not
Properties of the Immune System
Which branch of the immune system is ‘mobility’ attributed to?
innate
Properties of the Immune System
Which branch of the immune system is ‘replication’ attributed to?
acquired = innate
Properties of the Immune System
Which branch of the immune system is ‘specificity’ attributed to?
acquired»_space; innate
Properties of the Immune System
Which branch of the immune system is ‘memory’ attributed to?
acquired
Properties of the Immune System
Which branch of the immune system is ‘diversity’ attributed to?
acquired
