Blood and the immune system Flashcards
1
Q
How many L of blood does an adult human have?
A
4-6L
2
Q
What is the haemocrit?
A
The packed cell volume in blood
3
Q
What % of the blood is plasma?
A
55%
4
Q
What technique is used to collect blood for analysis?
A
Venipuncture from a superficial vein
5
Q
Why is blood taken from a vein?
A
Superficial veins are easy to locate
Vein walls are thinner than arteries
Blood pressure is low, so wound seals easily
6
Q
When would an arterial puncture be used?
A
To check gas exchange efficiency in the lungs
7
Q
What are the 5 key functions of blood?
A
- Transporting dissolved gasses
- Regulating pH and ion composition of interstitial fluids
- Restricting blood loss at sites of injury
- Defence against pathogens and toxins
- Stabilising body temperature
8
Q
Explain how blood regulates pH and ion composition
A
- Diffusion to eliminate local ion deficiencies or excesses
- Absorb acids produced by active tissues e.g. lactic acid produced during exercise
9
Q
Explain how blood stabilises body temperature
A
- Heat redistribution from active skeletal muscles
- Heat loss through skin if body temp is too high
- Warm blood directed to sensitive organs e.g. brain is temperature too low
10
Q
What are albumins?
A
Major plasma proteins that contribute to plasma osmolarity
11
Q
What is the key role of albumins?
A
‘Molecular taxis’
Transport hydrophobic molecules including fatty acids, thyroid hormones, and steroid hormones
12
Q
How do albumins maintain blood pressure?
A
Can pull water from interstitial tissues into the blood
13
Q
How do albumins transport other molecules?
A
Hydrophobic pockets allow other molecules to bind to albumins and be transported around
14
Q
What type of molecule is an antibody?
A
Immunoglobulin
15
Q
How is each immunoglobulin domain coupled?
A
Disulphide bonding via cysteine residues
16
Q
How many immunoglobulin domains make up a heavy chain?
A
4
17
Q
How many immunoglobulin domains make up a light chain?
A
2
18
Q
How many antigen binding receptors does IgG have?
A
2
19
Q
What kind of binding molecule is an antibody?
A
Bivalent - it binds by both its arms at the same time
20
Q
What is the role of globular transport molecules?
A
Bind small ions, hormones, and compounds that would otherwise be removed by kidneys or have low solubility in water
21
Q
Give 3 examples of transport molecules
A
- Hormone-binding proteins
- Metalloproteins e.g. trasnferrin
- Apolipopproteins
- Steroid-binding proteins
22
Q
What is the role of fibrinogen?
A
Soluble fibrinogen is converted to insoluble fibrin during blood clotting
A meshwork forms to prevent blood loss
23
Q
What is the structure of fibrinogen?
A
- Made of 6 chains
- 2 gamma chains with a globular domain and an alpha helical region
- 2 beta chains with a globular and alpha helical region
- 2 alpha chains that are all alpha helical
24
Q
How is fibrin generated during clotting?
A
- Thrombin is produced during coagulation cascade
- Thrombin is a serine protease
- Thrombin clips the end of the fibrinopeptides off the alpha and beta chains of fibrinogen
- Gly-His-Arg or Gly-Pro-Arg sequences are exposed
- These sequences can bind to the globular domain of the gamma chain, forming a meshwork of insoluble fibrin
- Blood clots
25
What is the role of plasma expanders?
Increase blood volume temporarily e.g. after blood loss or injury
26
Properties of plasma expanders
Large carbohydrate molecules to maintain proper osmotic concentration
27
What proportion of human cells do rbcs make up?
1/3
28
4 structural points of rbcs
Biconcave disc
Large SA:V ratio
Form stacks like dinner plates through narrow vessels
Bend and flex when entering small capillaries
29
Red blood cell composition (2)
- Lose most organelles during differentiation, giving more space for oxygen an carbon dioxide
- Retain only the cytoskeleton
30
How are rbcs produced?
From development of haemopoietic stem cells in the bone marrow
31
How do rbcs obtain energy?
By anaerobic metabolism of glucose that they absorb from plasma - aerobic respiration would use the oxygen that they are transporting
32
Which protein has a dual role in platelet activation and the coagulation cascade?
Thrombin
33
What is the pathway of rbc development?
Early erythroblast —> Late erythroblast —> Normoblast —> Reticulocyte —> Erythrocyte
34
What antibodies and antigenss do rbc type A have?
Anti-B antibodies
A antigens
35
What antibodies and antigens do rbc type B have?
Anti-A antibodies
B antigens
36
What antibodies and antigens do rbc type AB have?
No antibodies in plasma
A and B antigens
37
What antibodies and antigens do rbc type O have?
Anti-A and Anti-B antibodies in plasma
No antigens in rbc
38
What is the role of wbcs?
- Defend the body against pathogens
- Remove toxins, wastes, and abnormal or damaged cells
39
Characteristics of circulating wbcs?
- Can migrate out of the bloodstream to move to the damaged area
- Capable of amoeboid movement
- Chemotaxis
40
Which wbcs are capable of phagocytosis?
Neutrophils, eosinophils, and monocytes
41
Which wbcs are the most phagocytic?
Macrophages
42
What is a monocyte?
- The cell type in the blood
- They migrate outside of the bloodstream and become macrophages or dendritic cells
43
What is the role of neutrophils?
- Part of the body’s non-specific (innate) defense system
- First white blood cells to arrive at the site of injury
- Specialised in phagocytosing bacteria marked with antibodies or a compliment
- Dead neutrophils form pus - leave the body
- Can extrude their nucleus to form a net of DNA that can trap bacteria last line of defense when overwhelmed
- 2-5 lobed nucleus
44
What is the role of eosinophils?
- Innate defence system
- Attracted to the site of injury
- They do phagocytosis
- Attack objects that are coated with antibodies
- They attack by exocytosis of toxic compounds - makes them specialised in attacking multicellular parasites
45
What is the role of basophils?
- Innate defense system
- Attracted to sites of injury
- Promote inflammation by releasing histamine to dilate blood vessels
- Associated with allergic reactions
- Release other chemicals to attract white blood cells
- Lifespan is not known
46
What is the role of monocytes?
- Innate defense
- Attracted to sites of injury - here they become phagocytic tissue resident macrophages and engulf pathogens and debris
47
What types of cells are lymphocytes?
T cells
B cells
NK cells
48
What is the role of T cells
- Cell mediated immunity
- Attack abnormal cells or control activity of other lymphocytes
49
What is the role of B cells?
- Humoral immunity
- Produce antibodies
50
What is the role of NK cells?
-Immune surveillance
- Attack abnormal cells
51
How are platelets made?
Develop from bone marrow megakaryocytes
52
What is haemostasis?
- The stopping of bleeding
- The prevention of excessive blood loss upon injury
53
What are the 3 stages of haemostasis?
- Vasoconstriction to limit blood flow
- Platelet plug formation
- Coagulation cascade to stabilise the platelet plug
54
How do IgG antibodies bind to Nk cells?
Antibody constant domain binds to Fc receptors on NK cell
55
What cells make antibodies?
B lymphocytes
56
How are antibodies made?
- Pathogen with a surface antigen that is recognised by a b cell binds to the antigen
- Binding triggers b cell to proliferate
- Created either memory cells or plasma cells
57
What do plasma cells secrete?
Soluble form of the surface B cell receptor
58
3 ways in which antibodies can work
- Neutralisation
- Opsonisation
- Complement activation
59
How do antibodies work by neutralisation?
Bind to toxins, bacteria, or viruses to prevent them acting in the body
60
How do antibodies work by opsonisation?
- Antibodies bind to antigens on pathogen and coat it
- Macrophages have Fc receptors on their surface that recognise the Fc portion of antibodies
- Macrophage can bind and form a pathogen-antibody complex
- This complex is internalised, phagocytosed, and degraded via lysosomes
61
What is the classical pathway for the complement cascade?
Antigen-Antibody complexes formed
62
How do antibodies work by complement activation?
- Complement cascade can assemble on an antibody-antigen complex
- The complement cascade forms a membrane attack complex that punches holes into the target that is about to be engulfed anyway
63
What is the alternative pathway for the complement cascade?
Pathogens or injured tissue is detected
64
What is the lectin pathway for the complement cascade?
Lectin binds to mannose on pathogens
65
What happens when cells are too big to phagocytose?
- Antibody binds antigens on surface of target cell
- NK cells have Fc receptors that bind to the antibodies of the target cell
- NK cell then degranulates and releases toxic components in its granules
- Granules perforate the cell and the toxic compound called granzymes will enter the cell and cause apoptosis
66
Benefits of antibody being bivalent?
If one arm disengaged the other arm would interact and give the other arm a change to reattach
67
What are the 5 mechanisms of therapeutic antibodies?
- Blocking
- Signaling
- Targeting
- Complement-dependent cytotoxicity
- Antibody-dependent Cell-mediated cytotoxicity
68
What are the 3 roles of the immune system?
Recognition: distinguishes self from non-self
Elimination of non-self identities
Immunological memory: can respond quickly to new infection
69
What type of stem cell can differentiate into any blood cell?
Pluripotent hematopoietic stem cells
70
What cell is equally important in innate and adaptive immunity?
Cytokines
71
What cells act as a bridge between innate and adaptive immune responses?
Dendritic cells
They phagocytose bacteria and present their antigens before moving to the lymph node to activate helper t cells
72
What prevents autoimmunity?
Negative regulatory checkpoints
73
What are DAMPS?
Danger-Associated Molecular Patterns
74
What do DAMPs do as a response to severe injury?
- When a cell undergoes this necrosis, DAMPs are released and these signals are recognised by patterns recognition receptors - PRRs
- PRRs are found on the surface of cells such as macrophages
- There are also soluble PRRs floating around
- Binding of these danger signals triggers activation of the macrophage
75
What do DAMPs do as a response to mild injury?
They just flag up to macrophages that they should be phagocytosed without alerting the immune system
76
What is the role of PRRs?
- Bind DAMPs and PAMPs
- Soluble PRRs can bind to bacteria so they can be bound to macrophages to be engulfed
Macrophage will release cytokines to activate othger immune cells
77
What is the key role of cytokines?
Activate other cells and induce differentiation
- Dendritic cells
- Macrophages
- The endothelium
78
What is the key role of chemokines?
Chemotactic factors to guide other cells to the site of infection
79
How does endothelium activation help in the immune reponse?
Endothelium lines all blood vessels and when it is activated, it can capture neutrophils out of the blood and allows them to transmigrate through from the blood to the site of injury
80
What is a sentinel cell?
Monitors the presence of potentially harmful cells in the body
81
How are macrophages formed?
Monocytes transmigrate from the blood into the tissues and specialises into a macrophage, waiting for injury or infection
82
Summaries the acute inflammatory reaction
- Happens immediately after infection
- Bacteria are attacked by tissue macrophages that phagocytose them
- Release chemokines and cytokines that increase permeability of blood vessels by acting on endothelial cells
- This allows neutrophils to get to site of injury by crossing between endothelial cells
- Compliment proteins can activate other cells and increase vascular permeability
83
What are the three types of granulocytes?
Neutrophils
Eosinophils
Basophils
84
What is the role of granulocytes?
Granules contain toxic substances to kill pathogens e.g. microorganisms or parasites
When they are activated they release granules that have toxic substances, as well as releasing DNA content
85
What is the role of neutrophils?
Key components of the innate immune system
Important during early injury stages
Can degranulate and release DNA content in the form of NETs that mop up bacteria
NET = neutrophil extracellular trap
Neutrophils can produce cytokines
86
What are the 3 activation pathways of the complement cascade?
Classical by Ag-Ab binding
Lectin membrane protein binding to pathogens
Pathogens and injured tissue
87
What is the key converging point of the 3 potential activation pathways in the complement cascade?
C3 convertase enzyme is activated
C3 must be broken down into C3a and C3b by C3 convertase enzyme
88
Where do immature dendritic cells reside?
Peripheral tissue
89
How do dendritic cells become activated?
PAMPs and other signs of infection e.g. cytokines released by activated macrophages e.g. interleukin 1 and tumor necrosis factor
90
Immature dendritic cell state (4)
Non-motile
Low MHC
Highly phagocytic
Low B7 levels
91
How do dendritic cells become activated?
Travel through lymphatics to lymph nodes where t cells reside
92
What is signal 1 in regards to dendritic and t cells?
TCR recognises peptide-MHC and activate the t cell upon engagement
93
What is signal 2 in regards to dendritic and t cells?
t cell membrane protein CD28 recognises b7 on activated dendritic cell and they engage
94
Which cells express MHC class I?
All cells in the body continually present endogenous proteins on the cells surface
95
Which cells express MHC class II?
Antigen presenting cells: dendritic, macrophages, b cells
96
Where do MHC class II come from?
Anything foreign, dendritic cells take up proteins and bacteria and present them as 20bp long peptides on cells surface
97
What are the key functions of t cells? (3)
Help with antibody production
Killing virally-infected cells
Regulatory role
98
What triggers t cells to clonally expand?
T cell recognising MHC-peptide receptor on the surface of a dendritic cell
99
What are the 3 main cell types produced by clonal expansion of t cells?
Helper t cells
Cytotoxic t cells
Regulatory t cells
100
What triggers B cells to clonally expand?
Antigen b cell receptor, or cytokines from t cells
101
What types of cells do clonal expansion of b cells produce?
Memory and plasma cells
102
Explain antibody-mediated phagocytosis activation
Fc receptors on phagocytes and neutrophils can send signals to the cell interior of the cell it is bound to
This will induce phagocytosis of whatever the antibody is bound to
103
How does ADCC kill virally infected cells?
Virally infected cell expresses a viral protein on cell surface
Fc receptors on NK cell recognise and bind to IgG antibody, then kill cell
104
3 ways to kill a virally infected cell
ADCC
T-cell cytotoxicity
Nk cell activates receptor-mediated cytotoxicity
105
How does granule-dependent killing of cells work?
NK cells recognise cell by non-self markers and cytotoxic t cells recognise antigens presented by MHC1
Perforin is released
Cytotoxic granules release granzymes
Granzymes are released through these pores and induce apoptosis
106
What 3 cell types are sentinels of innate immune system/
Macrophages
Mast cells
Dendritic cells
107
Mast cell functions as a sentinel (3)
Produce chemotactic factors
Produce histamine
Produce cytokines
108
Macrophage functions as a sentinel (4)
Phagocytosis
Cytokine production
Antigen presentation
NET formation
109
Dendritic cell functions as a sentinel (2)
Process and present antigens to t lymphocytes
Produce cytokines
110
What is opsonisation?
The binding of complement proteins to bacteria
111
What technique is used to sample bone marrow?
Trephine biopsy
112
What is the name of the bone network within bone marrow?
Trabecular bone
113
What is an indicator of healthy bone marrow?
High quantities of fat deposits
114
In which bones do haemopoietic stem cells reside/?
Bone marrow of long bones e.g. sternum, skull
115
What is the role of transient amplifying cells?
Proliferate to generate a bulk of cells that can differentiate
116
What is a precursor cell?
Cell type before it becomes terminally differentiated
117
Stem cells are a population of cells able to:
Sustain themselves by a process of self-renewal
Generate progeny that sustain both the mass and functional competence of the tissue
118
What is restriction in relation to stem cells?
Them losing the ability to differentiate into certain cell types as they become more specialised
119
What does selective IgA deficiency cause?
Recurrent respiratory and gastrointestinal infections
120
What is CVID?
Common Variable Immunodeficiency
Low antibody levels
Recurrent infections
Caused by mutations in lymphocyte membrane proteins or cytokine receptors
121
What is SCID
Severe Combined Immunodeficiency
Defective T and B cells
Caused by IL-2 receptor common gamma chain mutations
This protein is shared by IL-2/4/7/9/15/21
Severe bacterial, viral, fungal infections
Treatment by bone marrow transplant
122
What are the major causes of autoimmune disease?
Genetic susceptibility genes
Linked to hormones
123
Give 2 organ-specific autoimmune diseases in the thyroid
Graves disease
Hashimotos disease
124
How does graves disease progress?
Immune system mistakenly targets thyroid gland and generates antibodies: thyroid-stimulating immunoglobulins
TSI's bind to Thyroid Stimulating Hormone receptors on thyroid
Results in hyperthyroidism
125
How does Hashimotos disease progress?
Thyroid cells are destroyed
Antibodies or autoantibodies are made against thyroid peroxidase and thyroglobulin
Cytotoxic t cells mistakenly attack the antigenic peptide presented by MHG
126
Give an example of a non organ-specific autoimmune disease
Lupus erythematosus
127
How does lupus erythematosus progress?
Apoptotic cells have blebs that contain histones
Apoptotic cells are usually cleared by complement
Mutation in c1q means they are not cleared
Dendritic cells present the histones and activate helper T-cells and immune system
Antibodies are made for the blebs
Clumping of blebs by antibodies gets lodged in kidneys
128
How is lupus erythematosus treated?
Immunosuppressants
129
Progression of cancerous cells
Normal
Hyperplastic
Dysplastic
Neoplastic
Metastatic
130
What is genetic heterogeneity?
Where two different mutations can cause the same disease
Solid tumors have genetic heterogeneity
131
How do DAMPs help in the immune response against cancer?
Dying tumor cells release DAMPs
DAMPs are not usually exposed to blood
Dendritic cells become activated by DAMPs in blood
Dendritic cells upregulate antigens from dying cancer cells
Dendritic cells present the peptides as MHC class II
T-cells become cytotoxic and kill cancer cells
132
What is the role of immune checkpoints?
Molecules in the immune system that either turn up a signal or turn down a signal
133
How do tumor cells use checkpoints?
As tumor cells evolve, they can suppress immune checkpoints to stop the immune cell attacking them
134
Outline the process of T-cell inhibitor CTLA-4
CTLA-4 is present on T cells
CTLA-4 can bind B7, stopping the immune system from becoming overactive
CTLA-4 deficient mice die from lymphoproliferative at 3-4 weeks
135
Outline the process of T-cell inhibitor PD-1
Tumor cells are upregulated by antigen-presenting cells
CD28 (+ve) and CTLA-4 (-ve) regulators of T-cell activation via cytokines
Effector T-cell TCR binds to MHC-I to kill tumor cell
PDL-1 is expressed by normal cells as well as tumor cells
PD-1 on effector T cell binding to PD-L1 on tumor cell will shut down that T-cell
136
When does CTLA-4 checkpoint occur?
Before dendritic cell is activated
137
When does PD-1 checkpoint occur?
At the effector phase
