Immunology Flashcards
1
Q
What do all blood cells derive from?
A
Multipotential haematopoietic stem cells
2
Q
What do common myeloid progenitors specialise into?
A
Megakaryocytes
Erythrocytes
Mast cells
Myeloblasts
3
Q
What do megakaryocytes specialise into?
A
Platelets
4
Q
What do myeloblasts specialise into?
A
Basophils
Neutrophils
Eosinophils
Monocytes
5
Q
What do monocytes specialise into?
A
Macrophages and dendritic cells
6
Q
What do common lymphoid progenitors specialise into?
A
NK cells and small lymphocytes
7
Q
What do small lymphocytes specialise into?
A
T and B lymphocytes
8
Q
What is the innate immune system?
A
The initial rapid and non-specific response to antigenic material with no immunological memory
9
Q
What do haematopoietic stem cells specialise into?
A
Lymphoid and myeloid progenitors
10
Q
What causes acute lymphocytic leukaemia (ALL)?
A
Lymphoid progenitors causing increased amounts of immature lymphocytes
11
Q
What cells does chronic lymphocytic leukaemia affect (CLL)?
A
Naïve (not exposed to antigen) mature B cells
12
Q
What cells do lymphomas affect?
A
Mature naïve T cells and B cells in germinal centres
13
Q
What is multiple myeloma?
A
Cancer of plasma cells
14
Q
What is acute myeloid leukaemia (AML)?
A
Cancer of myeloid progenitors causing a decrease in their downstream cells
15
Q
Give some examples of myeloproliferative disorders
A
Chronic myeloid leukaemia
Proliferation of granulocytes
16
Q
What are the primary lymphoid organs?
A
Bone marrow and thymus
17
Q
Where do all immune cells originate from?
A
Bone marrow
18
Q
Where do B cells mature?
A
Bone marrow
19
Q
Where do T cells mature?
A
Thymus
20
Q
What are the secondary lymphoid organs?
A
Lymph nodes and spleen
21
Q
What happens within the lymph nodes?
A
Site of B and T cell interaction. They also interact with dendritic cells that are delivering the antigen
22
Q
What happens within the spleen?
A
Site of removal of RBCs and Ab-coated bacteria
23
Q
What are the tertiary lymphoid organs?
A
Transient formation of germinal centres, usually pathology related
24
Q
What is the role of secondary lymphoid tissues?
A
(Lymph nodes) provide the stage to allow foreign antigen to interact with lymphocytes
25
What are tertiary lymphoid organs?
Lymph node like ectopic structures that form during chronic inflammation such as in chronic infection, transplant graft rejection and autoimmunity
26
Give an example of a condition where tertiary lymphoid organs are involved.
In multiple sclerosis focal TLOs form in the brain which produces anti-myelin antibody leading to the demyelinating pathology
27
What happens to dendritic cells once they enter the lymph nodes?
DC enter with Ag in afferent lymphatics and interact with naïve CD4+ cells to activate them in the paracortex. T cell either become effector cells or memory cells.
28
What are lymphoid follicles?
Germinal centres which are the site of somatic hypermutation (this achieves a higher affinity Fab and class switching)
29
What is the role of the red pulp of the spleen?
Mechanical filtration of RBCs
30
What is the role of the white pulp in the spleen?
Active immune responses through humoral and cell-mediated immunity
31
What makes up the white pulp of the spleen?
Primary follicles
Marginal zone
Periarteriolar lymphoid sheath (PALS)
32
What is found within the periarteriolar lymphoid sheath (PALS) of the spleen?
Rich in T cells
33
What is found within the lymphoid follicles of the spleen?
Rich in B cells
34
What is the role of the spleen only in the foetus?
Production of RBCs up to the 5th month of gestation
35
What is the role of the spleen in people with thalassaemia?
Results in haemolytic anaemia so the spleen produces RBCs once more
36
What is thalassaemia?
Decreased Hb
37
What does the spleen store?
RBCs, lymphocytes, platelets and other elements
38
What percentage of lymphocytes are stored in the spleen?
~25%
39
What percentage of RBCs are stored in the spleen?
~30%
40
When are the RBCs stored in the spleen released?
In hypovolaemia and hypoxia
41
What does the spleen clear from circulation?
Old platelets
42
Describe the receptors of the innate immune system.
Primitive and broad
43
Describe the receptors of the adaptive immune system.
Highly specific (T and B cell receptors)
44
Describe the kinetics of the innate immune system.
Fast (hours-days)
45
Describe the kinetics of the adaptive immune system.
Slow (days-weeks)
46
What type of immunity is highly regulated?
Adaptive immunity
47
What type of immunity can be amplified?
Adaptive immunity
48
What type of immunity can self-discriminate?
Adaptive immunity
49
Describe the duration of the innate immune response.
Short (days)
50
Describe the duration of the adaptive immune response.
Long (months/years)
51
What type of immunity has an aspect of memory?
Adaptive immunity
52
Which WBC is most abundant in the blood?
Neutrophils
53
What percentage of WBC in the blood is neutrophils?
70%
54
Describe the lifespan of neutrophils.
Short lived
55
Where do neutrophils travel to?
Rapidly egress into tissues during acute infection
56
What type of cell is a neutrophil (other than being a WBC)
Phagocytic and bactericidal
57
Describe the nucleus of a neutrophil.
Polymorphonuclear cells (multilobed)
58
What are pathogens detected by in phagocytosis?
Pattern recognition receptors of innate phagocytic cells
59
What is the principal cell of acute inflammation?
Neutrophils
60
How do neutrophils carry out phagocytosis?
They kill by internalising bacteria and degranulating their contents into a phagolysosome
61
What are the major components found within a phagolysosome?
Alpha-defensins and lactoferrin
62
Other than phagocytosis, how else can neutrophils kill bacteria?
Respiratory burst
63
What is the first stage of the respiratory burst carried out by neutrophils?
Electrons are pumped into the phagolysosome by NADPH oxidase
64
What happens after electrons have been pumped into the phagolysosome during the respiratory burst carried out by neutrophils?
The electrons combine with molecular oxygen to produce superoxide ions
65
What happens after the formation of superoxide ions during the respiratory burst carried out by neutrophils?
These ions combine with protons present in the granules to produce peroxide which is bactericidal in itself
66
What happens after the formation of peroxide during the respiratory burst carried out by neutrophils?
Myeloperoxidase can then chlorinate the peroxide to produce a hypohalous acid which is also bactericidal
67
What is the first stage in the movement of neutrophils out of capillaries in acute inflammation?
E-selectin is activated by IL-1 and TNF-α from damaged cells, and binds to the glycoprotein CD15 on neutrophils in blood
68
What is E-selectin?
An adhesion molecule on the capillary endothelium
69
What happens in the movement of neutrophils out of capillaries in acute inflammation after the neutrophils have bound to E-selectin?
This causes neutrophils in the blood to slow down and roll along the endothelium lining
70
What happens in the movement of neutrophils out of capillaries in acute inflammation after neutrophils have rolled along the endothelium lining?
ICAM-1 on endothelium (induced by LPS, IL-1, TNF-α) binds to integrin on neutrophil; the neutrophil stops
71
What happens in the movement of neutrophils out of capillaries in acute inflammation after neutrophils have stopped rolling?
Diapedesis: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles))
72
What is the role of macrophages?
Phagocytosis, antigen presentation and cytokine secretion
73
What cytokines do macrophages secrete?
TNFα, IL-1, IL-6, IL-8, and IL-12
74
Describe the nuclei of macrophages.
Round single nuclei often with a small indentation
75
What do macrophages derive from?
Blood monocytes or as tissue resident macrophages
76
How do macrophages detect pathogens?
Detect pathogens and damage markers by pattern recognition receptors
77
In what type of inflammation are macrophages one of the principal cells?
Chronic
78
Where do tissue resident macrophages derive from?
Tissue resident macrophages are derived from the yolk sac and foetal liver during development
79
Where are tissue resident macrophages found?
Persist in tissues via self renewal
80
What are M1 macrophages?
M1 is considered pro-inflammatory due to its ability to metabolise arginine to nitric oxide
81
What are M2 macrophages?
M2 are considered anti-inflammatory due to their ability to metabolise arginine to the repair molecule ornithine
82
What do pattern recognition receptors (PRRs) on macrophages detect?
Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
83
What is the role of TLR4?
Found on macrophages and detects LPS on g-ve bacteria
84
Where do antibodies bind to pathogens?
By their Fab regions
85
How do macrophages use receptors and antibodies to phagocytose bacteria?
Macrophages have Fc receptors that bind antibody and in turn phagocytoses the bacteria the antibody has bound
86
What do macrophages do when antibodies bind to pathogens?
Complement then binds antibody Fc regions forming a complex. Macrophages have complement receptors that recognise this complex
87
When do basophils release histamine?
Upon IgE crosslinking Fcε receptors
88
What do basophils release?
Histamine, serotonin and heparin
89
In what conditions are basophils important?
Asthma, anaphylaxis, atopic dermatitis, and hay fever
90
What cells can basophils be compared to?
Circulating mast cells - they do not egress into tissues and become mast cells
91
What type of infection are eosinophils important in?
Parasitic infections
92
What do eosinophils release?
Release cationic granules such as major basic protein, ROS, eicosanoids, leukotrienes, elastase etc.
93
What cells are classed as granulocytes?
BEN: basophils, eosinophils and neutrophils
94
What is the role of mast cells?
Important in parasitic infection and allergic reactions
95
Where are mast cells found?
At mucosal surfaces
96
What is important for the development of mast cells?
Stem cell factor
97
What cell is the main source of histamine?
Mast cells
98
How are mast cells activated?
By immune complex IgE cross-linking FcεR1
99
What do mast cells secrete?
Histamine, cytokines (IL-4, IL-13 and TNFα) and lipid mediators (leukotrienes and prostaglandins)
100
What does histamine do?
Increases vascular permeability and causes smooth muscle contraction
101
What does IL-4 do?
Promotes Th2 differentiation
102
What does IL-13 do?
Promotes IgE production
103
What does TNFα do?
Promotes tissue inflammation
104
What do lipid mediators such as leukotrienes and prostaglandins do?
Increase vascular permeability
Cause smooth muscle contraction
Stimulate mucus secretion
Chemoattractants for T cells, eosinophils, mast cells and basophils
105
What happens when IgE binds to an allergen?
Activates mast cells via Fc receptor
106
Where are NK cells found?
In blood and tissues
107
What receptors do macrophages have?
CD14+ and CD40+
108
What receptors do NK cells have?
CD16+
109
What process do NK cells use to kill pathogens?
Antibody-dependent cellular cytotoxicity (ADCC) - not phagocytic
110
How do NK cells kill pathogens?
Release lytic granules that kill virus infected cells
111
How do NK cells recognise self and non-self?
NK cell's inhibitory receptors detect levels of MHC-I on cell surfaces
112
What molecule does ADCC not require?
Complement
113
How many cell types does ADCC use?
1
114
What is the first stage of ADCC?
IgG will bind surface antigens on the pathogen-infected cell
115
What happens during ADCC once IgG is bound to antigens?
NK cells have Fc receptors (CD16) that recognise the antibody Fc region
116
What happens during ADCC once NK cells have bound to the antibody?
This cross-linking triggers degranulation and cell apoptosis
117
How do viruses become antibody targets?
Viral proteins are expressed on the surface of cells during viral replication
118
What do the lytic granules of NK cells contain?
Perforin and granzymes that induce apoptosis and cell lysis
119
What is the effect of cancer on NK cells?
Cancers tend to downregulate MHC-I mediated antigen presentation
120
What happens if there is not enough MHC-1 on the cell surface due to cancer?
NK cells will activate and try to kill the cell
121
What is the purpose of MHC-!?
Cells that have MHC-I activate the inhibitory receptor and therefore does not elicit a response from NK cells.
122
When do cytotoxic T cells act on tumour cells?
In response to NK cell cytokine production
123
What are the professional antigen presenting cells?
Macrophages
B cells
Dendritic cells
124
What do the professional antigen presenting cells present?
Exogenous Ag on cell surface in the context of MHC-II
125
Which type of cell is the most potent antigen presenting cell?
Dendritic cells
126
Where do dendritic cells travel to?
Egress to secondary organs to aid the adaptive response
127
Which cells are capable of MHC-I presentation?
All nucleated cells (although thrombocytes are anucleate and still have MHC-I molecules but RBCs do not)
128
Which chromosome codes for MHC molecules?
Chromosome 6
129
Where is exogenous antigen processed in antigen presenting cells?
ER
130
Give some examples of endogenous proteins that might be present in the cytosol of an antigen presenting cell.
Viral proteins
| Cancer-related proteins
131
Where are endogenous proteins processed in antigen-presenting cells?
Endosomes
132
How are endogenous proteins presented on antigen-presenting cells?
In the context of MHC-I
133
Which cells are capable of cross-presentation?
Dendritic cells
134
How do dendritic cells carry out cross-presentation?
They can present exogenous Ag in the context of MHC-I in order to activate Tc cells
135
What can dendritic cells be thought of as?
The bridge between the innate and adaptive immune responses in secondary lymphoid organs
136
What happens when immune cells come together?
They form an immune synapse
137
What must happen for a response to occur upon formation of an immune synapse?
Binding of primary receptors e.g. TCR to MHC-II
Binding of co-stimulatory molecules e.g. CD28/CTLA4 to CD80/CD86
A robust release of the appropriate cytokines
138
What happens if there is MHC binding without other stimulation?
Anergy
139
What is anergy?
T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter
140
What happens to T cells during initial encounter with a novel antigen?
T cell will differentiate into either memory or effector T cells
141
What is the common T cell marker?
CD3 - the identifying co-stimulating molecule for all T cells
142
What are the 2 different T cells following maturation?
CD4 or CD8
143
What receptors do T cells have?
CD3
CD4/CD8
T cell receptor - TCR
CD25
144
What is the main function of the CD3 molecule?
Intracellular signalling that activates the T cell
145
What is the structure of the CD3 molecule?
It is a protein complex comprised of one gamma, one theta, and two epsilon polypeptide chains.
146
What do T cells start off as?
In the bone marrow as HSCs
147
What do T cells differentiate into from HSCs?
Differentiate through the lymphoid pathway into immature T cells
148
What are naïve T cells?
Not encountered the antigen yet. How immature T cells start as.
149
Do naïve T cells present CD4 or CD8?
Both - they are double positive cells.
150
What happens to naïve T cells during maturation?
They undergo thymic education to retain either CD4 or CD8, and they undergo VDJ recombination in the thymus to determine the antigen epitope that their TCR will recognise
151
How do T cells recognise antigens?
T-cells must recognise antigen in the context of MHC molecules using their T-cell receptors (except for superantigens)
152
What do superantigens do?
Superantigens bind the beta chain of TCR regardless of TCR
153
How are naïve T cells identified?
Naïve T cells are identified by being CD45RA+
154
How are memory T cells identified?
Memory T cells are identified by being CD45RO+
155
What receptors do cytotoxic T cells present?
CD8
156
What do cytotoxic T cells release?
Perforins and granzymes
157
How do cytotoxic T cells recognise Ag?
In the context of MHC-I
158
What do cytotoxic T cells become?
Effector or memory cells
159
How can cytotoxic T cells kill pathogens?
Perforin and granzymes
| Expression of Fas ligand
160
How do cytotoxic T cells use perforin to kill pathogens?
Allows salt and water to enter cells and causing them to lyse
161
How do cytotoxic T cells use granzymes to kill pathogens?
They cleave a caspase protein (CPP-32) which will activate a nuclease (CAD) which initiations DNA degradation and apoptosis
162
What are granzymes?
Group of serine proteases
163
What is perforin?
Pore forming cytolytic protein
164
How do T cells use the Fas ligand to kill pathogens?
CD8 T cells also express the Fas ligand, this binds Fas on target cells which activates the caspase cascade and therefore apoptosis
165
What type of immunity are Th1 cells involved in?
Cell-mediated
166
What do Th1 cells do?
Activate/regulate macrophages, monocytes, cytotoxic T cells and NK cells
Elimination of cellular antigens (viruses, intracellular bacteria, tumour cells)
167
What type of immunity are Th2 cells involved in?
Humoral
168
What do Th2 cells do?
Stimulation of B cells
Boost in the synthesis of IgE, IgG1 and IgG3 antibodies
Regulate eosinophils, basophils and mast cells
169
What are Treg cells the principle cell in?
Peripheral immune tolerance
170
What is the key cytokine of Treg cells?
IL-10
171
What is the role of IL-10?
Mass anti-inflammatory action
172
Where are Th17 cells important?
Mucosal membranes
173
What is the principle cytokine of Th17 cells?
IL-17
174
What does IL-17 do?
Affects innate immune cells to produce IL-8
175
What is the relationship between Treg and Th17 cells?
They are antagonistic
176
How are Treg and Th17 cells antagonistic?
Transcription factors and cytokines produced by Th17 cells suppressive T reg cells and vice versa
177
What is the purpose of IL-8?
The most important cytokine in neutrophil production and recruitment
178
What is the purpose of IL-23?
IL-23 maintains Th17 populations and is a target for biologics
179
What receptors do B cells have?
BCR - B cell receptor
CD19
CD20
(CD15)
180
What is the CD19 receptor?
Co-stimulatory molecule of mature B cells
181
What is the CD20 receptor?
Mature B cell marker
182
Where does B cell activation take place?
Secondary lymphoid organs (lymph nodes)
183
What 2 processes are aided by dendritic and T cells?
Somatic hypermutation and affinity selection
184
What can activated B cells become?
Short lived plasma cells (IgM+) or long-lived plasma cells (IgG, E, or A+)
185
How are B cells activated in the absence of T cell help?
Directly by antigen
186
Describe the response when B cells are activated directly by the antigen.
Rapid but short lived response
| Less affinity and IgM releasing
187
How are B cells activated?
When they internalise antigen and present it to T cells in the context of MHC II
188
What happens to B cells after activation?
They migrate to newly formed germinal centres to undergo somatic hypermutation
189
What is somatic hypermutation?
When RAG enzymes (activation-induced cysteine deaminase - AID) introduce random mutations in the variable region of the antibody gene
190
What is the role of dendritic cells within the germinal centres?
They will present the same antigen to the B cell to test if the avidity of its antibodies has increased (affinity selection)
191
What is affinity selection?
B cells with less avidity will be negatively selected and those with greater avidity will be positively selected and undergo class switching and clonal proliferation
192
What type of cell appears in Hodgkin lymphoma?
Reed-Sternberg cells
193
What are Reed-Sternberg cells?
These are B-cell derived giant cells that are distinctive of Hodgkin lymphoma
194
What is the distinctive marker of Reed-Sternberg cells?
CD15
195
What do Reed-Sternberg cells look like?
They have prominent eosinophilic inclusion-like nucleoli (thus resembling an "owl's eye" appearance) under microscopy
196
What B cell receptor is targeted by rituximab?
CD20
197
Which part of the lymph node is the B cell region?
Cortex
198
Which part of the lymph node is the T cell region?
Paracortex
199
Which part of the lymph node is the plasma cell region?
Medulla
200
What happens when memory B cells encounter their specific antigen?
They become activated and undergo clonal proliferation and begin secreting IgG
201
What does the constant region of antibodies do?
Determines antibody type and therefore effector function
202
What does the Fab (antigen-binding fragment) region of antibodies do?
Binds epitopes of antigen
203
How are Fab regions determined?
Initially determined by a process called VDJ recombination during maturation in the bone marrow
204
When does the avidity of an antibody for its antigen increase?
During infection through somatic hypermutation in the germinal centres of secondary organs
205
What is the Fc (fragment crystallisation) region of antibodies?
The area that binds Fc receptors on immune cell surfaces
206
What does the Fc region of antibodies do?
Binds complement to aid in opsonisation of pathogens for phagocytosis
207
What are the functions of antibodies?
Neutralisation of toxins, opsonisation of pathogens, complement activation via the classical pathway
208
Where is IgA found and what as?
The mucosal Ab as a dimer
209
What fluid is IgA found in?
Present in colostrum and coats neonate gut
210
What does IgM look like?
Pentameric
211
What are the features of IgM?
Not entirely specific to antigen
| Highest capacity to activate complement
212
What antibody is most abundant in the blood?
IgG
213
How many subclasses of IgG are there?
4
214
Which antibody can cross the placenta?
IgG
215
What are the features of IgG?
Highly specific
| Important during secondary responses (second infection - levels spike most of all antibodies)
216
What antibody is least abundant in the blood?
IgE
217
What is IgE bound to?
Mast cells and basophils by FcεR
218
What is IgE important in?
Allergy and helminth infection
219
What are the features of IgD?
Not that important. Function is debated in the literature
220
What does IL-5 promote?
IgA class switching
221
What does IL-4 promote?
IgE class switching
222
What does colostrum contain?
IgA, IgM, and IgG where IgA is the principle antibody
223
What is type I hypersensitivity?
Anaphylactic
224
What is type II hypersensitivity?
Cell bound
225
What is type III hypersensitivity?
Immune complex
226
What is type IV hypersensitivity?
Delayed hypersensitivity
227
What is the mechanism of type I hypersensitivity?
Antigen reacts with IgE bound to mast cells
228
Give some examples of type I hypersensitivity.
Anaphylaxis
| Atopy (e.g. asthma, eczema and hayfever)
229
What is the mechanism of type II hypersensitivity?
IgG or IgM binds to antigen on cell surface
230
Give some examples of type II hypersensitivity.
Autoimmune haemolytic anaemia
Goodpasture's syndrome
Pernicious anaemia
Rheumatic fever
231
What is the mechanism of type III hypersensitivity?
Free antigen and antibody (IgG, IgA) combine
232
Give some examples of type III hypersensitivity.
Systemic lupus erythematosus
| Post-streptococcal glomerulonephritis
233
What is the mechanism of type IV hypersensitivity?
T-cell mediated (Th1)
234
Give some examples of type IV hypersensitivity.
Tuberculosis/tuberculin skin reaction
Graft versus host disease
Multiple sclerosis
Guillain-Barre syndrome
235
Describe the rate of type I hypersensitivity reactions.
Fast reaction occurring in minutes
236
What happens in a type I hypersensitivity reaction?
Cross-linking of antigen to IgE on mast cells and basophils causes massive degranulation and therefore massive release of histamine
237
What happens in a type II hypersensitivity reaction?
IgM or IgG binds to self antigen leading to cell destruction by the membrane attack complex and cellular mechanisms
238
What is the first stage of a type III hypersensitivity reaction?
IgG binds soluble antigen forming a circulating immune complex
239
What happens after IgG has bound soluble antigen in a type III hypersensitivity reaction?
These deposit in vessel walls especially in the kidneys
240
What happens after the circulating immune complexes have deposited in vessel walls in a type III hypersensitivity reaction?
Here they kick off an inflammatory response causing complement deposition, opsonisation, phagocytosis etc
241
What happens after the inflammatory response in a type III hypersensitivity reaction?
RBCs carrying the complement receptor 1 bind complement coated immune complexes and transport them to the liver and spleen for phagocytosis
242
What is the first stage of a type IV hypersensitivity reaction?
Th1 are activated by antigen presenting cells
243
What happens after Th1 cells are activated in a type IV hypersensitivity reaction?
Memory T cells are formed
244
What happens after memory T cells are formed in a type IV hypersensitivity reaction?
When the memory T cells encounter the antigen again they will activate macrophages leading to tissue damage
245
What happens in a type V hypersensitivity reaction?
IgM or IgG bind cell surface receptors and either stimulating or blocks endogenous ligand binding
246
Give some examples of type V hypersensitivity reactions.
Grave’s disease and myasthenia gravis
247
What happens during anaphylaxis?
IgE binds antigen which then cross-links FcεRI on mast cells and basophils leading to massive degranulation and histamine release
248
What is the first thing to administer to an anaphylactic patient?
IM adrenaline is 1st line
249
What is given to an anaphylactic patient after adrenaline?
Chlorphenamine (antihistamine) and hydrocortisone (cortisol)
250
What do you check if you suspect a patient is anaphylactic?
```
Airway
Breathing
Circulation
Disability
Exposure
```
251
What do you look for to confirm a patient is anaphylactic?
Acute onset of illness
Life threatening airway and/or breathing and/or circulation problems
Skin changes
252
What are some life-threatening airway problems?
Swelling, hoarseness, stridor
253
What are some life-threatening breathing problems?
Rapid breathing, wheeze, fatigue, cyanosis, SpO2<92%, confusion
254
What are some life-threatening circulation problems?
Pale, clammy, low blood pressure, faintness, drowsy/coma
255
How does autoimmunity develop?
Thymic education
Tregs
CD4 activation against autoantigen
256
What are the features of autoimmunity?
Often relapsing-remitting
Organ-specific vs systemic
Damage to or destruction of tissues
Altered organ growth/function
257
What is central tolerance?
When TCRs and BCRs are tested against self antigen
258
Where are B cells tested in central tolerance?
Bone marrow
259
What happens to B cells in central tolerance?
BCRs that recognise self antigen either leads to clonal deletion (apoptosis), receptor editing, or anergy
260
What is positive selection?
T-cells that recognise MHC molecules
261
What happens if T cells can't recognise MHC molecules in positive selection
They don't receive survival signals
262
How is CD4 or CD8 lineage determined?
Positive selection
263
Where does positive and negative selection of T cells take place?
Thymus
264
What happens in negative selection?
This tests the T cell's affinity to self
265
What happens if the T cell binds to self antigens in negative selection?
They receive signals to apoptose
266
What happens to T cells that pass both positive and negative selection?
They move to secondary organs as mature naïve T cells
267
What is peripheral tolerance?
Low affinity self reactive T cells can escape the thymus to the periphery
268
What happens in secondary lymphoid organs in peripheral tolerance?
T cells are presented self antigen again by dendritic cells and if they recognise they either are clonally deleted or converted to Treg
269
How is autoimmunity treated?
Tx involve reducing inflammation and suppressing the immune system. This usually relieves symptoms but do not typically cure.
270
What is the most common CNS immune mediated condition?
MS
271
What type of condition is MS?
Demyelinating
272
What causes MS?
Failure of central and peripheral tolerance to eliminate self reactive T cells. These T cells are reactive to myelin proteins such myelin basic protein.
273
What forms in the brain in MS patients?
Tertiary Lymphoid organs form in the brain of MS allowing T and B cell interactions and the generation of autoantibodies
274
What are the different types of MS?
```
Relapsing-remitting (RRMS)
Primary progressive (PPMS)
Secondary progressive (SPMS)
```
275
What is RRMS?
Where there are periods of disease activity and no activity. Often incomplete recovery will occur > disability. Some will progress to secondary progressive
276
What is PPMS?
Worsening neurological function from onset of symptoms with no early relapses or remissions
277
What is SPMS?
Progressive worsening of neurological function over time. There will be periods of active disease with progression of the disease as well as periods of non-active disease where it still progresses
278
How is MS diagnosed?
Spinal tap; demonstrating MS associated autoantibodies
MRI; Highlights brain lesions.
Evoked potential tests, which record the electrical signals produced by your nervous system in response to stimuli
279
How are acute MS attacks managed?
IV methylprednisolone
280
How is RRMS managed?
Immunomodulators > Interferon beta 1a, or 1b, or peginterferon beta 1a
281
How is SPMS managed?
Siponimod or methylprednisolone
282
How is PPMS managed?
Ocrelizumab and anti CD20 MAb similar to rituximab
283
What is primary immunodeficiency?
Those born with intrinsic defects in their immune system
284
How common is primary immunodeficiency?
Rare and mostly genetic disorders
285
Give an example of primary immunodeficiency.
SCID - severe combined immunodeficiency
286
What is SCID?
Severe combined immunodeficiency (bubble boy disease) = Where both B and T cells lose functionality. The most severe primary immunodeficiency with various genetic causes and subtypes
287
What is the main hallmark of AIDS?
Profound immunodeficiency
288
Give some examples of secondary immunodeficiencies.
Hypothyroidism, diabetes and hypoglycaemia
289
What is secondary immunodeficiency?
These are acquired and are referred to generally as immunosuppression
290
What drugs can induce secondary immunodeficiency?
Steroids, azathioprine, chemotherapy
291
What diseases can induce secondary immunodeficiency?
Cancers of the bone marrow and blood cells (Leukaemia, Lymphoma, and Myeloma)
AIDS
292
How do steroids cause immunodeficiency?
Suppress cell-mediated immunity by inhibiting NF-κB transcription factor which supresses IL-2 production which in turn reduced T cell proliferation
293
How are steroids anti-inflammatory?
Steroids, specifically glucocorticoids, are anti-inflammatory by blocking eicosanoid production
294
How does azathioprine cause immunodeficiency?
Azathioprine is an immunosuppressive drug that is a purine analogue that inhibits fast proliferating cells such as T cells
295
How does HIV cause immunodeficiency?
HIV has a cell tropism for CD4+ T cells. In uncontrolled infection there is increasing destruction of CD4 cells
296
What must the CD4 T cell count be to diagnose AIDS?
Once it drops below 200 cells/uL there is profound immunodeficiency and is defining aspect of the development of AIDS
297
What is the negative phase?
A period after initial antigen exposure where ones immunity is actually lower than before encountering the antigen.
298
How many doses are most vaccines?
A lot of vaccines have an initial “prime” dose followed by a “boost dose”
299
What will an ideal vaccine do?
Induce both T and B memory cells
300
What do adjuvants do?
Help boost the immune response
301
What is often used to boost the immune response?
Viral vectors
302
Where are monocytes found?
Bone marrow/blood
303
Where are Kupffer cells found?
Liver
304
Where are sinus histocytes found?
Lymph nodes
305
Where are alveolar macrophages found?
Alveoli
306
Where are tissue macrophages leading to giant cells found
Connective tissue
307
Where are microglia found?
CNS
308
Where are Hofbauer cells found?
Placenta
309
Where are intraglomerular mesangial cells found?
Kidney
310
Where are osteoclasts found?
Bone
311
Where are epithelioid cells found?
Granulomas
312
Where are sinusoidal lining cells found?
Red pulp of the spleen
313
Where are Langerhans cells found?
Skin
314
What is the main source of IL-1?
Macrophages
315
What is the main source of IL-2?
Th1 cells
316
What is the main source of IL-3?
Activated T helper cells
317
What is the main source of IL-4?
Th2 cells
318
What is the main source of IL-5?
Th2 cells
319
What is the main source of IL-6?
Macrophages, Th2 cells
320
What is the main source of IL-8?
Macrophages (can be released from any TLR bearing cell)
321
What is the main source of IL-10?
Th2 cells
322
What is the main source of IL-12?
Dendritic cells, macrophages and B cells
323
What is the main source of tumour necrosis factor-α (TNF-α)
Macrophages
324
What is the main source of interferon-γ?
Th1 cells
325
What is the function of IL-1?
| Pro/anti-inflammatory?
Acute inflammation
Induces fever
Pro-inflammatory
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What is the function of IL-2?
| Pro/anti-inflammatory?
Stimulates growth and differentiation of T cell response
| Pro-inflammatory
327
What is the function of IL-3?
| Pro/anti-inflammatory?
Stimulates differentiation and proliferation of myeloid progenitor cells
Pro-inflammatory
328
What is the function of IL-4?
| Pro/anti-inflammatory?
Stimulates proliferation and differentiation of B cells
Promotes class switching to IgE in B cells
Anti-inflammatory
329
What is the function of IL-5?
| Pro/anti-inflammatory?
Stimulate production of eosinophils
| Pro-inflammatory
330
What is the function of IL-6?
| Pro/anti-inflammatory?
Stimulates differentiation of B cells
Induces fever
Pro-inflammatory
331
What is the function of IL-8?
| Pro/anti-inflammatory?
Neutrophil chemotaxis (can attract all granulocytes but neutrophils most)
Promotes phagocytosis
Pro-inflammatory
332
What is the function of IL-10?
| Pro/anti-inflammatory?
Inhibits Th1 cytokine production
| Anti-inflammatory
333
What is the function of IL-12?
| Pro/anti-inflammatory?
Activates NK cells and stimulates differentiation of naive T cells into Th1 cells
Pro-inflammatory
334
What is the function of tumour necrosis factor-α (TNF-α)?
| Pro/anti-inflammatory?
Induces fever
Neutrophil chemotaxis
Pro-inflammatory
335
What is the function of interferon-γ?
| Pro/anti-inflammatory?
Activates macrophages + NK cells
| Pro-inflammatory
336
What phenotype of macrophage does IL-4 promote?
Promotes M2 phenotype macrophages and therefore aids in wound healing
337
What happens when IL-4 is released from T cells?
Positive feedback loop when released from T cells so Th2 is favoured and Th1 is suppressed
338
What is IL-8 also known as?
CXCL9 and an angiogenesis promoter
339
What are interferons?
Cytokines released by the body in response to viral infections and neoplasia
340
What interferons bind to type 1 receptors?
IFN-alpha (all WBC) and IFN-beta (fibroblasts)
341
What interferons bind to type 2 receptors?
IFN-gamma (NK and Th)
342
Give some examples of immune based therapies.
Monoclonal antibodies
Immunosuppressive drugs
Cytokines and anticytokines
Intravenous immunoglobulin
343
What is the mechanism of monoclonal antibodies as a therapy?
Very targeted. Do not carry antigenic segments. Designed to either deplete certain cell populations or functionally downregulate a population
344
Give some examples of immunosuppressive drugs.
Glucocorticoids
Ciclosporin, tacrolimus and rapamycin
Purine analogues (most important is azathioprine)
Alkylating agents e.g. cyclophosphamide
345
What is the mechanism of cytokines and anticytokines as therapies?
Either activate or block cytokine receptors to achieve immunomodulatory effects e.g. pegylated interferon
346
What is the mechanism of intravenous immunoglobulin?
Replacing IgG in patients with immunodeficiencies. Can also be used in certain inflammatory conditions
347
Give an example of monoclonal antibody therapy.
Anti-TNF therapy
348
What is anti-TNF therapy used to treat?
Autoinflammatory conditions e.g. Crohn's disease - Infliximab is a chimeric mAb used in CD often in acute infusions. Adalimumab is a humanised mAb that is a subcut injection that is patient administered and can be preferred when encouraging patient autonomy.
349
Give some examples of glucocorticoids.
Hydrocortisone, prednisone
350
What do glucocorticoids do when given as an immune based therapy?
They downregulate the monocyte production of IL-1 and TNF-alpha. They block the T-cell production of IL-2 and IFN-gamma and therefore humoral immunity. They also reduce the activation and migration of innate and adaptive cells in general
351
What do ciclosporin, tacrolimus and rapamycin do when given as immune based therapies?
Are all calcineurin inhibits and inhibit Ca2+ dependent second messenger signals in T cells following TCR activation. This makes them potent T cell inhibitors
352
What are purine analogues used for?
IBD and organ rejection
353
What do purine analogues do when given as immune based therapies?
They incorporate into DNA resulting in chain termination. They are a potent antiproliferative in dividing adaptive immune cells
354
What do alkylating agents do when given as immune based therapies?
Interfere with DNA synthesis and induce immunosuppression
355
What do cytokines and anticytokines do when given as immune based therapies?
Cytokines are pleotropic and regulate the immune system so are attractive targets for therapy e.g. anakinra and pegylated interferon
356
What does anakinra do?
IL-1 receptor antagonist which is beneficial in type 2 DM
357
What does pegylated interferon do?
Used in chronic hepatitis C infection
358
What is IV immunoglobulin?
A preparation of poly specific IgG pooled from a large number of healthy donors (>20k)
359
What is IV immunoglobulin used for?
Patients with primary or secondary immunodeficiencies e.g. selective IgA deficiency
Recommended for a small number of other diseases such as immune-mediated thrombocytopenia, and Kawasaki’s
360
What are the possible mechanisms of IV immunoglobulins?
Fc receptor blockade to prevent phagocytosis, inhibition of autoantibody synthesis, inhibition of complement activation, induction of T cell regulation
361
What is complement?
An acute phase protein that are synthesised by the liver and circulate in an inactive form
362
How is complement activated?
Complement proteins are cleaved by convertases into two components e.g. C3 becomes C3a and C3b
363
What are complement components ending in 'a' involved in?
Inflammation and chemotaxis
364
What are complement components ending in 'b' involved in?
Opsonisation of pathogens - the membrane attack complex inserts itself into pathogen membranes and causes lysis
365
What do all complement pathways converge to?
Activate C3 convertase
366
What is the complement classical pathway?
Initiated by antigen-antibody complexes (IgM/IgG) which bind complement and activate the cascade
367
What is the complement alternative pathway?
The alternative pathway is activated when C3b (which is free and abundant in plasma) binds pathogens surfaces directly e.g. in G-ve bacteria
368
What does the complement protein C3 do?
C3 has the ability to auto hydrolyse into C3a and C3b where C3b then goes on to activate the cascade
369
What is the mannose binding lectin (MBL) pathway?
MBL binds mannose on pathogens’ surface. Mannose is not present on human cells. This activates MASP proteins (serine proteases) and cleave C2 and C4
370
What markers are found on haematopoietic stem cells?
CD34
371
What markers are found on helper T cells?
CD4, TCR, CD3, CD28
372
What markers are found on cytotoxic T cells?
CD8, TCR, CD3, CD28
373
What markers are found on regulatory T cells?
CD4, CD25, TCR, CD3, CD28
374
What markers are found on B cells?
CD19, CD20, CD40, MHC II, B7
375
What markers are found on macrophages?
CD14, CD40, MHC II, B7
376
What markers are found on NK cells?
CD16, CD56
377
What are CD1 molecules?
MHC molecule that presents lipid molecules
378
What are CD2 molecules?
CD2Found on thymocytes, T cells, and some natural killer cells that acts as a ligand for CD58 and CD59 and is involved in signal transduction and cell adhesion
379
What are CD3 molecules?
The signalling component of the T cell receptor (TCR) complex
380
What are CD4 molecules?
Found on helper T cells. Co-receptor for MHC class II Used by HIV to enter T cells
381
What are CD5 molecules?
Found in the majority of mantle cell lymphomas
382
What are CD8 molecules?
Found on cytotoxic T cells. Co-receptor for MHC class I Found on a subset of myeloid dendritic cells
383
What are CD14 molecules?
Cell surface marker for macrophages
384
What are CD15 molecules?
Expressed on Reed-Sternberg cells (along with CD30)
385
What are CD16 molecules?
Bind to the Fc portion of IgG antibodies
386
What are CD21 molecules?
Receptor for Epstein-Barr virus
387
What are CD28 molecules?
Interacts with B7 on antigen presenting cell as costimulation signal
388
What are CD45 molecules?
Protein tyrosine phosphatase present on all leucocytes
389
What are CD56 molecules?
Unique marker for natural killer cells
390
What are CD95 molecules?
Acts as the FAS receptor, involved in apoptosis
391
What is passive immunisation?
Transfer of performed antibodies to the circulation can be natural or artificial
392
When does natural passive immunity occur?
This occurs naturally by the transfer of maternal antibodies across the placenta to the developing foetus
393
What does natural passive immunity provide protection against?
- Diptheria
- Tetanus
- Streptococcus
- Rubella
- Mumps
- Polio virus
394
When is artificial passive immunity used?
- Those with agammaglobulinaemias - essentially B cell defects, these are
treated with pooled normal human IgG
- Exposure to a disease that could cause complications - like an
immunocompromised patient who is exposed to measles for example
- When there is no time for active immunisation to give protection i.e. a
pathogen with a short incubation time e.g. rabies
395
For what diseases is passive immunisation used?
Botulism, tetanus, diphtheria - given anti-toxin
| Hepatitis, measles, rabies - used prophylactically to reduce the chance of establishing infection after exposure
396
What are the drawbacks of passive immunisation?
- Does not activate immunological memory
- No long term protection
- Possibility of reaction to antisera (due to the fact its non-self so if used second time will be immune to it itself and could result in anaphylaxis)
397
What is active immunisation?
- The production of high affinity protective antibodies against the immunogen
- Protection that is produced by an individuals own immune system and is usually long- lasting
398
What is the goal of active immunisation?
The goal of immunisation is to achieve initial exposure without the risks of an actual infection
399
What are the aims of a perfect vaccine?
- To achieve long term protection (ideally from a small number of
immunisations)
- To stimulate both B cells and T cells
- To induce MEMORY B cells and T cells
- To stimulate protective high affinity IgG production (IgA too if possible (can migrate through mucosal barriers useful some pathogens infect primarily through mucous membranes))
- The importance the memory B cell response depends on the nature of the pathogen
400
What happens in active immunisation?
The first stage of any immunisation is to engage the INNATE IMMUNE SYSTEM:
• Elicit ‘danger’ signals that activate the immune system - triggers such as pathogen-associated molecular patterns (PAMPs) to engage the toll- like receptors on T cells
• Activate specialist antigen presenting cells - e.g follicular dendritic cells
• Lastly engage the ADAPTIVE IMMUNE SYSTEM - generate memory T and B cells and active T helper cells
401
Which diseases use a live attenuated (not harmful) pathogen as a vaccine?
Tuberculosis:
- Bacilus Calmette-Guerin (BCG)
- Polio Sabin:
- Polio virus grown on monkey kidney epithelial cells
- Typhoid
- Mumps
402
What are the advantages of live attenuated vaccines?
- Attenuated pathogens sets up a transient infection
- Activation of full natural immune response
- Prolonged contact with the immune system
- Stimulation of a memory response in the T and B cell compartments
- Often only a single immunisation is required - advantages in the third world
403
What are the disadvantages of live attenuated vaccines?
- Immunocompromised patients may become infected as a result of immunisation
- Complications:
- In live measles vaccine occasionally the attenuated
organism can revert to its virulent form
- Refrigeration and transport:
- Typically live organisms need to be refrigerated for stable storage
- Can be a issue in remote areas of the world
404
Which diseases use a killed, inactivated pathogen as a vaccine?
- Anthrax
- Cholera
- Hepatits A
405
What are the advantages of killed, inactivated pathogens as vaccines?
- No risk of infection
| - Storage is less critical
406
What are the disadvantages of killed, inactivated pathogens as vaccines?
- Tend to just activate the humoral response
- Lack of T cell involvement
- Without transient infection the immune response can be quite weak
- Repeated booster vaccines required - patient compliance can be an issue
407
Which diseases use toxoids (inactivated exotoxins) as a vaccine?
Diptheria:
- This toxin is an inhibitor of translation resulting in necrosis of the heart and liver
Tetanus:
- Neurotoxin resulting in uncontrolled contraction of
voluntary muscles
408
What are the advantages of toxoid vaccines?
- Theoretically safer than handling live or inactivated pathogens
- No risk of infection
- Easier to store and preserve
409
What are the disadvantages of toxoid vaccines?
- Immune response is less powerful than to live attenuated vaccines
- Repeat vaccinations required and adjuvants
410
What are adjuvants?
- Any substance that is added to a vaccine to stimulate the immune system
- Ensures a powerful immune response
411
What can be used as an adjuvant?
- Whole killed organisms - trigger the immune system and send out ‘danger signals’
- Toxoids - trigger the immune system and send out ‘danger signals’
- Proteins
- Chemicals:
- Aluminium salts (extend the half life of immunogen in the site of the injection, resulting in a depot effect - the slow release of vaccine)
- Paraffin oil
412
What do DNA vaccines do?
- Aim to transiently express genes from pathogens in host cells
- Generates immune response similar to natural infection leading to T and B cell memory responses
413
What are the advantages of DNA vaccines?
- DNA vaccines do not require complex storage
| - Delivery can be simple and adaptable to widespread programs - no refrigeration is necessary
414
What are the disadvantages of DNA vaccines?
- As with ‘killed’ vaccines and subunit vaccines there is no transient infection
- DNA vaccination is likely to produce a mild immune response and will require subsequent boosting
415
What is the aim of recombinant vector vaccines?
Aim is to imitate the effect of transient infection with pathogen but using a non-pathogenic organism
416
How are recombinant vector vaccines used?
Genes for major pathogen antigens are introduced into a non- pathogenic or attenuated microorganism and introduced into the host
417
What microbes do recombinant vector vaccines use?
Can be viral (e.g. attenuate poliovirus) or bacterial (e.g. attenuated strains of salmonella)
418
What are the advantages of recombinant vector vaccines?
- Produce immunological memory
| - Safe - relative to live attenuated pathogen
419
What are the disadvantages of recombinant vector vaccines?
- Requires refrigeration for transport
| - Immune response to virus in subject can negate effectiveness
420
What does complement do when activated?
- Lyse microbes directly (Membrane Attack Complex - when a group of complement proteins make a hole in a pathogen which causes an inrushing of fluids that results in lysis and thus the destruction of the pathogen)
- Increase chemotaxis (C3a & C5a)
- Enhance inflammation
- Induce opsonisation (C3b) - process by which an antigen becomes coated with substances (i.e. complement) that make it more easily engulfed by phagocytic cells since macrophages have special receptors for specific complement proteins
421
What is the purpose of the complement pathway?
The major purpose of the complement pathway is to remove or destroy antigen, either by direct lysis or by opsonisation
422
What is an epitope?
The part of the antigen that binds to the antibody/receptor binding site
423
What is affinity in terms of antibodies?
A measure of binding strength between an epitope and an antibody binding site - the higher the affinity the better
424
What are cytokines?
Soluble proteins secreted by lymphocytes or macrophages/monocytes that act as stimulatory or inhibitory signals between cells
425
What is MHC I glycoprotein?
- Intracellular i.e virus
- Found on the surface of virtually all cells of the body except erythrocytes
- Cytotoxic T cells (CD8) require an antigen to be associated with class I MHC proteins before they kill the cell containing the intracellular pathogen
426
What is MHC II glycoprotein?
- Extracellular i.e. phagocytosis
- Found mainly on the surface of macrophages, B cells & dendritic cells (i.e antigen presenting cells)
- Helper T cells (CD4) require class II MHC proteins before they help B cells to make antibodies to the extracellular pathogen
427
What is atopy?
Inherited tendency for overproduction of IgE antibodies to common environmental antigens
428
What is immunodeficiency?
Deficiency in the immune response, can either be acquired (HIV) or inherited (defects in T cell function)
