Immunology and Healthcare Theme 1 Flashcards
1
Q
what is immunology
A
the study of the body’s defence against infection- allow tolerance of pathogenic infections
2
Q
what is the importance of immunology
A
Infections including oral infections are common in individual as they are epidemics of infectious disease. E.g influenza
There are a wide range of clinical conditions (including those with oral manifestations) associated with immune dysfunction.
Rational diagnosis and therapy of disease relies on the understanding of pathogenesis
Vaccination as a key healthcare strategy for both individuals and population
Population disease experience is dynamic
3
Q
what is the involvement of immunology in gingivitis and periodontitis
A
Gingivitis- driven by plaque microbiome, presented by acute inflammation. Inflammation Is when the immune system is facing a challenge, redness and swelling.
Periodontitis- chronic associated with tissue destruction. Alveolar bone receded.
4
Q
what are the symptoms and of inflammation
A
Symptoms: pain, redness, swelling (increased blood flow) , heat and loss of function.
Causes: chronic infection, autoimmune, hypersensitivity (environmental stimulus), metabolic disorders and immunodeficiency (age and genetic factors).
5
Q
what is necrotising ulcerative gingivitis (NUG)
A
Microbial disease (mixed bacterial infection) of the gingiva in the context of an impaired host response
Associated with stress, smoking, HIV & nutritional deficiency
Ulcer- loss of epithelium due to acute infection.
Very painful
Treatment:
- Plaque control (Chlorhexidine, ultrasonics or OHI)
- Metronidazole
6
Q
what is sjogren’s disease
A
Autoimmune disease of salivary gland
Inflammation of salivary glands
Infiltration of white blood cells
Swelling in the salivary glands- should be distinguished from abscesses (common) and glandular fever (less common).
7
Q
what is involved in the pro-inflammatory cytokines stimulate matrix
A
Diagnosis and therapy rely on understanding the disorder
The ways in which the immune system works. Can stimulate periodontal cells to cause tissue destruction.
Inflammation brings more blood to the region which is good, but in the chronic state the gingival fibroblasts will make MMPs which destroys proteins such as collagen.
Typically this is what a fibroblast does, but when over stimulated the balance tips towards disease.
IL-1 isn’t the only molecule that will stimulate MMP
- E.g . Leptin (present in the inflammatory state)
8
Q
why is the number of reported cases lower than estimated actual cases
A
because it is possible to have the virus but not have the actual disease. Asymptomatic.
9
Q
what are the main functions of the immune system
A
- Recognition of non-self microbes & viruses
- Effector function (contain/eradicate infection)
- Regulation (appropriate and measured response) -prevent inappropriate immune responses such as chronic inflammation or hypersensitivity
- Memory - immediate and stronger response on second exposure.
10
Q
what are the features of innate immunity
A
all multicellular organisms have this. Enhanced by adaptive.
•Rapid response
•Fixed response (rate/intensity always similar)
•Limited number of specificities
•Constant during response
Innate immunity will activate adaptive immunity
Innate will reinforce adaptive -integrated response (i.e. complement system)
11
Q
what are the features of
Adaptive immunity
A
- Slow immunity (days to weeks)- requires several cell to cell interactions and processes
- Variable response due to antigen specificity- immune reponse to any macromolecule. It can change and develop.
- Numerous highly selective specificities
- Improve during diagnosis
- Antigen specific, targeted, effective response
12
Q
what are the innate immunity effector mechanisms and signs and symptoms of this
A
immediate defenses
- physical, chemical, and microbiological barriers
- complement
- phagocytosis
no signs and symptoms: natural homeostatic function
13
Q
what are the adaptive immunity effector mechanisms and signs and symptoms of this
A
Induced defenses:
- cytokines and chemotaxis
- interferon response
- antibodies
- cell mediated immunity
- memory
14
Q
what can malfunction of the immune response lead to
A
e.g. persistent or inappropriate inflammation
analysis and manipulation of the immune repsonse are health care strategies
15
Q
what can cytokines do
A
induce chemotaxis and an interferon response (cytokine involved in viral infections)
16
Q
how is the skin a physical barrier to infection
A
external body surfaces
- keratin-dry barrier to infection
- thick
- cell-cell junctions
- low pH inhibits microbial growth
- lactic acid from sweat glands lowers pH
- fatty acids from sebaceous glands lowers pH
17
Q
what are the external bod surfaces that are barriers ti infection
A
skin
nails (keratin)
ducts (fluid flow)
18
Q
how do bacteria enter when we have a burn
A
acute infection and serious inflammation. Burns remove epithelium, expose tissue, bacteria gets in, moist surface, vascular damage e.g. Pseudomonas aeruginosa
19
Q
how do bacteria enter when we have curs/surgery
A
Staphylococcus aureus (normally on skin, however will penetrate the dermis)
20
Q
what occurs in acne
A
infected sebaceous gland ducts/hair follicles- blocked glands
21
Q
how are the Mucosal surfaces susceptible to infection
A
airways, GI tract etc, no keratin- epithelial tissue very susceptible to infection.
22
Q
outline the mucosal defence system
A
- Mucin = highly glycosylated protein
- Mucin (protein secreted by glands in the epithelium-) + water = mucous
- Secreted by goblet cells
- Ciliated epithelium in airways which traps bacteria/particles
- Cells destroyed by smoking/tobacco or in CF- mucous dysfunctional, particles clogging up trachea and lungs
- Airways infected due to loss of innate immunity
23
Q
how are the Internal body surfaces (mucosal surfaces) barriers to infection
A
- Large surface area
- No keratin
- Mucins (form mucus with water): coat microorganisms preventing attachment
- Ciliated epithelium (protection and ejection of large particles)
- Flow of air and fluid
24
Q
how is saliva a barrier to infection
A
- Lysozyme: digests bacterial cell walls
* Lactoferrin: removed iron required by bacteria
25
how is the GI tract a barrier to infection
* Acid environment in stomach, bladder, kidney, bile
| * Digestive enzymes inhibit growth
26
what are Other disorders of compromised physical barriers
* Abnormally thick mucus (e.g. in Cystic Fibrosis) leads to lung infections e.g. P. aeruginosa infection
* Corneal and ear infections upon water exposure (dirty)
* Smoking damages ciliated epithelia in the airways
* Higher rate of sepsis (blood poisoning) after surgery in area of high flora e.g. colon
27
what is the role of bacteria at mucosal surfaces
* Pathogens can overwhelm host defences and are adapted to do so
* Symbiotic relationship ‘mutualism’
* Can cause disease after trauma e.g. E. coli into blood leading to sepsis and septic shock (sepsis that happens very quickly leading to loss of blood pressure involving acute chronic inflammation- acute shut down of major organs ).
28
how do Non-pathogenic (commensal) bacteria also protect surfaces from pathogenic infection
* Stimulate colonic epithelial cells giving a balanced state called physiological inflammation
* Dysregulation of this interaction leads to pathology (e.g. Crohn’s disease)
* Compete with pathogens for nutrients, attachment sites and living space
* Fatty acids from propionibacteria (on skin) are toxic to streptococci
29
how does c difficile cause mucosal injury
colonisation by large numbers of commensal bacteria
antibiotics kill many of these commensal bacteria
c.diff gains a foothold and produces toxins that cause mucosal injury
neutrophils and red blood cells leak into the gut between injured epithelial cells
30
what are soluble mediators of innate immunity
* Enzymes: lysozyme and phospholipase digest cell walls and membranes respectively (in tears, saliva and phagocytes)
* Complement components: 3 FUCNTIONS lysis, opsonisation (more attractive for phagocytosis) and chemotaxis (movement of WBC in tissues)
* Antimicrobial peptides: gets into bacteria cell membrane and disrupts - cell lysis
31
what are Antimicrobial peptides (AMPs)
* Defensins disrupt cell membranes via their amphipathicity (have both hydrophilic and hydrophobic properties)
* Made by epithelial surfaces
* Kill bacteria, fungi and enveloped viruses by perturbing their membranes
* Selective action of individual AMPs but some 21 different AMPs made by Paneth cells (intestine at the bottom of crypts- protection) alone
* Neutrophils/Paneth cells - α-defensins
* Epithelial cells - β-defensins
* Broad range of action
32
What are cathelcidins, histadins and lectins?
•Cathelcidins – family of polypeptides
Found in lysosomes of macrophages and leukocytes
Disintegrates cell membranes of organisms
•Histadins -Produced by salivary glands
•Lectins – carbohydrate binding proteins
Found in foods/nature
Involved in biological recognition & mediate attachment of bacteria/viruses to their targets
33
what are paneth cells
* Specialised epithelial cells of the small intestine
* Make α-defensins (also called cryptidins)
* Make lysozyme and phospholipase
* AMPs and enzymes kill enteric pathogens
* Important as there is lots of bacteria in and around the gut
34
what is the Innate immune effector functions I: The complement system
* A group of some 30 blood and tissue fluid proteins
* Proteolytic cleavage of a cascade of proteins (c.f. blood clotting, activation of apoptosis)
* function to directly attack pathogens
* Also, function to mark pathogens for phagocytosis (opsonisation)
* Work with (‘complement’) antibodies
* Stimulates chemotaxis e.g. neutrophils- enter region of acute inflammation.
35
outline how complement activation works
1. alternative pathway- pathogen surface creates lcal environment conductive to complement activation
2. lectin pathway- manose binding lectin binds to pathogens surface
3- c-reactive protein or antibody binds to specific antigen on pathogen surface
this is causes complement acitvation
then cleavage of C3 to C3a and C3b - C3b covalently bound to surface components of pathogen
recuritment of infammaotry cells
opsnization of pathogens
perforation of cell membranes
PATHOGEN DEATH
36
why is c3 important
people lacking it are prone to severe infections
• C3 activates and cleaved into C3A and C3B
• C3B (large) becomes covalently bound to the pathogens surface - complement fixation (tags pathogen for destruction)
• C3A acts as chemoattractant to recruit effector cells
37
what is the Action of complement 1:
Formation of membrane attack complex with consequent disruption of bacterial outer membrane and bacterial cell death
38
what is the Action of complement 2
Opsonisation for phagocytosis- antibody binds to bacteria which is encapsulated and activates complement and bonding of C3b to bacteria
bacteria engulfed by neutrophils mediated by fc recpetors and complement receptors
granules fuse with phagosomes, releasing toxic oxygen metabolites that kill bacteria
39
what are the 2 categories of lymphoid tissues
primary lymphoid tissues
| secondary lymphoid tissues
40
what are the primary lymphoid tissues
bone marrow and thymus
41
what are the secondary lymphoid tissues
SITE OF IMMUNE RESPONSE
widely distributed in the body
where lymphocytes are activated.
These include: lymph nodes, tonsils, spleen, Peyer's patches and mucosa associated lymphoid tissue (MALT)
42
what is the function of red bone marrow
Haematopoiesis – makes white and red blood cells- In bone marrow and periphery
Haematopoiesis driven via cytokine production & stroma
Homeostatically controlled – different branches can be switched on/off depending on demands
Replaced by yellow (fatty) bone marrow that doesn’t undergo haematopoiesis.
43
what do cytokines do
Cytokine encourage the development of WBCs
Cytokines dictate the type of immune response we get
44
what does lymph flow rely on
muscular activity – reason why if you are bed ridden accumulation of lymph occurs
45
what is stroma
connective tissue cells which have a structural/functional role in every organ
46
what is the function of the thymus
* Train and develop T-lymphocytes (maturity)
* Small bilobed organ above the heart
* Has a connective tissue capsule – defines it as a distinct organ
* Extension of bone marrow
* T-cell maturation- thymus takes the T-cell and fine tunes the maturation of them- key regulators of the immune response.
47
what do t-cells orignate from
pluripotent haematopoetic stem cell in the bone marrow
48
what are the 2 mechanisms of WBC production
- lymphoid - lymphocytes
| - myeloid line- generates the rest- eosinophils, basophils, monocyte, neutrophils, platelets and erythrocytes)
49
where are mast cells and macrophages found
aren’t found circulating in the blood – are a result of circulating blood cells differentiating in tissues.
50
What is the name of the precursor cells which forms platelets and where is it found?
Megakaryocyte- found in bone marrow
51
What is the function of neutrophils and how can they be identified?
Involved in phagocytosis- engulf bacteria and digest. The granules contain lysosomal enzymes.
Identified by: multi globular nucleus, lobes on nucleus
52
What is the function of eosinophils and how can they be identified?
Fight parasites and infections
Contains major basic protein (MBP) which is alkaline
Granules appear red
53
What is the function of basophils and how can they be identified?
Involved in allergic reactions
Contains histamine, heparin and peroxidases
Granules appear blue
54
what are NK cells
(natural killer) cells – concerned with anti-viral immunity, innate lymphoid cells
55
what are Innate lymohiud cells (ILC)
look like lymphocytes but are part of the innate system
56
what cells are part of the adaptive immune response
B cells and T cells are part of the adaptive immune response
57
outline thymus histology
* Lobular structure
* Fibrous capsule on outside (distinct)- defines boundaries
* Has a cortex and medulla
* Dots – production of WBCs
58
what occurs in thymus
* Maturation of T cells takes place in the thymus
* Entry of t cells to the cortex, as you go to the inner medullary some T-cells diminish - filter out the t-cells you don’t want.
59
how can you differentiate between peyers patch and thymus
• Peyer’s patch on tonsils don’t have fibrous capsule
60
what is secondary lymphoid tissue and its function
* Composed of aggregates of leukocytes (lymphocytes/DCs/macrophages) and stromal cells- support and survival signals
* Capture antigens and antigen presenting cells from sites of infection
* Initiate immune responses i.e. activation and expansion of particular immune cells
61
what is the role of the spleen in secondary lymphoid tissue
The spleen protects against blood-borne infections-especially encapsulated bacteria- has a well-developed blood supply (cleans blood)
62
where do lymph nodes appear
Lymph nodes appear at the convergence of lymphatics and protect against tissue infections
63
where is Mucosa associated lymph tissue (MALT)
airways, GI/urogenitary tract , nasopharynx, thyroid, breast, lung, salivary glands, eye, and skin (exposed to environment - most pathogens will enter body this way).
64
what is the function of MALT
initiates immune responses to specific antigens encountered along all mucosal surfaces.
MALT inductive sites are secondary immune tissues where antigen sampling occurs and immune responses are initiated
Provide composed of aggregates of lymphoid (lymphocytes/DCs/macrophages) and stromal cells (which provide support and survival signals)..
65
outline Lymph node histology
follicles- ring like structures
germinal centre where new cells are generated
(see notes for image)
66
what is the function of the Peyer’s patch of the small intestine and where are they located
* Secondary lymph tissue responsible for maintaining the health of the immune system
* Underneath epithelium is the peyers patch
* have Dendritic cells – very good antigen presenting cells. Activate B and T cells in secondary lymphoid tissues
67
what is the function of M cells in peyers patches
Between microvilli
take up pathogenic antigens and provides the antigen for the dendritic cells and the peyers patch
68
outline the histology of peyers patches
Ring of lymphoid cells•
No defined structure/ has surface epithelium
No fibrous capsule- its just the collection of WBC that has collected under the surface
69
what is the function of the tonsils
Waldeyer’s ring – ring of lymphoid tissue at back of throat (tonsils)
- Provides protection to the back of the throat AND the top of the GI tract
- Common site of infection – tonsillitis - lots of ridges in tonsil area and things get stuck causing acute inflammation.
May lead to tonsillectomy- not as common due to general anaesthetic complications, and we also have good antibiotics.
70
outline the histology of tonsils
* Have follicles with germinating centre/ epithelium
* Epithelium isn’t wavy like in Peyer’s patch.
* Lots of riges- oppourtinity for collection of food
* No villi so not peyers patch
* Glandular tissue therefore NOT a peyers patch
71
outline the Immune responses in mucosa-associated lymphoid tissue (MALT)
• Stimulated lymphocytes move between MALT sites rather than in the general circulation
• Similar mechanism in different MALT sites; greater functional importance than internal lymphoid organs
- Massive surface area of mucus membranes (400m2)
- Load of antigen from food, air, natural microflora
72
how is the MALT protected
• Antibody from activated cells secreted externally- protection of mucosal surfaces
- We swallow bacteria generate immune response in peyeres patches
- cells transport to salivary glands which have plasma cells secreting antibodies into saliva (providing protection against carious bacteria)
73
Other than the gut, what other anatomical locations have MALT tissue?
Tonsillar tissue and thymus
74
what do phagocytes do
activate all different types of immune responses (wont have to identify)
75
what are monocytes and what do they do
Precursor of macrophages.
Circulate blood, enter tissues on infection and develop into macrophages. Kidney shaped and large
76
what are Macrophages and what do they do
Granular, large cell with an irregular surface. They phagocytose bacteria, virus and fungi - does this to activate t-cells, process that takes place in mucosa and lymphoid tissues.
77
what are the cells involved phagocytosis
```
Phagocytes
Monocytes
Macrophage-
Granulocytes
Mast cells
Dendritic cells
```
78
what is the functions of macrophages
multitasker
| phagocytosis and cytokine activation
79
how are macrophages involved in cytokine function
* Responds to the presence of bacterial components by secreting cytokines. They will signal other cells and help in the immune response
* Signal neutrophils and initiate inflammation via cytokines – key trigger of chemotaxis
80
how are macrophages involved in phagocytosis
•Have a role in presenting antigen (fragments of microorganism which generative adaptive immune responses) and activating T-cells
-Activate acquired immune response
•Act as scavenger cells to clear debris and dead cells – used neutrophils undergo apoptosis and are taken up by macrophage
- Sit in the spleen
81
what is the function of neutrophils
phagocytose to CLEAR infections
• Part of the myeloid lineage
• A ‘granulocyte’ or ‘polymorphonuclear’ leukocyte
• Short lived effector cells (unlike macrophages)
• Capture, engulf and kill microorganisms
• Rapidly mobilised in the early stages of infection
• Gingivitis- lots of neutrophils in gums – inflammation allows neutrophils to get to the site of infection
• Require a lot of energy – if not healthy susceptible to more infection as can’t supply the energy required to drive these cells
• Contribute to inflammation
82
what wbc is in the bone marrow and when is it released
neutrophils
released when needed to fight infection
neutrophils travel to and enter the infected tissue, where they engulf and kill bacteria. the neutrophils die in the tissue and are engulfed and degrade by macrophages
* Tissue is red -gingivitis
* Swells
* Neutrophils flood in
* Neutrophils phagocytosed by macrophages
83
what are the Stages of phagocytosis
* Driven by receptors on neutrophils such as complement Fc.
* Internalised into phagosome
* Phagosome acidified (kills most pathogens)
* Fuses with lysosomes to form phagolysosome
* Neutrophils have primary and secondary granules also which contains additional enzymes and AMPs (go into cell membrane and lyse bacteria)
* Toxic molecules such as nitric oxide and reactive oxygen species (ROS) are also generated
84
what is the function of dendritic cells
* BEST antigen presenter
* Activate cells and initate immune responses
* Antigen presenting cells (APC)- macrophages, dendritic cells and B-cells
* Take up antigens in the periphery, pass via the lymph node and present antigens to B/T cells
* Phagocytose microorganisms and antigens in tissues
* Purpose to present antigen in the initiation of immune responses in secondary lymphoid tissues (lymph nodes and MALT)
DCs do not have a role in clearance of microorganisms
85
what is the function of Mast cells
* granules contain histamine which induce muscle contraction/ wheezing
* Signalling cells – aim to get rid of parasites (we don’t need these if we don’t live in africa
* Mast cells mediate hypersensitivity
86
what are the responses involved in signalling of the effector due to phagocytic recognition of a pathogen
chemotaxis of new phagocytes
interferon response
systemic effects: acute phase response
activation of adaptive immunity
87
what is the interferon response
specific mechanism to combat viral infections. cytokine produced by immune cells involved in antiviral immunity
88
what is signalling of the effector response mediated by
distinguish self from non-self
89
outline the receptor characteristics of the innate immune system
specificity inherited in the genome
expressed by all cells of a particular type e.g. macrophages
triggers immediate response
recognises broad class of pathogens
interacts with a range of molecular structures of a given type
•Innate immunity recognises common structures within bacteria/fungi (i.e. lipopolysaccharide endotoxin)– cannot differentiate between these molecules.
90
outline the receptor characteristics of the adaptive immune system
- encoded in multiple gene segments
- requires gene rearrangement
- clonal distribution
- able to discriminate between evenly closely related molecular structures
• Adaptive immunity has a limited diversity of molecule recognition (will recognise a very specific structure/antigen)
Adaptive immunity involved a large range of different molecules, so that it is equipped to respond to a wide range of different antigens
• Adaptive immune response receptors are unique to each cell
91
what is innate signalling mediated by
pattern recognition receptors (PRR)
92
what are pattern recognition receptors (PRR) and what do they recognise
are proteins capable of recognizing molecules, they recognise a wide range of molecular signals
PAMPs - found in pathogens ( Pathogen-Associated Molecular Patterns—PAMPs), not found on host cells
MAMPs- microbe-associated molecular patterns are molecular signatures that are highly conserved in whole classes of microbe
93
what are the Important Pattern Recognition Receptors (PRRs) in activating the adaptive immune response
1.Free receptors in serum e.g. mannose binding lectin (MBL) activated as part of the lectin pathway of complement activation (2nd activated)
2. Membrane bound phagocytic receptors in macrophages and neutrophils - most common.
e. g. Manose receptors recognise particular carbohydrate structures on pathogens
3. Membrane bound and cytoplasmic (endosomal) signalling receptors
- E.g. toll-like receptors (TLR) –membrane bound receptor, NOD-like receptors (NLR)
94
what are Toll Like Receptors (TLRs)
they are single, membrane-spanning, receptors usually expressed on sentinel cells such as macrophages and dendritic cells, B-cells and epithelial cells, that recognize structurally conserved molecules derived from microbes.
95
what do Intracellular (endosomal) TLR detect and why is this important
phagocytosed pathogens- pathogens can invade cells so this is important
96
what are some important toll like receptors
TLR-1: TLR2 heterodimer
- lipomannans
- lipoproteins
- lipoteichoic acid
- cell-wall B-glucans
- zymosan
TLR2:TLR-6 heterodimer
(same as above)
TLR-3- double stranded RNA (viruses)
TLR-4
- LPS (g-ve)
- Lipoteichoic acids (g+ve_
97
outline the cellular location of the mammalian Toll-like receptors
Receptors which span the membrane- signal to the inside in which intracellular signalling pathways can be activated – leads to an immune response.
98
outline the Signalling pathways when a PAMP binds to a TLR or NLR
2 pathways:
1. activation of NF-kB, AP-1 which induces the following molecular responses and immune effector responses:
- cytokines which induce inflammation and adaptive immunity
- chemokines which induce chemotaxis
- AMP (paneth cells) which induce bacterial lysis
2. activation of IRF which induces Type 1 Interferon as the molecular response and and then an Anti-viral response as the immune effector response
99
what can mutations in the TLR signalling pathways lead to
the absence of an inflammatory response due to distruption in the NF-Kb signalling - this can lead to immunodeficiencies and reccurrent bacterial infections
(Immunosuppressants also interfere with signalling pathway)
100
outline the adaptive immune response that occurs when a LPS activates TLR-4
```
LPS activates TLR-4
Activates transcription factor NF-Kb
Activate pro-inflammatory response
Induces an effector immune response
Involves release of cytokines (inflammation), chemokines (chemotaxis) and AMP (bacterial lysis)
This is an adaptive response
```
101
what are NOD-like receptors (NLR) and RLH
Other PRPs:
NOD-like receptors respond to intracellular infections
RLH can also (RIG-1 like helicases) sense viral RNA and stimulate IFN secretion
102
what is the function of NOD-like receptors (NLR) and RLH
respond to intracellular infections
Identify cell wall peptidoglycans
Mutations cause Crohn’s disease (reduced AMPs)- normal commensal microbiome can invade colonic epithelium.
Activation of NLR mediates gout
103
what are the immune response we get from different cytokines
IL1/TNF have similar overlapping actions
IL1 – activates lymphocytes , local tissue destruction, high in GCF of periodontitis patients
IL-12 – T cell stimulator (adaptive immune response) and NK activator
IL6 – B cell stimulator (adaptive immune response) – fever (bacteria and viruses don’t like high temps)
Shift in metabolism to suit immune cells. Can lead to shock
CXCL8 – chemokine sometimes called IL8 which stimulates chemotaxins of neutrophils in particular
104
what is shock
Systemic inflammation that affect the function of your vital organs. Acute loss of BP due to increase flow of blood into the peripheral tissues/away from main organs.
105
outline Neutrophil function in the immune response
* Attracted to site of infection by inflammatory mediators (e.g. from macrophages)
* Extravasation (migration from blood into tissues) important
* Phagocytosis of a wide range of microorganisms
* 3 types of intracellular granules with a wide range of microbicidal substances
* Dead and dying neutrophils form pus at infected wounds – dental abscess- may drain pus which is dead neutrophils (white)
106
what the type 1 interferons
IFN-α and IFN-β
107
how are type 1 interferons linked to viral infections
theyre Secreted by all cells upon viral infection and engagement of (intracellular) TLP-3/RIG by viral nucleic acids
108
outline what occurs in the interferon response
Most cells will secrete type 1 interferons (IFN-α and IFN-β)
this will induce resistance to viral replication in all cells
increase MHC class I expression and antigen presentation in all cells
activate dendritic cells and macrophages
activate NK cells to kill virus-infected cells
induce chemokines to recruit lymphocytes
109
what are MHCs
molecules are expressed on the cell surface of all nucleated cells
in a virally infected cell, peptides derived from viral proteins may also be presented
110
how do NK cells kill virus infected cells early in infection
* Activated by type 1 interferons (and IL-12 and TNF-α from infected macrophages)
* Have complex array of activating and inhibitory receptors
* Recognise and kill infected cells (via TLR and Fc receptors)
* Recognise non-infected cells (by their characteristic MHC molecule expression) and leave them alone
* Secrete IFN-ϒ (type II interferon) which activates adaptive immunity (T-cells and macrophages)
111
why is herpes simplex contained within the trigeminal nerve
its contained due to NK and T cells
| - If patient is immunodeficent they will have severe spread
112
how do NK cells trigger adaptive immunity
Secrete IFN-ϒ (type II interferon) which activates adaptive immunity (T-cells and macrophages)
113
how are ILCs are distinguished from T- and B- lymphocytes
* ILCs are distinguished from T- and B- lymphocytes by their lack of antigen receptors
* ILCs amplify signals from innate recognition (via cytokine secretion)
* ILCs function as effector cells in response to innate recognition
114
why are NK cells a type of innate lymphoid cell (ILC) NOT an adaptive cell like T and B Cells
Don’t have T cell receptors or immunoglobulins (antigen specific receptors)
E.g. NK cells amplify the interferon response to viral infection
115
what are the three phases response to an infection occurs in
innate immunity (immediate)
Early induced innate
adaptive (late)
116
how does innate immunity (immediate) lead to removal of infectious agent
recognition by preformed, non-specific and broadly specific effectors
117
how does Early induced innate lead to removal of infectious agent
recuritment of effector cells
recognition of PAMPs. acitvation of effector cells and inflammation
118
how does adaptive (late) lead to removal of infectious agent
transport of antigen to lymphoid organs
recognition by naive B and t cells
clonal expansion and differentiation to effector cells
119
outline the features of innate immunity
* Innate immune system- first line of defence
* Quick response to infection
* Early induced immune response
* Recognise molecular patterns (PAMPS) on the pathogens via PRR- these cells produce mediators
120
what is adaptive immunity mediated by
mediated by lymphocytes
- B lymphocytes (cells)-Develop in bone marrow from a common progenitor
- T-lymphocytes (mature in the thymus) - CD8 and CD4
121
what happens when the innate immune response fails to eliminate pathogens
APC (dendritic cells) phagocytose the pathogen and present its antigens to the CD4+ T-cells to activate them
CD4+ T-cells provide help to CD8 (cytotoxic t cells) to kill infected t-cells and to B cells which produce antibodies
CD4s also provide help to innate cells
122
how are T cells activated
by processed forms of the antigen presented by antigen presented cells (APCs) that have become activated themeselves by the innate response
123
how do APC link the innate and immune response
when the innate response fails to remove the pathogen dendritic cells are activated, they phagocytose the pathogen and present its antigens on its surface. this activates the adaptive response
124
what is the evidence for the CD4+ t cells being key to the adaptive immune response
* HIV = severely reduced CD4+ T cells
| * Severe combined immunodeficiency (SCID) e.g. RAG deficiency = no T cells (or B cells)
125
what are the functions of dendritic cells
immunity to pathogens
tolerance to self antigens (if you are not self tolerance you can become autoimmune and develop diseases such as rheumatoid arthiritis
126
what must dendritic cells be able to do in order to interact with T cells
they must be able to migrate to lymph nodes
127
what do chemokines do (small cytokines
they're protein molecules that tell cells where to go- if a cell has a receptor for that chemokine it will
128
how do dendritic cells make their way from the tissues to the lymph nodes
when a pathogen is present, immature dendritic cells recognise the pathogen (e.g PAMPs such as LPS activate the dendritic cell.
this changes the chemokine receptor on its surface, one that will make it go to the lymph node. Lymph node contains T cells to which the dendritic cell can interact. dendritic cells also interact with chemokines in the lymph nodes
129
what are the 3 signals by which dendritic cells and chemokines interact in lymph nodes
* SIGNAL 1 – Recognition of antigen
* SIGNAL 2 - Co-stimulation
* SIGNAL 3 - Cytokines
130
what is the difference between teh antigen receptors in the innate immune system and the adaptive immune system
Innate immune system - invariant pattern recognition receptors (e.g. TLRs, NODs)
-Recognise one type of structure
Adaptive immune system - repertoire of highly variable antigen receptors recognising structures that are specific to individual pathogens:
- T cells = T cell receptor (TCR)
- B cells = B cell receptor (BCR)
131
how are Components of the pathogen (antigen) are processed and presented by APC
via their major histocompatibility complex (MHC) molecules
Provides adaptive immunity with greater sensitivity and specificity
132
what do PRRs do
Detect common microbial structures known as pathogen-associated molecular patterns (PAMPs) or the damage they cause
133
what are the Major histocompatibility complex (MHC) molecules
• Transmembrane glycoproteins expressed on the surface of cells
• Two types: MHC class I and MHC class II
- Differ in what kind of t-cells interact with them
• Encoded in a large cluster of genes (MHC)
• Also called the Human Leukocyte Antigen (HLA) system
• Genetic of MHC complex- lots of different gene
134
what are the Two separate properties of the MHC make it difficult for pathogens to evade immune responses:
1. MHC is polygenic - contains several different MHC genes, so that every individual possesses a set of MHC molecules with different ranges of peptide-binding specificities.
2. MHC is highly polymorphic - multiple variants (alleles) of each gene within the population as a whole
135
Most people are heterozygous (express two different alleles) for the MHC molecules - what does this allow for
increases range of peptides that can be bound
136
where are polymorphisms seen in different MHC alleles more common
in the regions that bind antigen- increase antigen types just by having a mutation
137
what are the benefits of Major histocompatibility complex (MHC) molecules
* Favours the presentation of vast number of different antigen
* Contributes to species biological ‘success’- inherited
138
how are Combinations of MHC alleles (genotypes) are inherited
```
in blocks (haplotypes) and these are selected in populations (in evolutionary terms) by infections
-Certain MHC haplotypes are associated with disease e.g. in rheumatoid arthritis
```
139
what are the Two main types of MHC
1. MHC class I
| 2. MHC class II
140
what does MHC class I do
* Present antigen to CD8+ T cells
* Most nucleated cells express MHC class I molecules (most nucleated cells can be killed by activated CD8+ T cells) - red blood cells do not express MHC
* Binds peptides of 8-10 amino acids long
141
what does MHC class II do
* Present antigen to CD4+ T cells
* MHC class II is expressed by APC (and cells in the thymus) (only a limited number of cells can activate CD4+ T cells)
* Only a few cells can activate CD4 T cells
* Binds peptides of 13-18 amino acids long
142
what is the MHC class I structure
* β2 macroglobulin subunit
* Single heavy chain encoded by 6 class I genes
* Antigen in pepride binding groove
* Table- large range of different proteins that can be expressed
143
what is the MHC class II structure
* α and β chains
* Encoded by 9 different class II genes (3 α and 6 β)
* Similar to class one there are lots of different allotypes (forms)
144
How are MHC class I/antigen complexes assembled?
* Most nucleated cells express MHC class I molecules
* Process Endogenous or intracellular/cytosolic antigens e.g. viruses
Via intracellular pathway
* Antigen in the cytosol of the cell
* It is degraded by proteasome into peptides
* Peptides are transported into the ER via TAP
* MHC class one already in ER
* This will move through ER through golgi and expressed on surface of APC
* CD8 t cell can kill infected cell with help of CD4
145
what cell types are class II/antigen complexes limited to
Professional: dendritic cells
Semi-professional APC: macrophages, B cells
Non-professional APC: fibroblasts, endothelium, epithelium
- Induced to present MHC to become APC
146
How are MHC class II/antigen complexes assembled?
* Exogenous, or extracellular antigens- pathogen in extracellular environment
* APC take up pathogen via phagocytosis
* Lysosomes secrete lysozymes which digest bacteria
* MHC class II antigen is made by the ER and transported to the golgi
* Fusion of the vesicle contain MHC with the lysosome
* Peptide is bound to the MHC
* If CD4 t cell recognises that t -cell it will come along and activate it
* MHC class II is now presented on the surface of the cell
147
what does the T cell receptor (TCR) do
* T cells recognise small fragments of protein (peptide epitopes) presented on MHC molecules on infected cells or antigen-presenting cells
* Each T cell carries cell-surface T cell receptors (TCR) of a single antigen specificity
- Each TCR only recognises one antigen
- Variation comes in here
•The large TCR repertoire of T cells can recognise virtually any protein antigen due to the high diversity in the antigen-binding sites of each TCR
148
what is the TCR structure
• Dimeric = composed of two chains:
• TCR α chain
• TCR β chain
• Both roughly equal in size and span the T cell membrane- extra and intracellular regions
• Each TCR chain has a variable region and a constant region
• The combination of the α- and β-chain variable regions creates a single site for binding antigen
• A T cell has about 30,000 identical TCRs on its surface
- One t cell has one t cell receptor
149
what is the TCR gene rearrangement
• Several genes encode individual regions (domains) of the TCR
• TCR are generated in the thymus by the random somatic DNA recombination (RAG enzymes)
- RAG enzymes stick together different genes to form active t cell receptors
150
what happens if there is a deficiency in RAG enzymes
- Deficiency in RAG enzymes- will not have functionally active t cells
151
what is the gene rearrangement in each individual t-cell
* Slightly different and randomly assembled TCR (based on different variable domains)
* Recognise a different antigen
152
how do TCR recognise antigens
* TCR recognises antigen ”presented” by molecules encoded by the MHC
* APC (MHCII) with antigen bound, presenting it to the T-cell
153
what is MHC restriction
• TCRs recognise features of both the peptide antigen and the MHC molecule to which it is bound
(any given TCR is specific for a particular peptide bound to a particular MHC molecule)
- T cell must recognise the MH as well as antigen
- If T cell receptor does recognise the MCH it will survive and move into the blood MHC restriction
• Occurs through a process called positive selection
154
outline CD8+ T cell TCR-MHC interaction
```
• TCRs expressed by CD8+ T cells recognise antigen with MHC I molecules
• CD8 co-receptor recognises a region of MHC class I protein
- Not just t cell receptors interacting with dendritic cell it’s the CD8
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outline CD4+ T cell TCR-MHC interaction
* TCRs expressed by CD4+ T cells recognise antigen with MHC II molecule
* CD4 co-receptor recognises a region of MHC class II protein
156
outline the whole innate and adaptive immune response
1. Pathogen might infect someone
2. The innate immune system (phagocyte) try to remove the pathogen by consuming it
3. If this fails, the cell become infected & starts to express the antigen on the surface by MHC Class I
4. Immature DC will come along & phagocytose the pathogen in the presence of the danger signals which will activate the immature DC into a mature one
5. Mature APC expresses both MHC classes
6. Through the chemokine receptor switch over & mature APC migrate to lymph nodes
7. Mature DC interact with CD4+ T-cells by MHC class 2
8. These T-cells, upon recognition, will convert into effector cells & proliferate to get a lot of them
9. Each effector cell is identical to the cell that recognizes the antigen
10. The CD8+ cell recognizes antigen by MHC class I
11. With help from CD4+, CD8+ cells activate and divide to get a lot of them. These are identical to the original one that recognised the antigen
12. The CD8+ cells move to the site of infection & kill the infected cell after recognizing them by their MHC Class I
13. Some of the activated effector cells, the CD4+ cells, help B cells by MHC Class II that the B cell expresses
14. Helps in term of cytokine production, helps B cells produce antibodies to fight off the infection.
15. The CD4+ T cells are subdivided into helper subsets: the key two of the oldest types are Th1 and Th2 cells
a. Th1 cells help cells like CD8+ by producing interferon gamma
b. Th2 help B cells produce antibodies
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why is the The activation of CD4+ T cells key to adaptive immune responses!
provide help to both CD8+ T cells (cytotoxic T cells) and B cells (antibody producing cells), can also help innate immune cells (such as macrophages)
158
outline the 3 signals that take place to produce cytokines in the lymph nodes
* SIGNAL 1 – Recognition of antigen- antigen taken up by dendritic cell. Process into fragments and presents. T cell interacts with the dendritic cell via MHC II. Signal from APC sent to CD4 T cell.
* SIGNAL 2 - Co-stimulation of the CD4 t cells.
* SIGNAL 3 – Cytokines- produced
159
outline signal 1 - recognition of the antigen
* A T cell receptor (TCR) recognises antigen ”presented” by APC on molecules encoded by the major histocompatibility complex (MHC)
* Antigen presented by MHC
160
Prior to interaction with APC, what have T cells already gone through
rigorous training - process
| Positive and negative selection in the thymus
161
where are t cells derived from
haematopoietic stem cells that are found in the bone marrow. The progenitors of these cells migrate to and colonise the thymus.
162
what things do t cells undergo in training
Attack foreign pathogens
Ignore self proteins (if not) autoimmune disease
(protection and self tolerance)
163
what are the two steps by which t cells are educated in the thymus
1. Positive selection – ensures T cells have a functional TCR that can bind MHC on APC
- T cells survives if it recognises the MHC antigen, if not it dies
2. Negative selection/central tolerance- ensures the TCR does not strongly recognise self proteins - Central tolerance
164
what is a MHC restricted t cell
T cell that survives if it recognises the MHC antigen, if not it dies
165
what happens if the t-cell recognises the antigen too much- why is this very important
clonal deletion occurs- If immature it likes the MHC antigen too much its destroyed by apoptosis.
this means the t-cells that express receptors for self antigens are removed before maturing - This prevents recognition and destruction of self host cells,
166
what occurs in signal 2 co stimulation of the t cell
* Activation of PRRs (e.g. TLRs) by PAMPs (e.g. LPS) triggers expression of cell-surface proteins called co-stimulatory molecules on APC
* Co-stimulatory molecules (CD80 (B7.1) and CD86 (B7.2) on APC interact with CD28 on T cells
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what do co stimulatory molecules do
• Co-stimulatory molecules support the ability of T cells to proliferate and differentiate into its final, fully functional form
168
what does signal 1 and 2 induce in t cells
makes t cell produce IL2 and IL2 receptor (IL2 is a key cytokine for t cells)
- Causes t cell to survive
- Causes t cells to proliferate
To know what kind of t cell it needs be a 3rd signal from cytokine
169
how is signal 3 produced and what is this determined by
the type of signal that occurs from the cd4 t cell is determined by the cytokine produced from the ACP (whcih is different depending on the pathogen)
e. g.
- Virus induces IL12 production from APC
- Parasite induces IL4 production from APC
•Polarising cytokines present when a naïve CD4+ T cell is activated:
•Determine type of effector T cell via transcription factor activity
- TF drive gene expression
- Cytokines will drive different TFs activity so different gene expression
•Ensures the CD4+ T helper (Th) cell response is appropriate for the type of pathogen
170
how will different cytokines be induced
following different pathogen-induced innate APC activation, e.g. many viruses induce IL-12, many multicellular parasites (e.g. worms) induce IL-4
171
what are the different t cells that can produce cytokine differentiation
```
Th1
Th2
Th17
Tfh
iTreg
```
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cytokines are considered proinflmamatory, except those produced from which t cell
iTreg
173
how do CD4+ T cells contribute to their continued polarisation
positive feedback loop
174
how do CD4+ Th cell responses also become increasingly polarised
negative feedback loops
release of cytokines that supresses prolieration and development of several t helper cells
175
When effector T cells detect antigen, they can manifest three broad classes of activity, what are they
1. Cytotoxic T cells (Tc; CD8+ T cells)
2. Helper T cells (Th; CD4+ T cells)
3. Regulatory T cells (Treg; CD4+ T cells or CD8+ T cells)
- Can be CD4 or CD8
176
what are Cytotoxic T cells (Tc cells)
* Effector CD8+ T cells
* Target cells infected with viruses or other intracellular pathogens
* Pathogenic antigens are displayed on the cell’s surface MHC class I
* Control infection by directly killing the infected cell:
* Release the cytotoxins, perforin and granzymes, which induce apoptosis
* Also induces apoptosis via FasL (molecule on Tc cell) interacting with Fas on target cell
* Are provided with help by CD4+ Th cells (Th1)
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outline the action of Th1
Produces inteferon gamma cytokine
• Can help other cells to either enahnce their effector function
o Helps macrophages much more better at killings pathogens
• Cell-mediated responses by helping other cells do their job
• Results in a lot of inflammation & cell-mediated immunity
• When wrong, it leads to auto-immune & inflammatory diseases
• Key drives of rheumatoid arthritis pathogenesis
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outline the action of Th2
Produce cytokines that help B-cells i.e. IL-4
Produce IL-13 which increases the production of mucus
• Getting rid of parasites, especially in the GI
Helps the innate cells & the B cells
Helps the humoral responses (B cell antibody production)
If they go wrong, they are linked to allergies
179
outline the action of Th17
Variety of cytokines e.g. IL-17, IL-22
Make other cells produce other mediators
Target neutrophils & extracellular bacteria
Tend to be linked to fungal infections e.g. candida
Induces inflamamtory response
180
outline the action of Tfh cells:
Their main role is to help B cells
• Provide signals e.g. cytokine IL-2, to cause B cell activation and produce antibodies
Very important for B cell maturation
If it goes wrong, causes autoimmune disorders
181
outline the action of Treg cells:
They inhibit cells e.g. dendritic cells & other T cells
Inhibits T-cell activation
• Key for tolerance & homeostatic control
182
what did regulatory t cells do (Tregs)
• Peripheral tolerance mechanism
• Maintain immune homeostasis – suppress the proliferation and activation of other effector T cells either to dampen immune responses or switch off self-reactive T cells
• Tregs have multiple mechanisms
• Several mechanisms of action are proposed that target effector T cells as well as other cells. e.g:
- Production of tolerogenic molecules
- Consumption of IL-2 (cytokine needed for survival of effector cells)
- Inhibition of co-stimulation-
- Killing of cells
183
what is Immunological memory
* After naïve T cells have been activated by antigen they proliferate (clonal expansion), generating effector T cells (clones – all progeny have the same TCR)
* Some effector T cells migrate to sites of infection, others stay in the lymphoid tissues to activate B cells
* Most effector T cells generated by clonal expansion in an immune response will eventually die
* Some effector T cells persist after antigen has been eliminated - known as memory T cells and form the basis of immunological memory
* Responsible for long-lasting protective immunity following exposure to pathogen – reactivate more quickly than naïve T cells
* Works by- naïve t cell with fucntonal t cell receptors. Pathgogen triggers expansion as they recognise antigen. Destroy the pathogen. Most die. A few stay and become memory.
Memory T cells can be reactivated (antigen-specific manner) much more quickly than naive T cells - memory T cells show a lower threshold for activation, but as a result of changes in the responsiveness of the cell and not because of changes in the TCR
184
outline what happens Once a B-cell has taken up and presented antigen to a TFH cell
the T-cell activates B- cell maturation into antibody- secreting plasma cells
B cell presents antigen in the same way as a macrophage or dendritic cell
TCR responds by providing B cells with help -stimulates differentiation of B cells into plasma cells to make antibodies
Although B cells have antibodies on the surface, they don’t secrete antibodies until they produce plasma cells
Plasma cells have a lot of rough ER for secretion of proteins. They are the end results of the development of B-cells.
IgM to IgG at the end stages. We get affinity maturation which is an improvement of the affinity for the antigen
T follicular helper cell- resides in lymph nodes and the other secondary lymph tissues in follicles.
185
outline Antibody function
• To recognise and bind to antigens
– To activate complement- powerful in opsonising, lysing and chemotaxis.
– To target bound antigen to other branches of the immune system (e.g. phagocytes, NK cells, mast cells etc). E.g. neutrophils have receptors on their surface as do NK cells and mast cells. Mast cells degranulate, NK cells kill target cells.
– To neutralise toxins- antibodies can neutralise the toxins.
– To prevent pathogens gaining entry to cells- many bacteria and viruses rely on intracellular presence
186
outline how Antibodies e.g. IgG comprise immunoglobulins
* IgG is the most abundant antibody in internal body fluids (lymph, blood)
* Made in lymph nodes, spleen, and bone marrow
* Smaller, more flexible than IgM (n.b. hinge region- large globular flexible protein)
* Can get into extracellular spaces and across placenta
* Has more effector functions than other antibody classes e.g. IgM
187
why is there Only limited variation between constant regions of antibodies
• 5 classes based on different heavy chain constant region amino acid sequences
188
outline the features of IgM
* Pentameric
* Biggest- lots of antibodies joined together
* Quick- The first antibody produced in immune responses (in lymph nodes, spleen and bone marrow)
* Circulates in blood and lymph
* Multivalent
* Stimulates complement activation and phagocytosis
* IgG takes over later in immune response which is more important
189
outline the features of IgA
* Found in saliva- protects against streptococci
* Needs J chain
* Monomeric form functions in blood
* May be made my tonisils, peyers patches
* Antibodies that develop in the gut can go anywhere is the mucosa as the MALT is all linked by blood.
* Dimeric is made by sub- mucosal lymphoid tissue
* Structure reflects need for secretion
* Found in the gut, saliva, sweat and tears
190
outline the features of IgE
Binds to Fc receptors on mast cells- they have already have IgE on their surface
Little circulating IgE as it binds to mast cell receptors with high affinity
Cross linking of IgE on mast cell surface leads to degranulation and activation of innate immunity- increased blood flow and neutrophil migration (inflammation)
Excessive activation leads to hypersensitivity- the hypersensitivity is an unfortunate response
191
outline how clones of effector cells are formed
Pathogen selects the lymphocytes that corresponds to specificity
Presentation of antigen allow selection of lymphocytes. Then proliferation into the effector cells
3 signals to activate the T-cells.
Different effector cells – plasma cells (clonal) every clone or copy has the same antibody
192
Q: How is diversity in the antibody binding regions (Fab) of Ig generated?
* Lots of immunoglobulin genes to chose from in every cell
* which then undergo rearrangement
* in B cells these genes are particular active- they make immunoglobin and secrete as antibody
* B cell can choose between chain proteins randomly
* Lots of genes in loci
* B cells process these genes and make proteins bases on different combiantions
* In between (yellow)- smaller regions, they’re there to allow for more varation
193
outline how diversity is specifically achieved in the b-cell as oppsed to other cells ii the body .
- Rearrangement of genes in DNA only takes place in the B-cell
- B cells select different genes and combine
whereas there is a GERM LINE- in every cell
194
The process of somatic recombination in B-cells
• A random process- rearrangements random but controlled by enyzyme
- Driven by a multi-enzyme complex called V(D)J recombinase
• This used enzymes common to DNA repair mechanisms in most cells
• Recombinase activating gene proteins1/ 2 (RAG 1/2) are specifically expressed in lymphocytes
• Diversity is gernerated by combonations of heavy and light chains and mechanisms outlined below
195
what is Junctional diversity
Different clones have different sequences
they are Added and removed some nucleotides. These are not encoded in the genome, they are added in during recombination. This amplifies diversity.
JD is generated during VDJ recombination
196
what are the Mechanisms of diversity generation in VDJ genes
* Combinatorial diversity I (multiple genes)
* Junctional diversity I: Imprecise cutting and pasting by recombinase (removes nucleotides)
* Junctional diversity II: Addition of non- germline nucleotides between D and J segments and V and DJ (N regions)
* Combinatorial diversity II (assemble of Ig molecule using different light chains)
197
what are the important changes in immunoglobulin genes during a b cells life
somatic hypermaturation
Isotype switch
Generate diversity and after you encounter antigen you improve the immune response By changing the class of iG by making the antibody have a higher affinity. These are irreversible. this is permanet.
198
what does Somatic hypermutation in Ig genes during successive immune responses introduce
mutations which alter the Ig protein structure: B-cells expressing high affinity Ig survive and those expressing lower affinity Ig die through a process of natural selection. Mutation in the DNA at a rate higher that expected (hypermutation)
199
what does more changes in the variable region allow for
The more changes the greater the affinity. Microevolution of affinity. Those that produce immunoglobulin with higher affinity are selected and maintained as they interact with. The antigen better. Same or worse affinity die off as those cells don’t act with antigen well (natural selection in lymph nodes)
200
what are the Changes in antibody responses throughout the course of repeated immunisations:
1. Increased quantity of antibody
2. Increased affinity of antibodies (due to somatic hypermutation)
3. Isotype switching from IgM to IgG- better immune response with more coverage. Increased affinity- stronger at the same concentration!!
More antibodies as immune response proceeds
More IgG- yellow taking over from the gene (isotype switching)
Best not just to have one, multiple boosters are better. So with the first immunisation you have good immunity not complete (hepatitis
201
In addition to plasma cells, what can B-cells in the lymph nodes (centrocytes) develop into
memory cells under the influence of cytokines from TFH cells.
• Specificty and memory- longer lived
• Vigorous and effective immune response
202
what is the Monetary impact of people living older
Age-related spending is projected to rise by 5% between 2016/17 and 2061/62
- equivalent to a rise of around £79bn -
spending on health care projected to rise by 2.3% of GDP
- equivalent to a rise of around £36bn
203
what at the sources of variation in immune function linked to age and nutrition
• Obesity
• Alcohol consumption-
• Gut flora- Amount of gut bacteria in the gut colon affected by the type of diet
• Hormonal status- linked with age (menopause in young girls)
• Obesity – reduced immune capacity- linked to exercise and lifestyle
Early life events- during pregnancy. What your mother eats will affect body composition.
other
* Exposure to pathogens
* Vaccination history
* Nutrition
* Age interlinked with nutrition
* Genetics methylation of genes = expression
* Exercise and smoking life style related
204
what is the Normal ageing process
* Despite stereotype most of the elderly age well!
* Our perceptions of old people are based on the frail sub-set who frequently use medical services
* Reduction in functional reserve capacity in tissues and organs – slowing down. Healthy younger individuals can function on energy reserve if we don’t eat less so with elderly
* At advanced age more common to see evidence of impaired homeostasis and response to external insults e.g. illness.
205
what is functional reserve capacity
occurs in the tissues and organs – slowing down. Healthy younger individuals can function on energy reserve if we don’t eat less so with elderly
206
what is the Biological basis of ageing
* Molecular damage of our cells e.g. due to stress, environment, daily proliferation
* Most will be repaired
* Over time an accumulation of cellular defects
* This relates to ageing
* Reduction in repair affected by stress, poor diet and adverse environment
* Good environment/diet/lifestyle can slow this accumulation of cellular defects (ageing) down
207
what is the link between Ageing and immune function
* Ageing results in a progressive dysregulation rather than a decline in immune function
* Many decreased immune responses described as age-related are linked to poor nutrition
* In carefully selected, very healthy individuals, decreased immune response are only seen in the very old (> 90 y). Nutrition is having that effect.
208
how does Under nutrition impair immune function and what is the evidence from developing and developed countries
Energy and macronutrients – decrease in protein/energy/fat will result in a decrease in micronutrients (fat soluble vitamins A, D, E and K)- if you don’t have enough vitA, you probably don’t have enough fat in your diet
Evidence from developing countries
o Food shortage, natural disasters, poor soils (selenium deficient obtained through wheat), poor living conditions & limited access to health services
Evidence from developed countries
o Elderly, preterm babies (LBW), hospitalised patients & cancer patients with restricted diets
o Hospitalised patients often become malnourished in hospital
209
what are the different places in which PEM occurs in the elderly
* 15% of community dwelling elderly
* 10-38% outpatients
* 5-12 % homebound patients
* 5-8% of institutionalised older patients
* Presence rarely recognised or treated
* Around 10% of uk elderly had PEM
210
what is the Effects of PEM on immune system in elderly
lymphocyte proliferation,
IL1, IL2, IL6, antibody production, gut barrier function all decreased in older people with PEM compared to healthy old- meaning they are more susceptible to disease
211
how is the interaction between nutrition and infection bidirectional
if you are Malnourished, you have a diminished host response.
Infection causes individual to become more malnourished i.e. diarrhoea
Much more likely to get an infection by pathogen
Cycle that gets worse and worse
212
what are the Nutritional consequences of an infection
Less likely to eat
May have diarrhoea or sickness due to infection so More nutrient losses and take less nutrients in
activation of the inflammatory response to try and remove this infection- there will be a subsequent effect on: anorexia, malabsorption, intestinal damage and diarrhoea
213
what is the link between Fish oil and rheumatoid arthritis
Essential fatty acids in fish oils
Positive effect on inflammatory diseases e.g. periodontitis
Durations ranging from 12-52 wks
• Used 1 to 6 g/d EPA + DHA (average 3.3 g/d)
• All show benefit in at least 2 clinical scores
- Some show > 4 clinical benefits (increased grip strength, decrease in swollen joints etc.)
3 studies monitored usage of NSAIDs as an outcome and reported significant reduction in usage
214
what are the Estimates of prevalence of micronutrient deficiencies in apparently healthy elderly
* Vitamin B6 (gene expression) – 6-26% of individuals deficient
* Folic acid/ B9 (DNA replication) – 9-16%
* Vitamin C (anti-oxidant) – 5-10%
* Vitamin E (anti-oxidant) - <1%
215
what is the link between Vitamin B6 and human immune function
* Healthy elderly subjects fed diets containing different doses of B6 for 3 weeks
* Measured resting B6
* Effect on immune function if you reduce B6
* Then a normal diet containing 41 mg B6 for 4 days
* Results in interleukin decrease
216
wha is the link between Zinc and immune function and what are the consequences of too much zinc
* It is well established that zinc deficiency results in defects in innate and acquired immune responses
* Zinc deficiency in mice is correlated with increased susceptibility to bacterial or viral infection
* At a cellular level, zinc deficiency results in complex immune deficiencies, affecting primary T cells and natural killer cells and reducing antibody formation
Cu deficiency and interferes with Fe and Cu metabolism. Other deficiencies.
• Deficiencies can have detrimental effect- however could have toxic effect due to dose
217
what is the link between zinc and pd
* 14 rats – 7 were fed zinc rich diet and 7 had no zinc
* Zinc deficiency can lead to loss of appetite
* Zinc has positive effect on inflammation
* Those on a zinc adequate had: Less plaque, lower gingival index, lower pocket depth
218
```
what problems can
Macronutrient deficiency (PEM) and micronutrient deficiency have on immune function
```
macro- inflammatory problems
Micronutrients deficiencies impair immune function. may make an individual more susceptible to infection
219
what effect can providing micronutrients to deficient individuals and increasing micronutrients above recommeded have
* Providing micronutrients to deficient individuals may restore resistance to infection
* Increasing the amounts of some micronutrients above the levels recommended may enhance immune function
However, Excess amounts of some micronutrients impair immune function
220
what effect can calories restriction have
* Monkeys that were calories restricted – 30% of energy restricted
* Still had all the macro and micro nutrients needed
* Not malnourished
* When should we start to calories restrict
221
what is the effect of Ageing compared to environmental factors on the immune system and why
* Ageing exerts less influence on immune system than environmental factors-most immune functions are preserved until old age
* Chronic low intakes of some nutrients are quite common in apparently health elderly population and may be responsible for the many immune-related changes that were previously thought to be age related
222
what is the effect of undernutrition
• Under-nutrition, irrespective of the nutrient concerned induces immunodeficiency, even in self-sufficient, non- diseased subjects
223
what is the link between inflammatory response and age
• Inflammatory response may be increased with age. There is potential for dietary modulation of inflammation
