Immunology and Healthcare Theme 2 Flashcards
(200 cards)
1
Q
outline the course of an immune response to infection
A
Dynamic: nature and intensity change with time
Organised: in time and location- particular roles (tonsils, peyers patches)
Improves: in terms of strength and precision
2
Q
what does the success of an infection depends on:
A
- Properties of a pathogen and therefore how it spreads
- Dose of inoculation - -larger doses needed to overcome innate immunity- more exposure, more likely to get the infection
- Route and mode of transmission -adaptive immunity needed if innate overcome-importance of antibodies
- Health, age, nutrition, co-existing infection and general host factors that influence immune response. Need someone who is healthy. With age you get a dysregulation of the immune system.
3
Q
what do the stages of an immune response to infection
A
local infection, penetration of epithelium
local infection of tissues
lymphatic spread
adaptive immunity
4
Q
outline how protection against infection occurs
A
wound healing induced antimicrobial proteins and peptides, phagocytes, and complement destroy invading microorganisms
complement activation dendritic cells migrate to lymph nodes phagocytes action NK cells activated cytokines and chemokines produced
pathogens trapped and phagocytosed in lymphoid tissue
adaptive immunity initiated y migrating dendritic cells
infection cleared by specific antibody, t-cell dependent macrophage activation
5
Q
why is the spread of infection critical
A
- Pathogen must establish a site of primary infection and then spread thus adherence, colonisation and penetration critical eg. To teeth, gingiva
- Pathogen may be eliminated or contained by barriers and/or innate immunity
- Most pathogens are not lethal if the infection is contained
- Obligate intracellular pathogens spread cell to cell
- Extracellular bacteria spread in blood and lymphatics
- Some diseases caused by pathogens which do not spread into the tissues: they secrete toxins- immunised against some of these toxins
- Establishment (non-elimination) of infection activates adaptive immunity (CLEARS INFECTIONS)
6
Q
what is the function of the innate and adaptive response
A
innate- contains the infection
adaptive- clears the infection
7
Q
what occurs in severe combined immunodeficiency
A
no adaptive response.
RAG DEFICIENCY
•Rag genes govern production of t-cell receptors- so we’d have no T or B cells because of these conditions.
- The infection is contained but not cleared
- Innate immunity is working, but its not got rid off.
8
Q
how does Immunodeficiency illustrates the importance of both innate and adaptive immunity
A
•TLR3 mutations in man leads to HSV-1- induced encephalitis (HSV-1 infection is normally limited to cold sores)
-Severe CNS effects in these individuals
•Severe combined immunodeficiency (SCID): defects in T-cell development lead to lack of cell mediated and antibody- mediated immunity and susceptibility to a broad range of infections- no t-cells, no functioning b-cells
9
Q
How are non-specific responses of innate immunity necessary for the initiation of adaptive immunity
A
complement activation helps neutrophil/monocyte immigration to clear infections
activation of endothelial cells in blood vessels by cytokines
T cells enhance macrophages
10
Q
what is the cytokine milieu and T-cell effector function
A
cytokine milieu determines specific t-cell transcription factors
differentiation of t-cells into diverse effector subsets
- TH17- reinforcement of innate immunity
- Treg- suppression of immune response
- TH1- macrophage activation
- TH2- mast cell/ b-cell activation
- Tfh- b-cell activation in lymph nodes
- No tregs- immune responses not switched off
- Th1- Link between adaptive and innate response
11
Q
what is the function between Th1
A
macrophage activation
Link between adaptive and innate response
12
Q
how are different effector mechanisms used to clear primary infections with different classes of pathogens and to protect against reinfection
A
• Different pathogens require different types of effector functions
• Humoral immunity- need antibodies to bind to toxins
• Streps cause pneumonia- inflammation of the lower respiratory tract
• If you don’t have complement you suffer from extracellular infections
• Needs cells that kill the infected cell or activate the infected cell
- Mycobacteria- cause leprosy
• Cd8 cells will kill infected cells
13
Q
outline the immune response against intra-cellular bacteria e.g mycobacterium tuberculosis
A
Macrophages take up bacteria- however these bacteria are adapted to avoid macrophage response so you get an adaptive immune response
co-receptor on th1 cell will help activate the macrophage by binding to MHC class II on its surface
(occurs in lungs when infected with mycobacterium)
14
Q
what are the Immune responses against intra-cellular bacteria involving TH1 responses
A
- IFNg and CD40 ligand important (co-receptor)
- Other pathways used to kill cells if pathogen is resistant to intra-cellular digestion: Fas ligand- receptors system for killing cells
- TH1 also promote recruitment of macrophages to site of infection- they will also promote the development of new macrophages
- Lots of macrophages in the lungs of someone with tuberculosis
- If microbial pathogens resist the action of activated macrophages, then chronic inflammation can develop
15
Q
what is the importance of tH1 response in mycobacterial infection
A
when macrophage is infected with mycobacterium tuberculosis , inteferon gamma activates macrophages and clears infection
16
Q
what are the 2 clinical forms of leprosy and what kind of Th response do they induce
A
tuberculoid leprosy - Th1
lepromatous leprosy - Th2
17
Q
how is the balance of effector T-cells in immune responses to bacteria is influenced by peptide: MHC density on APC (as well as the cytokine milieu)
A
- An abundance of peptide:MHC complexes will drive TH1 responses
- A limited number of peptide:MHC complexes will drive TH2
- Many infections require both TH1 and TH2 responses and there is a dynamic shift between them
- Cytokines determine- the type of t cells response we get and the antigen presenting function. If we don’t get this response we get an inappropriate response
18
Q
what are the Immune responses at mucosal surfaces:
A
Mucosal surfaces have own types of defences e.g. peyers patches
mucosal surfaces are thin and permeable because of their physiological functions
vulnerable to infection
vast majority of infectious agents enter by this route
have commensal microbiota and immune defences with distinctive features
19
Q
what are the Properties of the microbiota at mucosal surfaces
A
- Synthesise antimicrobial substances e.g. lactobacilli make lactic acid and anti-microbial peptides (baterocins)
- Stimulate epithelial cells to make their own microbial peptides
- Compete with pathogens for ecological niches
- If these are compromised disease may ensue (Self-study: look for examples of this effect)
- The microbiota influences the development of the immune system
- Does inter-individual variation in the microbiota influence disease susceptibility and response to immunotherapy?
20
Q
what are some distinctive features of the mucosal immune system
A
specialised antigen uptake mechanisms e.g. M cells in peyers patches, adenoids and tonsils
secretory IgA antibodies found in saliva- protection against cariogenic bacteria such as streptococci
tolerance- active downregulation of immune responses (e.g. to food)
21
Q
what occurs in Acute inflammation
A
- Calor- heat: increased blood flow
- Dolor- pain: pressure due to oedema, pus and chemical mediators e.g. bradykinin & prostaglandins (inflammatory mediator)
- Rubor- redness: blood vessel dilation
- Tumor- swelling: oedema (fluid accumulation) or increased cellularity at the area- lots cancers have tumours
- Loss of function: due to pain and swelling
22
Q
what are the wide range of agents which can cause this initial tissue response to acute inflammation
A
- Infections
- Physical agents e.g. trauma, ionising, radiation, heat, cold
- Chemicals e.g. acids, alkalis
- Tissue necrosis e.g. ischaemic infarction (death of tissue due to blockage e.g. blood vessel)- cells burst open, release material and stimulates inflammation
- Immunological disease
- Hypersensitivity reaction – inappropriate immune response to an environmental agent
23
Q
what are the vascular changes in the early stages of acute inflammation
A
- Oedema, neutrophil, fibrin accumulate in extracellular spaces
- Changes in vessel diameter which increases flow
- Increased vascular permeability-protein rich fluid (including fibrin-repair)
- Cellular exudate – neutrophils (exudate – cellular across cellular membrane)
- All mediated by molecules of the immune response (e.g. complement which induce chemotaxis)
24
Q
what are the beneficial effects of acute inflammation
A
- Dilution of toxins
- Entry of immune response elements
- Transport of drugs to region of inflammation- fuel mechanisms
- Fibrin formation – facilitates coagulation
- Delivery of nutrients and oxygen for neutrophils which have high metabolic activity
25
what are examples of acute inflammation
Suppurative (production of pus) inflammation
•If pus is walled off by fibrous (repair) tissue forms an abscess or if pus accumulates in a lumen it forms an empyma (pus in a natural space)
Membranous inflammation-coating of epithelium with fibrin, desquamated epithelial cells, neutrophils-
•e.g. laryngitis and pharyngitis due to Corynebacterium diphtheriae- membranous inflammation NOT suppurative (could ask)
26
what are some consequences of dental abscesses
infection can spread to the fascial layers of the muscle causing cellulitis and swelling
bone destruction- destruction of root not loss of alveolar bone (as in PD)
27
what is a more serious consequence of an abscess
sepsis- disseminated infection of the blood ( life threatening)
swelling puts pressure on the great veins on head and neck
28
there are several results of acute inflammation, what are they
resolution (usual result)
Suppurative- pus
repair and organisation
chronic inflammation
29
what is fibrosis and when does it occur
it is an over indulgent repair response - can lead to loss of function and/or scar formation (e.g. fibrosis of lung tissue)
also, a persistant causal agent can cause chronic inflammation which can lead to fibrosis
NOT good as it can cause thickening and scarring of connective tissue
30
what is a key example of Chronic inflammation (why is it chronic)
tuberculosis (TB)
contained BUT bacteria are still there so its chronic
31
how are TB granulomas formed
when macrophages are infected with Mycobacterium tuberculosis- they resist the microbiocidal effects of tissue macrophages
Eventually macrophages coagulate and become surrounded by T cells in an attempt to activate the macrophages.
form granuloma (giant cells)
32
how can a granuloma be identified
Few cells in the middle -Middle of granuloma become cut off from the blood supply, lose oxygen and nutrients and become necrotic
lots of cells on the outside (specs indicated lots of WBC)
pink- becoming necrotic, cut off from oxygen
(note: in the lungs is bad as this isnt lung tissue anymore)
33
what occurs in Granulomatous inflammation
* Granuloma formed when bacteria e.g. Mycobacteria resist the microbiocidal effects of tissue macrophages
* Has a central area of (infected) macrophages and an outer layer of T-cells (CD4 TH1 cells)
* CD4 TH1 cells engage antigen presented by macrophage and TH1 cells proliferate
* TH1 cells proliferate (IL-2) and activate macrophage (IFNg)
* Stimulates recruitment of more macrophages
34
outline Granuloma formation
* Occurs gradually (years)
* Bacteria resist macrophage digestion which leads to granuloma formation
* Centre of granuloma can be cut off from blood supply
* Cells die through anoxia and effects of excessive macrophage lytic enzymes
* Caseation necrosis can result
35
outline the Pathological presentations of TB
caseation of the adrenal gland (caused by tuberculosis)
caseation necrosis in a lymph node
confluent granulomas in pulmonary TB - problem with breathing
the Ghon complex- where TB bacteria first hit the tissue (enters lung here)
Miliary tuberculosis- (looks like seeds)
36
what is the actual disease is caused by
by loss of tissue function due to effects of (inadequate) host immune response and subsequent inflammation
e.g TB- loss of lung tissue function, pneumonia, PD
Infection is not the only cause of chronic (or acute) inflammation
37
what are the Systemic effects of inflammation I: Fever
• A systemic effect of IL-1, IL-6 and TNF-a (pro-inflammatory cytokines)
- Class PRO-inflammatory cytokines coming from cells such as macrophages
• Act on temperature control sites in hypothalamus- microorganisms cannot survive at high temperatures
• Act on muscle and fat altering energy metabolism to generate heat
• Adaptive immunity more potent
• Microorganisms prefer lower temperatures
38
what are the Systemic effects of inflammation II: The acute phase response
• IL-6 activated the liver to produce molecules that will produce a response
• IL-6 produced by macrophages acts on hepatocytes
• Induce synthesis of acute phase proteins
• C reactive protein (CRP) binds phosphocholine on bacterial surfaces acting as an opsonin and as a complement activator- increase in CRP
- Measure the CRP in the blood and its elevated e.g. in type II diabetes as there is an inflammatory element associated with this
• Mannose binding lectin binds to a carbohydrate on bacterial surfaces acting as an opsonin and as a complement activator
39
what are the Systemic effects of inflammation III: shock
• Circulatory collapse causing hypoperfusion of vital organs
• Caused by haemorrhage or generalised increase in vascular permeability and dilation
• Many medical causes
• E.g. septic shock as a consequence of sepsis infection of the bloodstream with endotoxin (LPS) producing gram –ve bacteria
- Systemic inflammation and all the blood is going to ithe tiseu and coming out of circulation. Blood goes to tissues at the expense of vital organs so you get multi organ failure
• I.e. T forsythia and P gingivalis (both gram -ve).
40
what occurs in a localised infection with gram negative bacteria
activated macrophages secrete TNF in tissues
increased release of plasma proteins into tissue. increased phagocyte and lymphocyte migration into tissue. increased platelet adhesion to blood vessel wall
phagocytosis of bacteria, local vessel occlusion, infection CONTAINED, antigens drain or carried to local lymph nodes
survival- stimulation of adpative response
Localised TNF leads to PROTECTIVE INFLAMMATION
41
what occurs in a systemic infection with gram negative bacteria (sepsis)
macrophages activated in the liver and spleen secrete TNF into the blood stream
systemic edema causes decreased blood volume, hypoprotinemia, and neutropenia, followed by netriophillia. decreased blood volume causes collapse of vessels
disseminated intravascular coagulation leads to wasting and multiple organ failure: septic shock
Death
Systemic- TNF leads to septic shock
42
what s acute inflammation mediated by
innate response
43
what does chronic inflammation relate to
an inadequate adaptive immune response
44
what does IgG do
protects the tissues and blood against pathogens
45
what do NK cells do and how
```
activated by type I interferons (IL12 and TNF-a) and has KIR receptors which recognise class I MHC molecules –kill virally infected/non-self cells
NK cells secrete IFN-g (Type II interferon) which activates macrophages
```
46
what receptors do NK cells have on their surface and what do they recognise
have KIR receptors (not antigen specific) which can determine whether a cell is infected or not. they recognise class I MHC molecules
47
what do NK cells secrete
IFN-g (type II inteferon) which activates macrophages (whic release pro-inflammatory cytokines)
48
how does herpes simplex work
prevents cell from expressing MHC so fools immune system so it thinks its not infected
49
outline the activation of CD8 cytotoxic t-cells
recognition and stimulation of naive t-cell
proliferating t- cell
effector function- active effector t-cells kill virus infected target cell
50
how does CD8+ cytotoxic T-cell recognise virally infected cells
via TCR/MHC/peptide
51
how are infected cells killed by CD8 t-cells
killed by the action of lytic granules that contain cytotoxic molecules such as perforin and granzymes which causes apoptosis
IFN-g is also secreted by CD8 T-cells promotes antigen presentation and dead cell scavenging- key cytokine in antiviral defences
52
outline Successive killing of virally infected cells by cytotoxic T-cells
CD8 t cell recognises virus infected cell
CTL programs target cell to die
CD8 cell jumps from cell to cell
Any viruses are presented
Induce apoptosis
53
outline The dynamic of cellular immune responses: during viral infections
• If you have NK cells it will prevent the viral infection getting worse but in order to clear the infection you need the CD8 t-cell.
54
how do High affinity neutralising antibodies prevent viral entry into host cells
* Antibodies will prevent the virus from entering the cells
* Coating virus particle prevents from entering cells
* Immunity is good as virus needs to infect cells to propagate
* CD8 cells need CD4 cells to function properly- provided by the signals (cytokines
55
why do HIV patients also suffer from viral infections
- HIV infects CD4 cells- patients with AIDS and low CD4 cell also suffer from viral infection. Because CD8 cells don’t work because they need help from CD4 which have been kills
56
what is Acquired immunodeficiency syndrome (AIDS) cause
DISEASE
• Severe reduction in CD4 T-cells (full blown aids)
• Severe infections by pathogens not suffered normally by healthy people
• Aggressive forms of Kaposi’s sarcoma and B-cell lymphoma
• Kaposi’s sarcoma – skin tumour (rare in patients who don’t have AIDS) characteristic of aids
• Fatal in all patients- maintain health, keep viral load down
• Antivirals- people can live a normal life
57
what is aids caused by
• Caused by HIV-1 and HIV-2 (less virulent)
58
what is HIV
VIRUS that causes the disease (AIDS)
59
how does HIV enter
• Enter via CD4 receptor (MH2) and the co-receptor CCR5 (chemokine receptor on memory T-cells - blocks memory) But also on macrophages and dendritic cells
60
what does HIV switch to and what do antiviral drugs do
switches to T-cell infection • (Seroconversion – generate an antibody response-if you have antibodies you have the virus ) later in the disease causing rapid decline in numbers and progression to AIDS (asymptomatic - symptomatic as T cells are destroyed quicker than they are produced in haematopoiesis)
Antiviral drugs – asymptomatic phase extended. Hinders ability of drug to replicate
61
outline the immune response dynamic in HIV infection
* Initial infection is asymptomatic or accompanied by flu-like symptoms
* Acute viraemia (increase in free viral particles after infection) - abundant virus in circulation after infection due to depletion of CD4 T-cells
* Activation of anti-HIV specific immune response – cytotoxic T-cells and anti-HIV antibodies (seroconversion) bring levels of virus to a minimum but never fully eradicare
* Diagnostic test for HIV seroconversion
* Virus-load decreases, CD4 T-cell levels recover.
* Asymptomatic phase (clinical latency) of 2-15 years
* High rate of mutation enables HIV to escape the immune response (implications for vaccine and anti-viral drug development)- sequence of genes change in the individual (not a population change as in individuals)
* Persistent infection and replication of HIV in T cells (infected cells killed by virus or CD8 cells)
* When rate of decline overtakes rate of replacement immunodeficiency ensues- CD4 cells depleted and not adequately replaced
* Progression to full blown AIDS
62
what is the Importance of fungal infections
* Often affect the oropharyngeal region-
* Associated with immunodeficiency e.g. HIV
* Or caused by treatments of disease - Associated with cancer (especially haematological malignancies and chemotherapy)- kills cells affecting susceptibly to infection
63
what are the 2 presentations of fungal infections
mucosa associated (localised to particular area e.g. orophangeal) & systemic (can be life threatening)
64
what are Examples of fungal infections
• Aspergillus (aspergillosis)
• Cryptococcus (a ‘yeast’)
• Most Candida – 12 or so species in the mouth
- 80% of oral candida in Candida albicans
- 50% of population infected but have no disease (Candida is a commensal)
65
what does the hyphae form do (what are the other forms)
can drill into epithelium and penetrate the tissue -one we want to avoid
more pathogenic type of yeast which penetrates tissues via its hyphae
other forms:
- budding yeast
- yeast pseudohypha
66
what are the Immune responses to Candida
* Inhibition of adhesion and growth by immune mechanisms by IgA
* Lactoferrin complexes iron – takes it out of solution thus inhibiting yeast growth
* Antimicrobial peptides (defensins produced by neutrophils, epithelial cells and basophils)
* Phagocytes: macrophages/neutrophils
* Mucosal dendritic cells also take up yeast
* Candida recognised via TLR2, 4 & 9 on myeloid cells- recognise the PAMPs – activate the innate immune response
* Cell-mediated immunity: IL-12 (T cell immunity) and IFNg from NK cells favours differentiation of CD4 TH1 cells (macrophage helper cells phagocytosis/cell mediated immunity). Important in candida infections
67
what are the Factors predisposing to candidiasis (aka candidosis)
• Broad spectrum antibiotics – destroy commensal bacteria (sterilise GI tract) which decreases competition for nutrients etc allowing candida to thrive
• Corticosteroids e.g. steroid inhalers in asthma
• Salivary abnormalities (xerostomia)
• Smoking – cytotoxic
• Chemotherapy for cancer and leukaemia/lymphoma (causes neutropenia – lack of neutrophils).
- Block immune system
- Treated with antifungal lozenges a
- Neutropenia
• HIV (lack of CD4 T-cells thus no TH1 cells activate macrophages)
68
what is Pseudomembranous candidiasis
* Superficial
* White patches can be scraped off
* Aren’t hyphal as not penetrating tissues
* Still infectious
69
what is Chronic hyperplastic candidiasis
* Hyphal- has penetrated the tissue
* Deeper
* Cannot be scraped off (without taking mucosal surface)
* Produced by hyphal form
70
what is Erythematous candidiasis associated with
* Erythema (redness)
* Unclean dentures
* Poorly fitted dentures
* Dentures and immunosuppressed
71
what is Pneumocystis jirovecii (formerly known as P. carinii)
* Associated with HIV infections
* Most common cause of pneumonia in patients with full blown aids
* Opportunistic fungal pathogen common in the environment
* Common cause of pneumonia in AIDS patients (and other immunosuppressed patients)
* Was often fatal before effective anti-fungal treatments became available
* Lack of CD4 TH1 cells leads to impaired alveolar macrophage function and P. jirovecii infection
72
outline the evolution of human pathogens
* In parallel to the evolution of the immune system e.g. adaptive immunity in higher species, the MHC
* Mechanisms to escape or subvert the immune response will be an advantage
* Study of microbial genomes reveal most pathogens have specific systems for this
* This is necessary to compete and to exploit their habitat
* Aided by short life cycles and ability to mutate rapidly
73
what is a serotype
variation of the antigenic structures on the surface will elicit different types of serum antibody responses
74
how is Protective immunity against S. pneunomoniae serotype specific. why can species prosper from the variety of serotypes
variation on bacterial capsule helps it evade the immune system. The serotype determines the specific antibody response so since the surface antigen changes the different serotype responses will be different.
if we have immunity to 1 serotype, bacteria can still infect us via a different serotype, this means species can prosper from the variety of serotypes
75
how is there genetic variation within a species, give examples
• Variation in cell surface molecules e.g. diverse capsular polysaccharides in S. pneumoniae
• Capsules- resistance to phagocytosis and antigenic variability
• Defined as strains or serotypes (i.e. generate unique antibodies)
-Specific antibodies to one serotype does not provide immunity against another serotype
* S. pneumoniae has over 90 serotypes (defined by antibody based ‘serological’ assays)
* Genus Salmonella has over 2500 serotypes- cant get immunity
76
how does the Evolution of new influenza variants come about
ANTIGENIC DRIFT
in the viral haemagglutinin gene. an altered hemagluttin means that neutralising antibodies against the original virus do not block binding of virus to cells - gradual change in genome (mutation in certain genes). Immunity to one does not give immunity to the other.
77
what is antigenic drift
gradual change in antigens (due to point mutations lead to subtle antigenic variability)
78
how does antigenic DRIFT occur (e.g. in the evolution of the influenza virus)
occurs when:
Mutation in genes encoding viral envelope antigens e.g. haemagglutinin and neuraminidase
• Different strains predominate at different times in different populations
• Individuals will become infected depending on their disease experience (there will be subpopulations of individuals with different degrees of immunity)
•Causes limited disease epidemics
79
when are vaccines effective
in diseases e.g. small pox which have a single serotype - no antigenic variability
80
how does recombination lead to the Evolution of new influenza variants by antigenic SHIFT
recombination of viral RNA in the secondary host prodcues a virus with a different hemagluttin
no cross protective immunity
* In antigenic shift there is a profound change in the virus which can produce a strain never seen before by the host species.
* Population is subsequently highly susceptible to the infection
* Results in pandemics (depend on the intrinsic properties of the host)
* Potential to transfer between species and transfer rapidly in the population
81
what is recombiantion
• Recombination- not the change in the nucleotide base as in a mutation, it’s the change in large chunks of the genome.
82
what is antigenic SHIFT
• A radically different strain appears suddenly
• Because of lack of pre-existing immune hosts
- Can infect large numbers of people
- Can cause severe disease
- This may lead to a pandemic (worldwide epidemic)-
• Depends of infectivity and virulence- how easy is it to get infected, does it cause serious disease (virulent).
• Can be caused by recombination of viral genomes between avian and human viruses
• Jumps between species –depends on demographics (china keep animals and humans in close proximity)
83
outline flue pandemics
* Deaths due to the First World War (191418): 15,000,000
* Deaths due to the outbreak of ‘Spanish’ Flu (1918-19): 50-100,000,000
* Including 675,000 in the USA
84
what occurs in latent viruses e.g. herpes viruses
* Hide from immune system – latency
* Most viruses replicate rapidly e.g. flu, providing lots of peptide for MHC class I
* Viruses which adopt a quiescent state (still viable but not replications and producing lots of virulence) have low replication rates and therefore don’t generate enough peptide for antigen presentation
* They also hide from immunosurveillance within cells
* They may be activated later and cause disease
More MHC class II the more attractive to CD8, more MHC I more likely to trigger adaptive response
85
outline the Persistence and reactivation of herpes simplex virus infection
• Herpes simplex virus infects and causes pathology in epithelial tissues
• Invades neurones where it evades the immune system (neurones express very few MHC class I molecules not susceptible to destruction)
• At times of stress (sunlight; bacterial infection; hormonal changes) the virus re-infects epithelial cells causing cold sores. Can also be red patches on gums and mucosa
• Neurones do not express much MHC class I – immune privilege (they can’t be replaced)
- Meningitis
• Can be transmitted from person to person
86
what are Other examples of latent viral infections
* Lentivirus group e.g. HIV
* Epstein-Barr virus (EBV) causes glandular fever (mononucleosis) by infecting B-cells then remain dormant in a minority of B-cells- swollen lymph nodes which can lead to latency of the virus. Rarely can develop lymphoma.
* More viral infections in immunosuppressed individuals
* In immunosuppressed individuals EBV can re-activate causing disseminated EBV infection or infected cell can transform into malignant B-cells (lymphoma)
87
outline Sabotage or subversion of host immune responses by viruses:
Viruses have the greatest variety of mechanisms as their life cycle depends on interactions with host cell metabolic and biosynthetic processes strong evolutionary pressure.
88
what are the viral strategies to Sabotage or subversion of host immune responses
1) Inhibition of humeral immunity
2) Inhibition of inflammatory response
3) Blocking of antigen processing and presentation
4) Immunosuppression of host
e.g. - Herpes simplex- lives where there isn’t much MHC class I and when it gets out it blocks the expression on MHC class I
89
outline Sabotage or subversion of host immune responses by bacteria:
* Treponema pallidium (syphilis) coats itself with fibronectin to evade antibody recognition
* P. gingivalis secretes proteases which digest antibodies
* Mycobacterium tuberculosis is phagocytosed by macrophages but inhibits phagosome/lysosome fusion- resistant to phagocytosis and destruction
* Phagosome formed when bacteria is taken up by phagocytosis
90
what are Bacterial super antigens
• Antigens that will stimulate the immune system over the normal that you would expect. They can activate t cells and bypass the normal mechanism of antigen presentation. - link T-cell receptors and MHC in the absence of specific peptide
* Bridges the TCR and MHC molecule thus enhancing the interaction such that the T cell is activated excessively (antigen independent)
* Results in inappropriate activation of immune system can lead to disease
* Staphylococcal enterotoxins (NOT ENDOTOXINS) bind MHC and TCR independent of antigen specificity
* Stimulate excessive, polyclonal response involving 2-20% of total T-cells (activate lots of t-cells)
* Excessive release of cytokines causing toxic shock syndrome (circulatory collapse, hypotension, loss of blood pressure and subsequently loss of blood delivery to vital organs.
* E.g. S.aureus contaminated vaccines
* T-cells will then undergo apoptosis removing many antigen specific clones from circulation
91
what is the difference between a primary and secondary immunodeficiency
Primary- Caused by genetic intrinsic problem with the immune system (secondary are caused as a result of something else e.g. viral infection or treatment to cancer – much more common)
92
what are the features of Primary immunodeficiencies
* Rare
* Over 100 described
* Affect immune cell development or function
* Aetiology (cause of a disorder without which you don’t get the disease) - gene mutations - pathogenesis = development of disease from point of infection to the symptoms being present. May diseases have common pathogenic pathways e.g. inflammation
93
what are the consequences of Primary immunodeficiencies
innate or adaptive immune deficiency manifesting as recurrent infections:
- T-cell deficiencies lead to candida or viral infections (intra-cellular pathogens)
- T-cell deficiency leads to B cell deficiency (rely on them for activation).
- Complement, B-cell and phagocyte defects lead to pyogenic bacterial infections (extracellular pathogens)
- Enables us to understand role of specific molecules in immune responses
94
what are Examples of Primary immunodeficiencies
* Severe-combined immunodeficiencies (SCID)
* Bruton’s X-linked agammaglobulinemia (XLA)
* Common variable immunodeficiencies (CVIDs)
* Others (complement & neutropenia etc)
* Many are caused by recessive mutations on the X-chromosome
95
what is SCID and how it it caused
Primary immunodeficiency- Defects in T-cell development lead to severe immunodeficiency: no T-cell, antibody, memory functions- T-cells are the master regulators of the immune system
X-linked SCID caused by mutations in genes for cytokine signalling molecules e.g. IL-2 receptor and Jak3 (a protein kinase)
96
what does SCID lead to
Severe and generalised susceptibility to infection
-Generalised susceptibility to infections- no memory functions because the cytokine that come from the t-cells regulate the function of memory cells
Results in lack of cells that rely on those cytokines for development: lack of T-cells and NK cells (lymphocytes without antigen specific receptors) and dysfunctional B-cells.
97
what are Other causes of SCID
include RAG 1/2 and adenosine deaminase (ADA) mutations
- Critical for development of immune cells
- ADA critical enzyme in the growth of T-cells
98
what are the treatments for SCID
bone marrow transplantation
| - Haematological malignancy is usually treated by bone marrow or stem cell transplantation
99
what are Common variable immunodeficiencies (CVIDs)
* Most common
* Variable
* Immunodeficiency mild
* Clinically and genetically heterogeneous- very variable
* Defects in immunoglobulin production limited to one subclass (isotype) e.g. IgA
* IgA deficiency: sporadic (occurred during embryogenesis- no family history) and familial (inherited)
* Some recurrent infections, many have no symptoms
100
what is Hyper IgE deficiency syndrome
* High IgE levels
* Deficiency in TH17 cells which typically reinforces the innate immune response
* Recurrent pyogenic bacterial and fungal infection
* Mutation in the transcription factor STAT3 which regulates TH17 cell differentiation (signalling pathway)
* Hence TH17 deficiency fungal infections/ regulate macrophage response
* Autosomal dominant form has dental abnormalities-
101
what does Flow cytometry peripheral T-cells from hyper-IgE syndrome patient reveal and what is it
TH17 cell deficiency
* Lab method of determining immunodeficiency
* Numerate the cells that have a particular phenotype. Look at cells that express IL-2 and IL-17 (Th17 cells) – uses antibodies
* Used to look at 2 different proteins on surface.
* IL-17 staining – shows cells which are T cells and IL-17 cells
* Patients have a lot less TH-17 cells in peripheral blood
see slides for image
102
what are Hyper IgE deficiency syndrome: dental abnormalities
* Supernumerary teeth
| * Amelogenesis imperfecta
103
what is Bruton’s X-linked agammaglobulinemia (XLA) why is it NOT severe combined
* Failure of B-cell receptor signalling (B cell receptor is an immunoglobulin expressed on the surface rather than being secreted) – get issues with cell development
* B-cells arrested at pre-B cell stage
* B-cell deficiency → lack of antibodies
* Recurrent infections with extra-cellular pyogenic bacteria e.g. Streptococcus pneumoniae
* Chronic infections with poliovirus, HBV or HCV
Not severe combined- only affects antibodies
104
what is the treatment for Bruton’s X-linked agammaglobulinemia (XLA)
antibiotics and human immunoglobulin infusion (providing patient with immunoglobulins (antibodies from someone else) – helps patient fight infection, immediate protection from pathogenic bacteria).
105
what do Complement deficiencies lead to
COMPLEMENT DEFICEINCEY = Recurrent infections with extracellular bacteria
* C3 deficiency: recurrent S. pneumoniae (pneumococcus) infections
* C5 deficiency: susceptibility to Neisseria meningitides (meningococcus) infection
* Also: congenital neutropenia, leukocyte adhesion deficiencies etc- if neutrophils cant stick to endothelial cells and tissues then you have an immunodeficiency as they cant spread.
106
what are Secondary (acquired) immunodeficiencies
• Not caused directly by gene mutation
Immune senescence- age and in poor nutrition- dysregulation
Trauma: burns, major surgery etc
Drugs: immunosuppressants (glucocorticoids)
Tumours: e.g. chronic lymphocytic leukaemia (CLL): in this disorder secondary infections are a common cause of death, vaccinations are ineffective- immune system wont work
Infections: HIV
107
what is the difference between prevalence and incidence
• Prevalence is the actual number of people alive with the disease, incidence is the rate of newly diagnosed cases of the disease.
108
what is the Prevalence and incidence of HIV infection 2012
* Worldwide prevalence in 2018: 37.9 million including 1.7 million children
* Only 79% of HIV+ individuals know their HIV status (9 million people don’t)
* Incidence of new infections in 2018: 1.7 million (5,000 a day) including 0.16 million children
* 0.77 million people died in 2018 from AIDS-related illnesses (36 million from the start of the epidemic but annual rate is falling-1.9million people died in 2004)
overall- Pandemic (everywhere), sub-Saharan Africa has the most HIV
109
what is HIV epidemiology
* 36 million deaths since worldwide epidemic began
* 5.2% of adults in sub-Saharan Africa are infected (1.5 million new infections here in 2013)
* Increasing numbers in India/China/Eastern Europe
* 33% of HIV positive people are 15-24 and largely unaware of positivity
110
what are Key properties of HIV virus
* Profound genetic variability
* High mutation rate
* Classified by nucleotide sequencing of genomes-
* 3 major groups: M, O and N
* Earliest identification in 1959
* Phylogenetic analysis suggests first infection earlier in 20th century
111
what are Factors which influence AIDs progression
• Degree of inoculation- depends on exposure. So breast feeding mother would be high exposure (mother/child relationship)
- Viral load upon infection (breast milk)
• Age
• Host genetic variation – some rare mutations can confer resistance to HIV infection.
• Antiviral drug treatment-
• Resistance in minority:
- Seroconverted individuals with low viral load (despite having antibodies- seroconverted)
- Virus negative individuals with high exposure
112
what is the Effects of age on AIDs progression
• Haemophiliac before 1943 then the progression time after infection to which full blown aids is developed is quicker
- The younger you are the longer it takes to get full blown aids
Haemophiliacs – need factor 8 from blood donations imported blood from America was contaminated with blood borne viruses such as HIV
- Now recombinant factor 8 used
113
what are Host genetics variants that influence AIDs progression
HLA alleles
KIR alleles
CCR5 (chemokine receptor) mutations
114
what are • HLA alleles
most polymorphic variants in the population
115
what are KIR alleles
receptors on ILC such NK cells (highly polymorphic)
- Polymorphism and HLA as it allow species to handle infections differently
- Variation in species is a great strength
- Some individuals more resistant and some more susceptible
- Autoimmune disease related to HLA
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what are CCR5 (chemokine receptor) mutations, are they good?
delta-32 mutation of CCR5 gene
- Advantageous mutation which prevents the progression of AIDS (AIDS binds to CD4 cells and CCR5- if CCR5 is mutated then the progression is slower)
- Frameshift: truncated protein
- Dose effect below:
- progression slow in heterozygotes (10% of caucasians)
- Progression halted in homozygotes (1% of caucasians)
- No mutations in African and Japanese populations
117
what are HIV pharmacotherapy: drug targets
• Retroviruses (RNA) such as HIV have reverse transcriptase- if this enzyme in blood then you have a retrovirus. Converts RNA into DNA
• Inhibit this enzyme then can stop replication
• Introduce analogues of the building blocks of nucleic acid can be advantageous too
- Many antiviral drugs are nucleotide analogues
• Protease inhibitors
• What are the therapeutic target for antiviral drugs? Look at the lifecycle of the virus
118
how does Resistance of HIV to protease inhibitors develops rapidly
* Virus particles encoded resistance will profit in the location where the drug is
* CD4 cells supressed
* Green- give drug so less replication, however virus mutated and you get resistance so CD4 cells go back down (less than a month this can occur)
119
How do antiviral drugs work?
* Interfere with drugs natural cycle – helps decrease its toxicity
* Inhibit reverse transcriptase
* Inhibit protease
120
what is Highly Active Antiretroviral Therapy (HAART)
* Combination drug therapy ideal because of development of resistance to some drugs
* Reduces viral load, reducing morbidity and mortality
* 20.9 million people accessing anti-retroviral therapy from July 2017 (up from <1 million in 2000)
121
what are the drawback of HAART
* Doesn’t clear virus hence lifelong treatment necessary – only stops viral replication (vaccination and avoidance is only way to not get infected in the first place)
* Expensive
* Some serious side effects
122
what is autoimmunity and how is it characterised
Responses to self-antigen (or commensal microbiota) leading to tissue damage
- Often endocrine tissues – clinical endocrinologists deal with autoimmune disease
•Autoimmunity is characterised by a breakdown in self-tolerance, mediated by autoantibodies and autoimmune T-cells
123
what is self tolerance
when lymphocytes which react with self antigen are eliminated or held in check
124
how can autoimmunity develop
if T-reg cells do not function properly
| - Hypersensitivities are inappropriate immune responses to outside antigens
125
what is the disease mechanism and consequence of type 1 diabetes (rare)
mechanism- autoreactive T cells against pancreatic islet cell antigens
consequence- destruction of islet B cells leading to nonproduction of insulin
126
what is the disease mechanism and consequence of rheumatoid arthiritis (common)
autoreactive T cells against antigens on joint synovium
joint inflammation and destruction causing arthiritis
127
outline a few Mechanisms of self tolerance
central tolerance:
deletion/editing at the thymus and bone marrow
regulatory t-cells:
suppression by cytokines, intracellular signals at the secondary lymphoid tissue and sites of inflammation
128
Breakdown in tolerance is not itself sufficient to cause autoimmune disease, why is this
* Environmental (infection) and genetic triggers may also be required (autoimmune diseases are multifactorial)
* Escaping autoimmune cells can still be controlled by Treg cells-potential therapeutic value
129
What are Mechanisms of autoimmunity
* Pathogenic mechanisms understood; aetiology/cause is not- do not know primary causative factor
* Similar effector mechanism which is used in killing pathogens- antigens persist in autoimmune disease
* Major difference is that self antigens cannot be eliminated hence a chronic, lifelong disease ensues (except Hashimoto’s/T1DM- thyroid destruction)
* Management required as cannot cure (don’t realise you have type 1 diabetes until most islets of Langerhann are destroyed- antigen is never removed)
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outline the Classification of autoimmune diseases
* Organ specific e.g. T1DM- target one cell/tissue
* Non-organ specific (many tissues affected) e.g. Sjogren’s syndrome- disseminated effect, effects salivary glands, gut etc.
* IBD e.g. Crohn’s – breakdown of tolerance to normal commensal microbiota
* Clustering of one type in families
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outline Examples of organ specific and systemic autoimmune diseases
organ specific-
- type 1 diabetes mellitus
- MS
- graves disease
systemic autoimmune disease:
- rheumatoid arthitis
- sjorgren syndrome
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outline the Progression of autoimmune diseases
• Activation phase leads to chronic phase
• Chronic phase effects may be dominated by the effects of
o Autoantibodies e.g. myasthenia gravis
o Autoimmune T-cells e.g. T1DM
* Tissue breakdown mediated by an integrated immune response
* Tissue breakdown replenished supply of antigen
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how does Autoimmune response develop
through epitope spreading –initial immune response to one element of the antigen but as the disease develops it develops immunity to other parts of the antigen
Epitope is a particular discrete structure within a molecule
134
outline the Classification of the pathogenesis of different autoimmune diseases
type II- antibody against cell-surface or matrix antigens
type III- immune complex disease. antigens and antibodies together cause problems
type IV- T-cell mediated disease
135
outline autoimmune blistering diseases that have occurred as a result of type II pathogenesis- explain the specific pathogenesis
antibody against cell-surface or matrix
bullous pemphigoid (BP) & pemphigus vulgaris (PV)
BP- basement membrane of epidermis
PV- autoimmune reaction to epidermal cadherin which causes blistering of the skin- life threatening as so much haemorrhaging
136
outline common type III autoimmune diseases
immune-complex disease
mixed essential cryoglobulinemia
rheumatoid arthritis-
autoantigen: rheumatoid factor igG complexes
137
what is an autoantigen
antigen recognized by the immune system of patients suffering from a specific autoimmune disease
138
outline common type IV autoimmune disease
t-cell mediated
type 1 diabetes
autoantigen: pancreatic b-cell antigen causing b cell destruction by t-cells clustering around so they cant make insulin
Rheumatoid arthirits
MS
Crohns disease
Psoriasis
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outline the pathogenesis of type 1 diabetes
the islets of langerhans contain several cell types secreting different hormones, each expressing different tissue-specific proteins
in type 1 diabetes an effector t-cell recognises peptides from a beta cell specific protein and kills the b-cell specific protein and kills the b-cell
glucagon and somatostatin are still produced by the alpha and delta cells but no insulin can be made
140
outline examples of Diseases caused by antibody cell surface receptors
graves disease
myasthenia gravis
type II diabetes (not autoimmune disease)
141
outline how graves disease occurs and what are the treatments
autoimmune b cells make antibodies against TSH receptor that also STIMULATE thyroid hormone production
thyroid hormones shut down TSH production but have no effect on autoantibody production, which continue to cause excessive thyroid hormone production - hyperparathyroidism
treatment- radioiodine, thyroidectomy was used but is a risk due to general anaesthetic.
142
outline how myasthenia gravis occurs and what are the treatments
Effects neuromuscular junctions- prevents signalling from neurones and muscles
loss of Ach due to problems with receptor resulting in lack of transmission
143
what occurs in Systemic lupus erythematosus (SLE)
it is an autoimmune disease- • DNA is one of the antigens
Widespread red patches, affects kidney glomerulus
144
what is the Evidence for a genetic component of autoimmune diseases
* Family studies-familial clustering
* Twin studies-increase concordance in identical twins but isn’t 100% suggests there is an environmental trigger (if it was purely genetic, would be 100%). Some identical twins one person has the disease even though they have the same genes.
* In bred mouse strains-some more susceptible than others
145
what is the Evidence for an environmental component in autoimmune diseases
* Lack of 100% concordance in identical twins
| * Different age of onset- e.g. in individual genetically identical mice (suggests environmental trigger)
146
what are Investigations carried out of genetic component of autoimmune diseases
* Candidate gene studies-association and linkage studies
* Knockout mice to identify candidate genes- do these genes affect the development of autoimmune disease?
* Genome wide association studies (GWAS) – compare genomes of individuals
* autoimmune diseases are polygenic being influenced by multiple alleles on numerous different gene loci
* Major genes are on the human leukocyte antigen (HLA)- encode proteins which present antigens to t -cells. Very polymorphic and associated with some autoimmune diseases
147
what does Amino acid changes in the sequence of an MHC class II protein correlate with
susceptibility to and protection from type 1 diabetes
148
what can Polymorphisms in HLA change, and why does this mean autoimmune diseases are hereditary
the way in which antigens interact with the molecule and can lead to autoimmune diseases
Mutations in HLA-associated with autoimmune diseases and we pass on HLA gene to offspring
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How can MHC gene variants influence the pathogenesis of autoimmune diseases?
* Antigen presentation
* T-cell development
* DR (Class II) polymorphism influences CD4 T- cells
* B27 (Class I) polymorphism influences CD8 cells
* The risk for an HLA allele in an autoimmune disease is defined as the relative risk (odds ratio)
* Breakdown intolerance can happen anywhere
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what is the Odd ration of getting the disease
if you have a particular variant in the HLA allele you are more or less likely to getting a disease
The ratio of the chance of a disease developing among members of a population
exposed to a factor (e.g. gene allele) compared with a similar population not exposed to
the factor.
151
what are Other genetic associations in autoimmune diseases
* IL-23 is a cytokine which regulates Th17 in Crohn’s disease binds to IL-23R
* NOD-2 like receptor (NLR) in Crohn’s disease
* Mutation in CTLA4 results in T cell activation autoimmune diseases including Hashimoto’s disease, RA, T1DM
152
what is The association of autoimmune diseases with infections
* Trigger disease in a susceptible host (someone who have the appropriate genotype)
* If you have an infection it activates APC infection increases possibility to getting autoimmune diseases
* This adjuvant effect has been demonstrated in animal models
* Molecular mimicry is another mechanism: rheumatic fever is caused by antibodies to Streptococcal cell wall antigens cross-reacting with cardiac muscle. Cross reaction.
153
what is a hypersensitivity reaction
inappropriate immune response to an environmental antigen classified as type I, II, III, IV
differs from autoimmunity which sensitivity to SELF antigens
154
what are common environmental causes of hypersensitivity reactions
inhaled materials- plant pollen, dust mite
ingested material- peanuts
injected materials- injected venom, drugs
contacted materials- plant oil, metal
155
how do allergens cause an allergic reaction
they're deposited on mucosal epithelium where they are ingested and processes by APCs. theyre presented to Th2 lymphocytes which release cytokines important in an allergic reaction
156
what are the type of hypersensitivity reactions
allergies (type I) and autoimmune (II, III, IV)
type I- immediate (allergies)
type II- immune response at the surface
type III- immune complexes in the tissues s
type IV- Delayed (T-cell mediated)
similar to the classification of different autoimmune diseases
157
outline the features of Type 1 hypersensitivity reactions
immediate type
• Range of consequences: mild irritation to life-threatening (e.g. anaphylaxis- severe medical effect )
• 10-40% of people in developed countries have an allergy
• Atopy – allergic reaction which has a genetic element – runs in the family (40% of Caucasians in Europe and North America)
- Hypersensitivities run in families e.g. asthma, eczema & uticaria (hives)
• Incidence of allergies increasing
158
how are Type I hypersensitivity reactions IgE mediated
IgE antibodies are pre-existing and interact with soluble allergens (Environmental antigen) upon immediate exposure.
This triggers release of chemical mediators from mast cells which triggers inflammation (mechanism to destroy allergen)
Increasing incidence may be explained by the hygiene hypothesis
159
outline Sensitisation to an inhaled allergen leading to Type I hypersensitivity
Allergens enter mucosal tissues via inhalation/swallowing and are taken up by a conventional route of antigen presentation
TH2 cell induces B-cell switch to IgE production (via plasma cells which have migrated to the tissues)
IgE binds to Fc receptor and mast cell
mast cell granule contents (degranulation) cause an allergic reaction
typically in early life immune system becomes sensitised to environmental antigens
160
how does the expression of IgE on mast cell surface via Fc receptors induce degranulation
CROSS-LINKING
These receptors are prepared for entry of allergen
When encounter the antigen again Cross-linking IgE on mast-cell surfaces on repeated exposure to allergen leads to the rapid release of mast-cell granules containing inflammatory mediators (via DEGRANULATION).
Mast cells typically encounter antigen in respiratory system mainly but also GI tract and skin
Treatment: counteract effects of mast cell agranulation
161
how can Mast cells be identified (must be able to identify in exam)
large, round, full of granules
162
what are the key Molecules released by activated mast cells
Toxic mediator e.g. (histamine/heparin) toxic to parasites, increases vascular permeability/smooth muscle contraction/anticoagulation.
Class of product: Cytokine e.g. (TNF-a) promotes inflammation, stimulates cytokine production and activated endothelium. If released locally can have beneficial effects, but if released systemically (in cases of bacteraemia) if can have bad effects on health
163
what are the 2 effects of Hypersensitivity
* Inflammation- redness, antigen
| * Physiological- wheezing, muscle contraction, diarrhoea (this is in place to rid them from your body)
164
what are IgE-mediated reactions to extrinsic antigens
Systemic anaphylaxis- life threatening
acute urticaria
hay fever
asthma
food allergy
165
how are immediate and late phase reaction characterised and what is the difference between the late phase reaction and immediate response
Late phase characterised by infiltration of CD4+ cells, monocytes and eosinophils. These cells will release a variety of th2-type cytokines (IL-4 and IL-5) further contribute to inflammation.
Resembles a delayed reaction.
Difference – presence of eosinophils and th2 cells in late phase but not in delayed reaction.
166
how is Systemic anaphylaxis caused
by allergens that reach the bloodstream and activate mast cells throughout the body
mast-cell degranulation and release of inflammatory mediators in:
- heart and vascular system
- respiratory tract
- GI tract
167
The physiological (normal)s function of IgE
Evolved to rid the body of metazoan parasites e.g. Ascaris (worms) & Schistosoma
Immune response involves CD4 T-cells (TH2) helping B-cells to switch to IgE production
IgE arms mast cells, eosinophils and basophils to respond to parasite antigens by binding to high affinity Fc receptors
Ejected by physical force: coughing; sneezing; vomiting etc.
168
what are other roles mast cells have in immune responses at mucosal surfaces
they express TLR (Tol-like receptors) and other Fc receptors.
- Mast cells will sense PAMPs as well
169
outline Type II hypersensitivity reactions
antibody reactions at the cell surface
This will activate complement cascade and target will be destroyed by the full complement system
170
how is Haemolytic anaemia caused
type II hypersensitivity reaction
patients own erythrocytes bind anti- erythrocytes autoantibodies
erythrocyte destruction by the spleen which is exaggerated due to hypersensitivity
171
outline Type III hypersensitivity
immune complexes in the tissues
due to reaction of IgG antibody with a soluble antigen causing complement (FcR cells).
e.g. serum sickness, systemic lupus ertyhematosus (SLE)
the Deposition of antibody complexes causes inflammation
• Response to injected therapeutic antibody such as mouse antibody/horse serum and drugs (penicillin).
- Can cause haemolytic anaemia and type III hypersensitivity
172
outline Penicillin allergy, hypersensitivities can this cause (I, II, III)
penecillin modifies proteins on human erythrocytes to create foreign epitopes
NOT a good example of individual hypersensitivity- its type I, II and III
they are susceptible to mounting :
Type 1- anaphlytic reaction, Type 2- haemolyoitc anaemia (modifies surface)
Type 3- serum sickness in some individuals (modifies large proteins)
173
outline Type IV hypersensitivity reactions
t-cell mediated- delayed type
activation of Th1 cell via APC presentation of the antigen- releases cytokines and recruites phagocytes (macrophages) and plasma causing visible lesion
e.g. blistering skin lesions
174
what is the CD4 and CD8 T-cell response to foreign proteins or modified self proteins
```
Body piercing (nickel)
-Nickel modified peptides (nickel allergy) –CD4 cells
Th1 cell activates macrophages which release cytokines changing vasculature of vessels
```
Pentadecatechol-modified proteins (poison ivy allergy) –CD8 cells
175
outline Allergies in dental practice
* Patients with allergic rhinitis (hay fever) may be mouth breathers and develop mild gingival hyperplasia
* Antihistamines can cause dry mouth (sympathetic NS)
* Angioedema (rapid swelling of dermis and mucosa in response to allergen)
* Affects the head and neck region (swelling to lips and floor of the mouth)
* Oral allergy syndrome
* Latex (not just in gloves!) allergies
176
what is Coeliac disease:
Inflammation of the upper region of small intestine caused by response to gluten
* Tissue damage to part of the small intestine
* Inflammation will destroy the tissue
177
what are the Histological features of coeliacs disease
* Inflammatory infiltrate
* Tissue damage
* Lengthening crypts
* Increased epithelial cell division leading to loss of function
178
what are the clinical consequences of coeliacs disease
* Abdominal distension
* Malabsorption
* Diarrhoea
* Failure to thrive
* Anaemia in some
* Intestinal cancer in some
* Cervical cancer begins with inflammation
179
what is gluten and its involvement in coelicas disease
→ Gluten: a complex of proteins found in wheat, barley and oats
* 1% of the UK population have coeliac disease
* Management: elimination from diet
* If they take gluten it causes inflammation in their GI tract
* Treatment is avoidance
180
what is the Molecular basis of immune recognition of gluten in coeliac disease
peptides naturally produced from gluten usually do not bind MHC class II molecules. but a an enzyme (only activated in those with gluten intolerance) allows these peptides from gluten to be taken up and presented by the MHC
this activates gluten specific-specific CD4 T-cells which kill mucosal epithelial cells by binding Fas (death receptor), also Secrete IFN-y which activates epithelial cells to produce cytokines/chemokines causing inflammation
181
outline the Genetic predisposition to coeliac disease
* Gene-environment interaction
* Coeliac disease does have a HLA association (95% have HLA-DQ2 allele)
• 6x higher incidence in individuals with Down’s syndrome - something on Ch21 may add to susceptibility.
• But most HLA-DQ2 + individuals in the population do not get coeliac disease
- HLA polymorphism- if you have the version of HLA then you have that allele so more likely to have gluten intolerance (individuals with gluten intolerance have higher amounts of allele). Can have allele without disease due to environmental factors
182
what is Inflammatory bowel disease and what does it induce
• Chronic inflammatory diseases with features of autoimmune disease
• Antigens derived from the commensal microflora in the intestines
- Result from immune response from commensal microflora
induces Crohn’s/ ulcerative colitis
183
what is crohns disease
* Inflammatory lesions (including granulomas) - can involve entire GI tract
* Inflammatory lesion is transmural - involves all layers of intestine
* Chronic and episodic (exacerbations and remission not linked to therapy)
* Frequent complications: thickened and fissured bowl leads to obstruction and fistulation (unusual openings/links within gut surgical correction).
* Have symptoms where there is MALT including inside the mouth, not just in the GI tract
* Pathogenesis - dysregulation of the mucosal immune functions
184
outline Immune regulation in gut epithelium and where does this go wrong in crohns disease
• Above the epithelial cells is layers of mucous
• Important to protect the epithelial tissue as well as invasion from bacteria in the gut
• Paneth cells and crypts make AMPs providing protection against any bacteria invading
• M cells- sample environment provide immune cells in connective tissue with antigen allowing them to mount an appropriate immune response, throughout the mucosa
- Help from b-cells will make IgA – main antibody in saliva that protects mouth
In crohns disease there is an inability to secrete AMPs properly. Inability to tolerate the normal microflora.
185
outline Oral Manifestations of Crohn’s Disease
- 60% of patients with Crohn’s disease have oral manifestation
- Cheilitis, oral ulceration (deep), fissuring and glossitis
- Might be the first sign of the disease
- Severe ulcers
- Groups of ulcers
- Fissuring of oral mucosa
186
what are Genetic associations with Crohn’s disease
NOD 2 mutation (PRR for bacterial cell wall molecules) - impaired AMP secretion causing sustained bacteria exposure
IL-23R mutation (lack of Th17 activation) - sustained inflammation and suppression of T-reg cells
Autophagy – process by which internal organelles of a cell are turned over (recycling)
187
outline Crohn’s disease pathogenesis
* failure of immunoregulatory mechanisms against commensal bacteria
* Failure of innate immunity (AMP) leading to failure of adaptive immunity (CD4 T-cells)
* Genetically encoded
* Leads to damaging inflammation at mucosal surfaces
* Also a microbial dysbiosis- interaction between microbial community and immune response
188
outline Inflammation and metabolic disorders
E.g. gout, type 2 diabetes mellitus (T2DM)
• Acquired disorders: more common in adults
• Complex (multifactorial) disorders: environmental (more prominent) and genetic elements
• Systemic effects
• Relationship and co-incidence with other conditions e.g. obesity, cardio-vascular disease (CVD)
189
what occurs in gout
Uric acid deposition in gout (crystals in peripheral tissues- not a granuloma)
Activates the inflammasome (senses biochemical changes in the cell, sensing crystals thus activating IL-1 secretion in response)- makes the cell make more IL-1 (pro-inflammatory cytokine)
Anti-IL-1 therapy effective
Inflammation due to gout in the metatarsal phalangeal joint: ‘gouty arthritis’
Amyloid robust fibrils of proteins which are involved in diseases such as Alzheimer’s
190
What is the Pathogenesis of gout
* Metabolic disorder – likewise so is diabetes
* Over or under production of uric acid
* Cause hyperuricaemia
* Crystal formation and deposition
* Result – gout flares
Genetic factors - primary
Secondary factors such as Drugs/chemotherapy (induced by treatments)
191
outline Diabetes and inflammation
• Diabetes has an inflammatory component- activation of proinflammatory pathways due to too much sugar in the blood- activates oxidative stress and Advanced glycation end production
* Regulation of bone turnover is an important feature of inflammation.
* Adipokines (lectin affects uptake of food and stimulate the immune response)
can all lead to immune dysfunction, cellualr stress and cytokine imbalance
More inflammation, impaired tissue repair and enhanced tissue destruction (periodontitis)
192
what is social demography
• The relationships between economic, social, cultural, and biological processes influencing a population
Influences health in the context of vaccines
193
outline the SWOT analysis of Vaccination against epidemic diseases
* Strengths: 3 centuries of experience (of vaccine use): scientific understanding (e.g. immunology, microbiology, molecular biology, biotechnology)
* Weaknesses: difficulty in developing vaccines against some diseases. Microorganisms such as HIV and influenza have high mutation rates. Parasitic organisms such as malaria has a complex life cycle.
* Opportunities: Rapid recent advances in knowledge, technology & communication
* Threats: the social demography of vaccine effectiveness
194
what are The pathway to vaccine effectiveness
research
development
implementation
maintenance
195
outline The pathway to vaccine effectiveness: the research phase
• What is the epidemiology of the disease?
• Route of infection
• Spread
• Demographics
• Cultural context e.g. coronavirus- Chinese markets have live animals.
• What is the microbiology of the disease?
• Microorganism its self and how it causes morbidity
• Morbidity
• Understanding the following:
o Cellular microbiology e.g. life cycle
o genome structure e.g. might reveal antigens
• What is the immune response?
• Nature of the immune responses
• Route of infection
• Key antigens
196
outline The pathway to vaccine effectiveness: the development phase
* Adequate research- vaccines take time
* Animal and human studies
* Route of immunization
* Formulation: adjuvants, combination; stability, safety
* Production capacity- issue in pharmaceutical company (monetary focused)
* Economics
197
The pathway to vaccine effectiveness: IMPLEMENTATION & MAINTANANCE
Personal views that compromise vaccine effectiveness - vaccine apathy
Demographic factors that compromise vaccine effectiveness
198
What causes vaccine apathy :
* Misconceptions of risk
* Religious and cultural beliefs
* Adverse publicity- e.g. newspapers
* Misinformation about side effects
* Reliance on social media for information
* Mistrust of science, medicine and health care systems
* Campaigns: anti-vaxxers
* Ignorance of the disease
* Cost puts off individuals – e.g. HPV only offered to certain groups
* Fear of needles
* Relating vaccines to calamitous drugs e.g. thalidomide
199
Demographic factors that compromise vaccine effectiveness
* Lack of health care infrastructure – no coordinated response to an epidemic/ vaccine programme
* Poverty e.g. 3.3x106 children unvaccinated against measles in Nigeria
* Isolation of terrorist groups e.g. boko haram – they will not be exposed to health care programmes
* Security issues e.g. polio vaccine programme
* Political issues e.g. hierarchy and insularity in china – slows response down
* Ageing, increasing obese populations
* Porous borders e.g. Ebola in conga- people in poverty are migrating across borders with no regulation (dilutes herd immunity)
* Diasporas – spread of the population of a country e.g. 1 million Romanians live in Italy. Immigration is one of the reasons for the maintenance of tuberculosis in the UK.
* Effectiveness of vaccine decreases with an ageing population
200
How do we address the issues that affect vaccine effectiveness
• Education e.g. STEM
• Campaigns e.g. The Global Vaccine Action Plan (WHO, 2011-2020)
• Improved surveillance and vigilance- aided by the internet
• Data in the public domain e.g. genome data
• Health partnerships between international agencies
- e.g. UNICEF/WHO and local health ministries
• Development of innovative funding initiatives
