Immunology and Healthcare Theme 2 Flashcards
outline the course of an immune response to infection
Dynamic: nature and intensity change with time
Organised: in time and location- particular roles (tonsils, peyers patches)
Improves: in terms of strength and precision
what does the success of an infection depends on:
- 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.
what do the stages of an immune response to infection
local infection, penetration of epithelium
local infection of tissues
lymphatic spread
adaptive immunity
outline how protection against infection occurs
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
why is the spread of infection critical
- 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)
what is the function of the innate and adaptive response
innate- contains the infection
adaptive- clears the infection
what occurs in severe combined immunodeficiency
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.
how does Immunodeficiency illustrates the importance of both innate and adaptive immunity
•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
How are non-specific responses of innate immunity necessary for the initiation of adaptive immunity
complement activation helps neutrophil/monocyte immigration to clear infections
activation of endothelial cells in blood vessels by cytokines
T cells enhance macrophages
what is the cytokine milieu and T-cell effector function
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
what is the function between Th1
macrophage activation
Link between adaptive and innate response
how are different effector mechanisms used to clear primary infections with different classes of pathogens and to protect against reinfection
• 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
outline the immune response against intra-cellular bacteria e.g mycobacterium tuberculosis
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)
what are the Immune responses against intra-cellular bacteria involving TH1 responses
- 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
what is the importance of tH1 response in mycobacterial infection
when macrophage is infected with mycobacterium tuberculosis , inteferon gamma activates macrophages and clears infection
what are the 2 clinical forms of leprosy and what kind of Th response do they induce
tuberculoid leprosy - Th1
lepromatous leprosy - Th2
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)
- 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
what are the Immune responses at mucosal surfaces:
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
what are the Properties of the microbiota at mucosal surfaces
- 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?
what are some distinctive features of the mucosal immune system
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)
what occurs in Acute inflammation
- 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
what are the wide range of agents which can cause this initial tissue response to acute inflammation
- 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
what are the vascular changes in the early stages of acute inflammation
- 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)
what are the beneficial effects of acute inflammation
- 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
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)
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)
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
there are several results of acute inflammation, what are they
resolution (usual result)
Suppurative- pus
repair and organisation
chronic inflammation
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
what is a key example of Chronic inflammation (why is it chronic)
tuberculosis (TB)
contained BUT bacteria are still there so its chronic
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)
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)
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
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
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)
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
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
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
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).
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
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
what s acute inflammation mediated by
innate response
what does chronic inflammation relate to
an inadequate adaptive immune response
what does IgG do
protects the tissues and blood against pathogens
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
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
what do NK cells secrete
IFN-g (type II inteferon) which activates macrophages (whic release pro-inflammatory cytokines)
how does herpes simplex work
prevents cell from expressing MHC so fools immune system so it thinks its not infected
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
how does CD8+ cytotoxic T-cell recognise virally infected cells
via TCR/MHC/peptide
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
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
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.
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
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
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
what is aids caused by
• Caused by HIV-1 and HIV-2 (less virulent)
what is HIV
VIRUS that causes the disease (AIDS)
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
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
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
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
what are the 2 presentations of fungal infections
mucosa associated (localised to particular area e.g. orophangeal) & systemic (can be life threatening)
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)
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
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
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)
what is Pseudomembranous candidiasis
- Superficial
- White patches can be scraped off
- Aren’t hyphal as not penetrating tissues
- Still infectious
what is Chronic hyperplastic candidiasis
- Hyphal- has penetrated the tissue
- Deeper
- Cannot be scraped off (without taking mucosal surface)
- Produced by hyphal form
what is Erythematous candidiasis associated with
- Erythema (redness)
- Unclean dentures
- Poorly fitted dentures
- Dentures and immunosuppressed
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
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
what is a serotype
variation of the antigenic structures on the surface will elicit different types of serum antibody responses
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
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
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.
what is antigenic drift
gradual change in antigens (due to point mutations lead to subtle antigenic variability)
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
when are vaccines effective
in diseases e.g. small pox which have a single serotype - no antigenic variability
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
