Integrity - Immunity Flashcards
Where is the microbiome
stomach, dji, colon
what constitutes the microbiome
firmicutes and bacteroidetes (breakdown carbohydrates in gut -fermentation- , in obesity there is a higher number of firmicutes and lower number of bacteriodetes)
changes in gut microbiome in life
antibiotic use in pregnancy, mother’s diet, hospital, length of gestation, mode of delivery, environment, formula or breast, solid food
breast milk
contains oligosaccharides (HMO), babies can’t digest but B . infantis can by releasing SCFAs which also help promote anti-inflammatory molecules and sialic acid for brain development
what is the function of the microbiome
energy biogenesis, protection from pathogens, immune system education, brain function, bile salt metabolism, vitamin production, drug metabilism
energy biogenesis
resistant starch breakdown by microbiome to SCFAs (fermentation). SCFAs are anti-inflammatory and anti-tumor properties and stimulate protein YY (PYY) whihc induces satiety
microbiome protection from pathogenic bacteria
niche competition and nutrient depletion from invading bacteria, SCFAs inhbit virulence gene expression and lower pH to below optimal growth. Microbiota produce bacteriocins that directly kill salmonella, listeria, clostridium
gut-brain axis
stomal nerve connections in central, autonomic and enteral nervous system contriubuts to GI disease and brain disease
bile acid metabolism
bile acids produced from metabolism of cholesterol involved in emulsification of fat. Microbiota produce secondary bile acids that activate cell surface and nuclear hormone receptors whch cause gut inflammation,
altered microbiome diseases
obesity, T2 diabetes mellitus, IBD, colon cancer, asthma
Probiotics
Little evidence of benefit exceot for T2 diabetes where it can lower cholesterol and fasting blood glucose
IBD
t cell. diarrhoea (blood,mucus), tummy pain
ulcerative colitis
affects colon, chron’s affects mouth to anus. treatment -immunosuppression, aminosalicylic acid, glucocoritcoids. andominal pain, diarrhoea, weight loss. ]fewer firmicutes and clostridium, more enterobacteriocace including e.coi
colon cancer
More common in lower SES, blood in stool, aged 50 fit test - colonoscopy. Rfs = obesity, insulin resistance, red and processed meat, in microbiome - fermentation of diet derived proteins to phenols, indole, n-nitroso compounds, secondary bile acids, ammonia. protective = fibre and excercise. In microbiome - scfas
helicobacter (H). pylori
attaches to gastric mucosa, has enzyme urease which breaks down urea to produce ammonia which neutralises gastic acidity, most common bacterial infection in humans. disrupts gastric mucus layer leading to exposure of mucosa to acidic environment which promotes inflammatory immune response. Causes chronic gastritis which can lead to peptic ulceration, increases risk of stomach cancer
peptic ulcer disease
often asymptomatic but can cause bleeding leading to anemia. upper abdominal pain, indigestion, heart burn, can perforate and lead to severe pain. investiagations = urea breath test with carbon 14 urea to detect CO2 in breath, stool anitgen test, endoscopy, biopsy. treatment: proton pump inhibitor (lansoprazole @prazole) which suppress acid secretion. antibiotics 7 day course of amoxicillin and clarithromycin or metronidazole.
clostridioles difficile
causes antibiotic associated colitis. prevention antibiotic stewardhip esp ciprofloxacin (resp and utis), clindamycin (lung, female reproductive tract), cephalosporins (septicaemia, pneumonia, meningitis, ). treat with metronidazole or rancomycin. can be treated with foecal microbiota trasnplantation (FMT) if disease is recurrent
Primary, opportunistic, commensal, obligate, zoonotic, saphrophytlm
primary - cause harm e.g e.coli
opportunistic - only in right circumstances
commensal - live in harmony but can be pathogenic by accident
obligate - depend on disease for transmission e.g tb
zoonotic- transmitted to animals via direct vector or contact with animal products
saphrophytic - environmental, water or soil
how do pathogens enter, spread, and exit the body
enter :mouth, eyes, nose, urogenital openings, wounds, bites
spread: blood, lymph, nerves (HIV,rabies), cerebrospinal fluid
exit: respiratory, urogenital secretions
pathogenisis
exposure, adhesion (colonisation), invasion, infection
how do pathogens evade detection
concealement of antigens, intracellular persistance, concealment by taking host mmebranes or molecules
people who are more susceptible to infectino
diabetes, chronic renal disease, chronic liver disease, COPD, malignancy, immunosuppression (primary -congenital, iatrogenic - chemotherapy,transplants, acquired - HIV)`
straphylococcus aureus
produces coagulase which clots plasma.colonises in anterior nares, axilla, throat, GI tract. gram + ve round, spreads through direct contact with person or object, particles. Skin infection common (cellulitis), blood (catheter), lung (pneumonia). Antibiotics
E.coli
commonest cause of UTI, ingestion of undercooked foods, water, person to person. Can cause scepticiemia
Sepsis and septicemia
septicemia = blood infection as a result of UTI,pneumonia,kidney infections commonly s.aureus.
sepsis is an extreme response to infection and a complication of septicemia. Signs : high HR, low BP, fever, shiver, feels cold, SOB, confusion, extreme pain, clammy, sweaty. Can lead to tissue damage, organ failure and death. In septic shock BP drops to dangerous levels
neisseria meningitidis
encapsulated gram -ve, 2nd most comomn cause of meningitis after s.pnuemoniae. colonises nasopharynx (GD1 ganglioside receptors), school children and young adults, person - person. PUBLIC HEALTH. pauparic non-blanching rash
streptococcus pneumoniae
colonises nasopharynx, throat and lobar lungs. sees PAMPs and recruits neutrophils to attempt phagocytosis which releases toxins and fluid accumulates
infection
invasion, multiplication, and establishment of one or more pathogens in the body
pathogenicity
ability of an organism to inflict damage on the host
virulence
relative ability of a pathogen organism to cause disease
colonisation
no harm carrier of pathogen
innante immune system
physical: anatomical barriers, mechanical, microbial colonisation
chemical: acid, antimicrobial peptides (kill bacteria by attacking membranes or interfering with cell functions), cytokines (recruit WBCs to infected area),inflammation eliciting mediators promote vasodilation, bronchoconstriction
cellular: neutrophils (very effective against bacteria, release cytotoxic chemicals, pus), eosinophils (effective for antibody-antigen complexes, release antihistamines, effective against parasites), NKCs ( recognise infected cells due to lack of MHC)
Haemophilus influenzae
upper-airway, capsulated strain gives meningitis in kids, pneumonia, epiclotitis. Vaccine Hib B
genome
complete set of genetic information provides all info required for organism to funciton. kept in nucelus of eukaryoyes
dna winding
double helix wound around histone protein complex making a nucleosome
nucleoside
base and sugar, adenosine, guanosine, cytidine, thymodine, uridine
nucleotide
base and sugar (joined 5’ to 3’ by phosphodiesterase linkage) and phosphate, linked covalently
base
pyrimidines (cytosine, thymine), purines (adenine, guanine) . a + t, c+ g. adenine, guanine, cytosine, thymine, uracil
two dna strands held together by
hydrogen bonds
chromatin
beads on a string
dna replication
semi-conservative, strands must be seperated before (DNA helicase) replication, initiator proteins recognise replication origins and open helax locally. DNA synthesis happens biderectionally at replication forks . DNA polymerase adds new stuff to 3’ direction so new strand is synthesised in 5’ to 3’. the energy rwequired comes from hydrolysis of dNTPs high energy phosphate bond. leading strands synthesised continuosly, lagging discontinuosly joined by DNA ligase. (okzaki fragments)
Short commings of DNA polymerase
can’t start synthesis without RNA polymerase aka primase making an RNA primer first. lagging needs continous primer.
xerodema pigmentosa
affected individuals can’t repair thymine dimers
mitichondrial DNA
circular, genome is not enveloped, not packaged into chromatum, inheritence is strictly maternal
Nuclear dna
linear, genome is eneloped, packaged in chromatum, equal inheritance
1 gene codes for
1 protein
Dna to protein
dna makes rna makes protein, transcription, translation
RNA synthesis
done by RNA polymerase but TPA/G/U/C (activated precursors ) used instead of primer
promoters and enhancers
promotors found on 5’ end of genee
enhancer 3i end - increae transcription and can act over long distances . Transcription factors bind to promoters and enhancers and increase or decrease gene expression. MyOD = muscle specific transcription factor
site of transcription and translation
transcription occurs in nucleus, translation occurs in cytosol
5UTR 3 UTR
found before and after translated mrna section respectively
before rna can leave the nucleus it must undergo
slicing, capping (guaninet methyl group on 5’ end), polyadenylation (3# end of MRNA)
mRNA ,tRNA, rRNA,
mrna = encodes proteins. trna = adaptor molecules between mrna and aminoacid rrna= componenet of ribosome
PCR
dna replication used for genotyping. 1. separate strands with heat 2. cool to anneal primers 3. dna synthesis
codon
nucleotides read in groups of 3
start and stop codons
start = AUG. stop = UAA, UAG, UGA
redundancy
many amino acids are coded for by more than one codon
ribosome subunits
large = catalyses formation of peptide bonds that covalently link amino acids small = matchers trnas to mrna codons
translation
- charged rna binds to vacant a site - basepairing with mrna codon determines which trna binds
- new peptide bond formed between p and a sites
- shifts to p and e sites
- ribosome with vacant a site
analagous networks
regulate selective gene expression
tryptophan
if low genes are ON
TFIID
general transcription factor which binds to TATA and controls position where all protein coding genes start (but not end )
How is memory of differentiation passed on
+ve feedback loop
DNA methylation
gene repression as transcription factors cannot bind
haematopoesis
blood cell differentiaion all from multipotent haemopoietic stem cell in bone marrow. GATA-1 transcription factor commits cells to lineage that will make RBCs
Stromal cell signals
regulate stem cell differentiation , contact between stem cell and stromal cell maintains stemness. division causes loss of contact between daughter cell and stromal
CSFs
released by endothelial cells, fibroblasts, and macrophages in response to tissue infection and act on precursor cells in bone marrow to promote production of neutrophils and macrophages
mitogens
stimulate cell division by triggering wave of G1/S - cdk activity that relieves intracellulart -ve controls blocking cell cycle
growth factors
extracellular signals proteins that promote cell growth. oestrogen for breast cancer, blocked by Tamoxifen
WNT pathway
WNT is produced by paneth cells and recieved by stem cells, it inhibits APC (apc degrated B-catenum) so b-catnim translocates to nuceleus which drives proliferation and stem cell state. Paneth cells tell neighbours to become stem cells
FAD
genetic predisposition to colorectal cancer
immune complement
system of soluble proteins serum proteins that activate each other
cytokines
immune messenger hormones
chemokines
cytokines specialised in making cells move
antibodies
secreted molecules which bind to pathogens
types of immune cell
innate: macrophages, dendritic, neutrophils, eosinophils, basophils, mast cells
adaptive: t cells, b cells ,lymphocytes
leukocytes: wbs innate and adaptive
where are immune cells made
bone marrow and thymus , b cells mature in bone marrow , t cells in thymus
primary lymphoid organs
where immune cells are made (bone marrow and thymus )
secondary lymphoid organs
where immune responses are initiated, lymph nodes, spleen
IFNa IFNb
released by virally infected cells
danger
signals indicating there is harm to the body and or infectious agents are present. DAMPS released from damaged cells and PAMPS released by infectious agents, both recognised by PRR
Adaptive immune response activation
danger and non-self
apoptosis
programmed cell death, caspases activated, non-inflammatory, membrane remains intact, energy dependant, individual cells
necrosis
cell swelling, loss of integrity, groups of cells, no energy required.
coagulative - hypoxia secondary to ischaemia
liquefactive - cell protein wet gangrene
caseous - end result of granulomatous formation (Tb)
gangrenous dry, fat - degradation of fat tissue to chalky
pathogens lead to the activation of complement (C1-C9) by one of the 3 pathways
classical - C1q binds only if antibodies present for specific antigen (IgM , IgG)
mannose-binding lectin- mannose not present on cells
alternative - C3 spontaneously activates and binds to nearby membranes host cells have control proteins to prevent activation, bacterial cells don’t
complement lysis
membrane attack complex forms in membrane of bacteria, barrel like structure formed from C6-C9, water rushes in and bacteria swells and bursts
opsonisation`
label for phagocytosis
macrophages
good at killing if activated (activated by cytokines especially IFN - y), tissue healing, clearence of dead cells . in skeletal muscle cloak trivial damage to reduce inflammation, splenic clear old and damaged RBCs
dendritic
poor at killing, initiate adaptive immune responses and take messages to T cells
neutrophils
killers . NETosis trap pathogens in a net and kills them . neutrophils get into circulation via extraversion rolling along endothelium, diapedisis is it exiting
phagocytosis
phagocyte detects pathogen and engulfs it forming phagosome, lysosome containing toxic products fuses with phagosome to make phagolysosome
B and t cell receptors
BcRs recognise antigens in harmful form
TcRs need an antigen broken down into peptides presented to it on an MHC. contain variable regions coded by variable, diversity, joining gene segments. Somatic recombination randomly selects
healthy immune system
sleep, active skeletal muscle (major source of myokines which support immunity and regulate inflammation)
obesity
stressed adipocytes release danger signals (pro-inflammatory adipokines (IL1b, TNF) which cause insulin resistance, inappropriate chronic inflammation accelerates cardiovascular and chronic diseases
IL-10 and TGF b
minimise immune response
liable, stable, permanent
liable cells divide in homeostasis, stable dont but can in response to injury, permanent never
scar formation
fibroblast migration and proliferation, extracellular matrix deposition, tissue remodelling
inflammations
red, pain, swelling, warm. loss of function
DAMPs and PAMPs
recognised by PRR (inflammation) which releases inflammatory cytokines IL1b and chemokines
Things that attract neutrophils
coagulation products, complemetns C5a,C8a, IL-8,
hyperalgesia
pain sensitisation
allodynia
pain to innocuos stimuli
resolution of inflammation
IL10, IGF1,TGFb
naive, effector, memory T and B cells
naive = never been activated effector = activated memory = stored
B - cells
antibody producing cells bind to pathogens and kills them/ mark them for phagocytosis
CD8+ CTL
kills mutated/infected self cells
CD4+ Th
organise immune responses and produce different cytokines that can differentiate into Th1, Th2, Th17, Treg
polygeny
multiple independant genes for each MHC type(MHC seen as non self in transplant reject)
polymorphisms
multiple variants of each gene within a population
MHC
Class I - only CD8+ CTLs bind, presents only endogenous antigens (Self)
Class II - only CD4+ Th bind on specialised antigen presenting ADC cells (dendritic) presents only exogenous antigens
T cell selection
in thymus , ability to bind to MHC - allows survivial (+ve selection)
binds stongly- death (-ve selection)
outcomes of chronic inflammation
focal scarring - protects. widespread - destroys and can lead to cancer
Differentiation, priming, tolerance, trained innate immunity `
differentiation (like square root) - maturation with long term changes in function and morphology
priming (wave that keeps going up) - failure of transcription to fully return to baseline after challenge
tolerance - big n small n, failure to reactivate after second challenge
trained innate immunity - small n big n, enhanced response to 2nd challenge after return to baseline
ulcer
eats away
abscess
puss surrounded by granulation
granulomas
organised clusters of mature activated marophages in response to persistant stimulus
Antibody Imunoglobulin
Ig MADEG
Fc receptors
receptors for antibodies on phagocyte surface
ADCC
antibody dependant cell cytotoxicity
anti-worm allergy respons
mast cells and basophils
anaphylactic shock
systematic mast cell degranulation
naive b cells
express IgM and G can be activated to express Ig A and E
IgA
dimeric, (Fca) found in mucosa, gut and lung, good for neutralising intestinal pathogens and ensuring they’re flushed out, poor at activating complement opsonising ADCC
IgG
monomeric (Fcy) activation depends on subclass but can oppsonise, neutralise, activate complement ADCC
IgE
monomeric, (FcE) action depends on subclass can opsonise, neutralise and activate complement ADCC
IgM
multimer, (FcM) great for trapping neutralising antigen, good at activating complmemnt, bad at ADCC
Signal 3 on CD4+ Th
Th1 - IFN y - intracellular bacterias and viruses - autoimmunity , IBD
Th2 - IL4 - parasitic worm - allergy
Th 17 - IL17 - extracellular bacteria and fungi - autoimmunity, IBD
Treg - IL10 - suppress immune response
Linked recognition
CD4 + th only provide help to b cells that recognise same antigen as them
what signals for macrophages
NK, ILC1,macrophages - —– IFNy —— Th1
what signals for eosinophils, basophils, mast cells
ILC-2 —— IL5, ILiB —–
eosinophils, basophils, mast cells
Th2 —- IL5, IL3 ——
what signals for neutrophils
ILC3 —- IL17, IL21
Th 17 — IL 17, IL 22
Autoimmunity in T1 diabetes
CTL kills islet b cells
Which figure is nearer skin thickness 1mm or 100 microns ?
100 microns
which is more cellualr compartment epidermis or dermis, and which is thicker?
More cellular = epidermis
thicker = dermis
is melanin soley located within melanocytes
No melanin is synthesised in melanocytes but is then passed into the surrounding keratinocytes
name the extracellualr components/ molecules of the dermis `
collagen, elastin, proteoglycans
what cells synthesise collagen
fibroblasts
mast cells are related to what other cell type
basophils
what is the predominant cell type of skin appendages
keratinocytes
when does UVR induced erthyema peak?
8-24 hours
The UVR induced erythema is due to vasodilation of the blood vessels situated where in the skin?
Dermis - none in epidermis
if no erythema is present no DNA damage has occures
false, damage occurs at any level of irradiation and at levels too low to produce visible erythema
what is more likely to induce erythema 320 nm or 390?
320 nm longer wavelengths produce less damage
what is the mode of inheritence of xeroderma pigmentosum
autosomal recessive
what causes freckles?
focal over production of melanin
what is more protective constitutive or facultative?
constitutive
what type of pigmentation is tanning
facultative
vitiligo is characterised by
aread of hypopigmentation
if the ration of eumelanin to phenomelann is low
red hair
why is melanin synthesised in melanocytes
melanin production emits free radicals, by keeping the production compartmentalised away from the rest of the cell, it reduces damage to other cell componenets
melanocytes communicate with keratinocytes
many keratinocytes per one melanocyte
albisinim is inherited
autosomal recessively
What is the nature of primers used in DNA polymerase chain reaction?
Pair of oligonucleotide DNA strands
age and immunity
As we age we lose NK cell function and this allows viral activation.
allergy
IgE on mast cells respond to the allergen and cause the cell to degranulate and initiating local inflammation.
