Immunopathology - Basics
Based on Australian university lectures
- Created by: nCaitlyn
- Created on: 05-11-15 07:45
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- Immuno-pathology
- Genetic Based
- T1 Diabetes
- autoimmne destruction of beta cells, beginning with environmental cue of beta damage, allowing self reactive T cells to recognise and subsequently attack beta Ag
- clinical presentation of insulitis where 10% of islets are inflamed
- 53 susceptibility loci recognising C-peptide (so only recognition of insulin producing beta cells, but other beta cells are safe)
- CD4+ activate macrophages and together with CD8 there is production of TNF and IL1 for beta destrction
- Fas/BAX pathways
- CD4+ activate macrophages and together with CD8 there is production of TNF and IL1 for beta destrction
- islet allotransplatnation, xenografts from pigs, transdifferentiation of other cells into beta cells, viacyte stem cell in to precursors that are protected by physical device work as treatments
- autoimmne destruction of beta cells, beginning with environmental cue of beta damage, allowing self reactive T cells to recognise and subsequently attack beta Ag
- Rheumatoid Arthritis
- synovial inflammation of joints with inflammatory infiltrate and resident activation(e.g. osteoblasts) leading to joint and bone damage
- extra-articular effects on liver, fat and muscle, also brain and bone (effects mediated through TNF, IL1 and IL6
- genetic factors due to 3rd hypervariable region of HLA-DR(b), allows targeting of self Ag, molecular mimicry
- also PTPN22 yrosine phosphate affects TCR/BCR signalling
- citrullination of Arg residue to citrulline (loss of side chain) increases risk of RA, smoking enhances citrullination effect
- increases risk by release of citrullinated factors that probably fit the DR(b) epitope better than uncitrullinated, causing increase in immune response, immune complex buil-up and causing further damage
- treatments include naprosyn and anti-inflammatories
- new treatments include anti TF and anti-GM CSF
- to prevent inflammatory maturation of macrophages and neutrophils
- new treatments include anti TF and anti-GM CSF
- Genomics
- two methods of obtaining microbial genome
- one is through culture of microbe and then amplicon sequencing to achieve only its genome
- the other is metagenomic non specific seqeuncing of entire sample so that there are several contaminant genomes included
- once genome is obtained, construct phylogenic, based on point mutation differences between other genomes of same species
- two methods of obtaining microbial genome
- T1 Diabetes
- Gut-Centred Disease
- Coeliac
- Genetic Based
- T1 Diabetes
- autoimmne destruction of beta cells, beginning with environmental cue of beta damage, allowing self reactive T cells to recognise and subsequently attack beta Ag
- clinical presentation of insulitis where 10% of islets are inflamed
- 53 susceptibility loci recognising C-peptide (so only recognition of insulin producing beta cells, but other beta cells are safe)
- CD4+ activate macrophages and together with CD8 there is production of TNF and IL1 for beta destrction
- Fas/BAX pathways
- CD4+ activate macrophages and together with CD8 there is production of TNF and IL1 for beta destrction
- islet allotransplatnation, xenografts from pigs, transdifferentiation of other cells into beta cells, viacyte stem cell in to precursors that are protected by physical device work as treatments
- autoimmne destruction of beta cells, beginning with environmental cue of beta damage, allowing self reactive T cells to recognise and subsequently attack beta Ag
- Rheumatoid Arthritis
- synovial inflammation of joints with inflammatory infiltrate and resident activation(e.g. osteoblasts) leading to joint and bone damage
- extra-articular effects on liver, fat and muscle, also brain and bone (effects mediated through TNF, IL1 and IL6
- genetic factors due to 3rd hypervariable region of HLA-DR(b), allows targeting of self Ag, molecular mimicry
- also PTPN22 yrosine phosphate affects TCR/BCR signalling
- citrullination of Arg residue to citrulline (loss of side chain) increases risk of RA, smoking enhances citrullination effect
- increases risk by release of citrullinated factors that probably fit the DR(b) epitope better than uncitrullinated, causing increase in immune response, immune complex buil-up and causing further damage
- treatments include naprosyn and anti-inflammatories
- new treatments include anti TF and anti-GM CSF
- to prevent inflammatory maturation of macrophages and neutrophils
- new treatments include anti TF and anti-GM CSF
- Genomics
- two methods of obtaining microbial genome
- one is through culture of microbe and then amplicon sequencing to achieve only its genome
- the other is metagenomic non specific seqeuncing of entire sample so that there are several contaminant genomes included
- once genome is obtained, construct phylogenic, based on point mutation differences between other genomes of same species
- two methods of obtaining microbial genome
- T1 Diabetes
- more of an autoimmue disease than allergic response to gluten
- gluten avoids digestion by high proline content, then passes into intestinal wall through paracellular pathway
- becomes deamidated by tTG, and deamidated form allows change from glutamine to glutamate, affecting the 4th, 6th and 7th negative charged positions of the peptide
- unless glycine or proline are nearby amino acids
- deamidation allows for better recognition betwen HLA 2.5, 2.2 and 8 of CD4+ T cells
- deamidation stimulates production of IL15 by IEC - upregulation of NKG2D for IEL stimulation, further IL15 production
- IL15 production stimulates arachidonic acid and lekotriene productino, and subsequent cytolytic effects on cells, and cell death
- symptomatic treatments target gluten digestion (glutenase), gluten entry (zonulin) and deamidation (tTG reduction), as well as suppressing immune response (steroids)
- disease modifying reatment includes hookworm which is to skew immune response towards Th2 instead of Th1
- NEX VAX for diagnosis and therapeutics (building tolerance)
- gluten consumption, breastfeeding, socioeconomic causes (hygiene hypothesis?
- Genetic Based
- Crohn's Disease
- IBD, involving discontinuous skip lesions and transmural inflammation in ascending colon and distal ileum
- involves genetic and enviromental factors, including microbiota
- innate and epithelial work together with JAM-A tight junctions, mucuous secretions, defensins and anti-microbial peptides
- innate also stimulates epithelial repair, autophagy response instead of IL1/6, and tolerance through NOD2
- microbiota alsoregulates immune tolerance, xenobiotic metabolism, but CD has altered composition and variation
- innate and epithelial work together with JAM-A tight junctions, mucuous secretions, defensins and anti-microbial peptides
- pathognesis basically consists of altered microbiota wtherefore lack of immune tolerance, already there is genetic influences with lack of NOD2, ATG6L1 gene for autophagy allowing for increased IL1/6 development and Th17/Th1 skewing, so that there is high inflammation iand leakage to allow pathogenic organisms?
- treatment with anti TNF, anti IL23R, anti p40, and IL10 producing T cells
- HBV
- Different genotypes based on more than 8% change in genome sequence
- allows for differences in geographical distribution, clinical presentation, and even affects treatment responses
- Asians and Africans most affected
- clinical presentation begins with acute infection, progressing to chronic hepatitis, cirrhosis and finally hepatocellular carcinoma
- begins with period of asymptomatic infection (tolerance?) before there is immune reaction and liver damage - which can be again followed by period of low replcation and little damage - cyclic effect?
- 2.7-3kb genome with Surface Ag, Core Ag, eAg (truncated form of cAg), xAg and polymerases
- enters using Pre-S1 +NTCP receptor
- once inside, releases genome to nucleus to turn into cccDNA to turn into minichromosome from which pgRNA and mRNA is created
- in cytoplasm, mRNA creates nucleocapsids, and when packaged with pgRNA, it creates genomic DNA
- due to this cccDNA treatments that worked for HCV won't work for HBV, also both nuclear and cytoplasmic elements involved
- potential treatment is HDACi to allow opening and transcription of cccDNA making it a viable target for antivirals like IFN
- can also use entry and ecretion inhibitors
- Different genotypes based on more than 8% change in genome sequence
- Coeliac
- Infectious Diseases
- HBV
- Different genotypes based on more than 8% change in genome sequence
- allows for differences in geographical distribution, clinical presentation, and even affects treatment responses
- Asians and Africans most affected
- clinical presentation begins with acute infection, progressing to chronic hepatitis, cirrhosis and finally hepatocellular carcinoma
- begins with period of asymptomatic infection (tolerance?) before there is immune reaction and liver damage - which can be again followed by period of low replcation and little damage - cyclic effect?
- 2.7-3kb genome with Surface Ag, Core Ag, eAg (truncated form of cAg), xAg and polymerases
- enters using Pre-S1 +NTCP receptor
- once inside, releases genome to nucleus to turn into cccDNA to turn into minichromosome from which pgRNA and mRNA is created
- in cytoplasm, mRNA creates nucleocapsids, and when packaged with pgRNA, it creates genomic DNA
- due to this cccDNA treatments that worked for HCV won't work for HBV, also both nuclear and cytoplasmic elements involved
- potential treatment is HDACi to allow opening and transcription of cccDNA making it a viable target for antivirals like IFN
- can also use entry and ecretion inhibitors
- Different genotypes based on more than 8% change in genome sequence
- Pneumococcal Disease
- streptococcus = gram + diplococci with polysaccharide capsule, pneumolysin, and PspC
- Pneumonia
- broncho/lobar pneumonia where nasopharynx colonisation descends to lungs
- polysaccharide Ag stimlate inflammatory influx, alveolar wall thickening and cell death (from pneumolysins, PspC and immune-mediated)
- characterised by fast and shallow breathing of 50-40 breaths per minute for infants and children
- Meningitis
- subarachnoid infection
- unregulated laminin, microglial activation, etc. relleases of pro-inflammatory cytokines in privileged environment, leading to intracranial pressure, swelling
- characterised by headaches, fever, seizure, etc.
- subarachnoid infection
- Otitis Media
- infection of middle ear, leading to build up of fluid within Eustachian tube
- can lead to developmental and balance problems, even hearing loss if the ear drum is burst
- typically self-limitting within 2-4 weeks
- Vaccines
- conjugate vaccine PCV contains 23 serotypes, but leads to serotype replacement issue where other serotypes not included begin to cause more disease
- whole cell vaccine includes internal cellular Ag that are conserved across all serotypes so no need to worry about serotype replacement?
- HBV
- Cancer Immunopathology
- immuno-suppressed more prone to cancer than those with immune system
- adoptive immuno-therapy = extract T cells, modify/proliferate, re-introduce as well as eliminating endogenous T cells
- chimeric Ag receptor = CAR T cells with Erb-B2 Ag receptor at the end of hinge with signalling domains of actual T receptor (tricking cancer cell into binding T receptor
- allows cytokine release for cytolytic action on cancer cell
- must also avoid checkpoint blockade of cancer cells (PD/PDL regulates and can inhibit adaptive system, therefore, require PD inhibitor)
- nivolumab = monoclonal Ab that binds with PDL to prevent association with PD
- CTLA4 is similar checkpoint blockade pathway, requires ipilumab to prevent binding with CD80/86
- Genetic Based
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