Immunopathology - Basics

Based on Australian university lectures

HideShow resource information
  • Created by: nCaitlyn
  • Created on: 05-11-15 07:45
View mindmap
  • 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
        • 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
      • 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
      • 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
    • 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
            • 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
          • 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
          • 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
        • 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?
      • 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
        • 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
    • 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
      • 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.
        • 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?
    • 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

Comments

No comments have yet been made

Similar Medicine resources:

See all Medicine resources »See all Immunopathology resources »