Recap 5 Flashcards
Examples of PRR (recognize DAMP, PAMP)
- Collectin = active complement
- Pentraxin = active complement (include C-reactive protein)
- TLR
- Cytosolic PRR
RIG (viral nucleic acid)
NLR (microbial DNA, activate STING pathway -> IFNy) - C-type lectin-R (fungi)
Signaling of TLR
- Binding of PAMPs active TIR (TLR1) which forms complex MyD88 (IL1-R associated kinase - IRAK) and TRAF6 -> activated TRAF activates MAPK cascade -> active NFkB (cytokines and adhesion molecules and interferon-regulatory factors IRF (antiviral cytokine, type 1IFN)
What are the enzymes mediating recombination of AG receptors for lymphocytes?
RAG1 et RAG2 genes
What are innate lymphoid cells (ILC)?
Heterogenous population of nonB nonT lympho not AG-Sp
Tissue resident lympho that lack LT-AG-R = can’t respond to AG but activated by cytokines produced at sites of damage
Groups of ILC***
GROUP 1
Transcription regulated by T-bet, IL7, IL15
Produce IFNy and TNF
IC bacteria and parasites
GROUP 2
Transcription regulated GATA-3, NOTCH, IL25, IL33, TSLP, TL1A
Produce IL4, IL5, IL9, IL13, Areg
Helminths, asthma, allergy
GROUP 3
Regulated by RORyt
Produce IL17, IL22, GM-CSF
Stimulated by AHR ligand, IL18, IL23
LT receptors (TCR)
1- aB-TCR (most peripheral blood lymphocytes) - covalently linked to 5 polypeptide chains = 3 CD3, 2 B-chain -> act as signal transduction after binding
- CD4+, CD8+
2- yd-TCR (intraepithelial lympho) - recognize peptides, lipides and small molecules without CMH - produce cytokines, CTL, induce/suppress CD4+, present AG
- early cell mediated immune response in neonates (CD3+)
3. NK-T lymphocytes - recognize glycolipids associated with CD1 (CMH-like molecule)
Genes for a, B, y, d chain undergo somatic rearrangement in thymus
Other molecules expressed on the surface of LT that assist TCR complex
CD2
Integrin
CD28
What do Treg express, produce?
CD25+
Produce IL4, IL10, TGFB
Examples of superantigen
- Chaine VB TCR
- a CMH II
What is the R for ligand C3b and C3d?
CD21 (CR2)
Function of Thelper
CD4+ LT recognixe AG displayed on APC, LT express CD40L engages CD40 on macrophages or LB = active these cells
Combination of CD40 and IFNy mediated activation = M1 macro
Types of activation of humoral activity
- T-dependent activation : LB recognize AG by Ig-R -> endocytosis -> degrade -> display peptides bound to CMH II for recognition by Th (CD40L, Ig isotype switching need LThelper)
- T-independent : polysaccharide and lipid AG can’t be rexognized by LT bc can’t bind to CMH, but have many epitopes that engage AG-R on LB -> LB activation -> stimule IgM production
What receptors do monocytes express?
CSF-1 (CD115)
CX3CR1
Blood monocytes = CD14, CD16
Receptor of white pulp macrophage (corps tingibles)
CD68
Importance of DC
Important for negative selection (thymus) and maintenance of peripheral tolerance
R for Langerhans
CD207
Molecules expressed by NK
Activation
Effectors
CD16 (R for IgG Fc tail)
CD56
CD2 (IL2-R)
Activated by IFNy, IFNB, IL12-15-18
Effectors = perforin, TNF
Cytokines in innate and adaptive response
Innate = TNF, IL1, IL12, IFN 1, IFNy, chemokines
Adaptive = IL2, IL4, IL5, IL17, IFNy
Phase of hyperS I
Sensitization phase = binding of AG-Sp IgE to Fce on mastocytes
Effector phase = binding of AG to IgE on mast cells
Immediate phase = release vasoactive amine
Late phase = intense inflammation ; eosino, neutro, baso, macro, CD4+ -> tissue damage
Major cytokines released from mast cells during hyperS I
IL4, IL5 = contribute to LB activation, IgE synthesis
IL5 = chemotactic for eosino
IL6, TNFa = shock
By what is the expression of peripheral AG in thymus regulated?
Autoimmune regulator = AIRE
Mechanisms of autoimmunity
- Genetic factors
- +++CMH
- Defects Fas or FasL, lack of AIRE, defect in CTLA-4 (LT anergy), IL2-R (Treg)
- HLA alleles
- Association of non CMH genes
PTPN22 = encode tyrosine phosphatase -> mutation = excessive lympho activation
NOD2 = cytoplasmic sensor of microbes -> mutation = entry and chronic inflamm of commensal bact - Microbial agent
- some cells induced by IFNy increase expression of CMH during inflamm
- molecular mimicry
- some virtus cause polyclonal LB activation with prod of autoAC
SCID in horse ;
Mutation
Autosomal recessive
Spontaneous mutation in gene encoding catalytic subunit of a DNA-dependent protein kinase
- required for recombination of Ig heavy chain and TCR genes during developement
- defect in DNA repair mechanisms
SCID in dogs
Clinic
Mutation
Lymphopenia, increase B, fewer to no T
Hypogammaglobulinemia, normal IgM, decrease IgG, IgA
Mutation in the common gamma subunit of IL2-4-7-9-15 receptor = LT nonfct because can’t express functional IL2-R
Agammaglobulinemia :
Clinic
Mutation
Inability to produce Ig and absence of mature LB and plasma cells
Probably Xlinked
Mutations BTK = encoded tyrosine kinase that arrest LB development at pre-B stage
EC bacterial infection
Deficiency in C3 complement
Most serious
Autosomal recessive
Deletion = stop codon
Deficiency in factor H of complement
Regulatory component of complement activation = block formation of C3 convertase and cofactor of C3b cleavage by factor I
= unregulated elaboration of C3b on activation
Deficiency in C1 inhibitor
Autosomal dominant
Hereditary angioedema
Chediak-Higashi syndrome :
Mutation
Defect in
Mutation in Lyst gene (regulates IC protein trafficking)
Defects :
Lysosome
Melanosome (hypopigmentation)
Platelet dense granules = excessive bleeding
Cytolytic granules (neutro) = recurrent infections
Defect in NK cells
Ocular abnormalities
Detection of ANA via indirect immunofluorescence
- Homogenous or diffuse nuclear staining = AC chromatin, histone, double-stranded DNA
- Rim or peripheral staining = double stranded DNA, nuclear envelope
- Speckled = Ac to non-DNA nuclear constituents
- Nucleolar pattern = AC to RNA
- Centrometric pattern = AC to centromeres
Acute and chronic graft rejection
- Direct pathway = graft AG presented directly to LT by graft APC = CTL mediated ACUTE rejection
- Indirect pathway = graft AG picked by host APC and presented to LT = CHRONIC rejection
Pathogenesis of hyperacute graft rejection**
Preformed AC linked to endothelial cells -> activation of complement -> endothelial injury, thrombosis, ischemic necrosis, arterioles fibrinoid necrosis
Rare because cross-match and blood type testing
Pathogenesis of acute graft rejection
Mediated by LT and AC (days/weeks)
- Acute cellular rejection = CTL directly destroys graft, CD4+ secrete cytokines -> damage
- Acute AC-med rejection = AC bind to vascular endothelium -> complement via classical pathway -> damage
Pathogenesis of chronic rejection
Months/years
LT reacts against graft alloAG and secrete cytokines stimule prolif of fibroblasts and vascular smooth muscle cells
Refractory to most tx, principal cause of graft failure
Depletion of donor LT before transfusion eliminate dz but recurrence of leukemia, graft failure and LB lymphoma increase
Defects in leucocytes fct
1- defect adhesion type 1 = B2 chain (LFA, MAC1)
2- defect adhesion type 2 = absence Sialyl-Lewis X bc of defect in fucosyl transferase
3- chediak-higashi syndrome = defect fusion phagosome et lysosome
X-linked SCID
Defects
Defects in y-chain subunit of cytokokines-R = IL11, IL15, IL21
IL7 = prolif lymphoid progenitor
IL15 = prolif NK
LT reduced, LB normal but reduced synthesis of AC
Autosomal recessive SCID
Deficiency in enzyme adenosine deaminase (ADA) = accumule deoxyadenosine = toxic to rapidly dividing LT
HyperIgM syndrome mutation
Mutation in CD40L
What do senescent cell express?
Senescence-associated B-galactosidase
Role of mTOR
Major inhibitor of autophagy
Steps of tumor development
- Initiation = cell morphologically normal with irreversible genetic changes = provide growth advantage under some conditions
- Promotion = not mutagenic = reversible = create proliferative environment
End of promotion phase = BENIGN TUMOR - Progression = irreversible, genetic/epigenetic changes, alteration in tumor environment
By what are encoded tumor specific shared AG
Encoded by genes that have a very limited expression in adult tissue but that are expressed by many types of tumor tissues
Ex : MAGE
Tumor immunosuppressive secretory products
TGFa = inhibe function/prolif of lympho and macro
FasL = binds Fas-R on LT and trigger apoptosis
Epithelial-mensenchymal transition morpho
Loss of intercellular adhesion (= little to no E-cadherin)
Enhance expression of protease
Mirgatory capabilities
Reduced expression of cytokeratine
De novo expression of vimentin
By what is facilitated cell migration and vessel penetration
By tumor associated macrophages that accompany invading tumor cells
Cause of neurological syndrome in cancer
HyperCa, hypoglycemia, hyperviscosity
Mechanisms of retroviral genomes (replicate after insert in animal genome)
Interrupt coding sequence of animal genes, abrogating their expression -> abnormal gene products
Juxtaposition of viral promoter elements adjacent to cellular coding sequences of host -> dysregulated expression of gene (often increase)
Cause of amplification mutation
DNA polymerase slippage during replication
Germline mutations and cancer syndrome :
1. Multiple endocrine neoplasia
2. Hereditary renal cystadenocarcinome
- Multiple endocrine neoplasia = MEN1, RET
- Hereditary renal cystadenocarcinome = BHD locus
Effet of DNA methylation ***
Add of methyl group to cytosine beside guanine (CpG dinucleotide) = cytosine - phosphate - guanine
HYPOMETHYLATION = gene activation (++ promoter region)
HYPERMETHYLATION = gene silencing
Effet acetylation of histone
Hausse acetylation = hausse transcription (chromatine lâche)
Deacetylase = baisse transcription
Role of mismatch repair enzyme MLH1, MSH2
Proof-read DNA to locate and fixe single nucleotide mismatch during normal DNA synthesis
Effects of radiation
All forms are carcinogens = initiate and promote tumorigenesis
Direct DNA damage by ionizing radiation = single or double stranded breaks and base elimination
Absorbe UV by DNA -> forms pyrimidine dimers (mutagenic)
Generate ROS (DNA damage = altered base, strand break, cross-link)
Papillomavirus mechanism
E6 inhibe p53
E7 inhibe pRb
R-tyrosine kinase in cancer
Most important in cancer
Normally : bind GF -> dimeric state -> autophosphorylate tyrosine residues on IC tail = recruit other signaling molecules RAS,m PI3K
In cancer = doesn’t need GF for activity
Mutation of downstream component of tyrosine kinase in cancer
- Point mutation of RAS
- MAPK activating mutation of BRAF = active transcription factor
- Gain of fct of PI3K or loss of fct of PTEN (regulator)
Functions of MYC***
- Some targets (cyclin D) involved in cell cycle progression
- Upregulates expression of rRNA = enhance assembly of proteins in ribosome
- Upregulate gene expression needed for metabolic reprogramming and Warburg effect
- Sometimes upregulate expression of telomerase
- Rare transcription factor contributing to reprogramming somatic cells into pluripotent cells
Mutation of RAS/MAPK, Notch, hedghog -> upregulate MYC
Mechanism of p53 after release from inhibitory state of MDM2 in DNA damage/hypoxia and oncogenic stress
DNA/hypoxia -> ATM and ATR stimule phospho of p53 and MDM2 -> disrupt binding and degradation of p53 = p53 accumule
Oncogenic stress -> active RAS -> sustained growth signal (MAPK, PI3K/AKT) -> cellular stress -> increase expression of p14/ARF = binds to MDM2 and displace p53 -> p53 accumulate
Immunosuppressive factors secreted by cancers
TGFB
IL10
PGE2
Metabolites from tryptophan
VEGF
What is the hallmark of mismatch repair defects
Microsatellite instability
What is the most common mechanisms that activate prot-oncogene?
Chromosomal translocations
Burkitt vs LB lymphoma with epstein barr virus
Burkitt = don’t express LMP-1, EBNA-2 and other EBV proteins (EBV not directly oncogenic act as mitogen)
LB = express LMP-1, EBNA-2 are antigenic and would be recognize by CTL in normal people
What do nasopharyngeal carcinome express?
LMP-1 (active NFkB = upregule VEGF, FGF, MMP, COX2) and PD-L1
Effects of hepatitis B virus
Random integration in genome
Active NFkB blocks apoptosis, dividing hepatocytes undergo genotoxic stress and accumulate mutation
Has some gene that directly promotes cancer
Mechanisms of helicobacter pylori
Gastric adenocarcinoma : Pathogenicity island that contains cytotoxin-associated A (CagA gene) penetrate epithelial cells and initiae signaling cascade that mimics upregulated growth factor stimulation
Gastric LB lymphoma : H.pylori reactive LT stimule polyclonal LB prolif to grow into monoclonal MALToma dependent on LT stimulation
Early stage = ATB cure by removing AG stimulation
Later = no because of additional mutations
