9. Regulation of immune response Flashcards
Regulation by antigen
- Chemical (polysaccharide vs protein)
- Soluble vs intracellular
- Large vs small doses
- Competition between antigens and peptides
- The route and administration of Ag
- Role of adjuvants
Adjuvant definition
Wiki: betegner en substans, oftest farmakologisk eller immunologisk, som modifiserer og forsterker effekten av andre substanser (f.eks virkesoff i vaksiner), mens et adjuvant i seg selv har få, om noen, direkte virkning gitt alene.
Response depending on dose of antigen exposure
Low virus dose (0.3)
= high antiviral cytotoxicity (+++)
= mainly Th1 (IFNγ) response
High virus dose (1000)
= low antiviral cytotoxicity (+)
= Mainly Th2 (IL-4) response (?)
Significance of APC
- Professional vs non-professional APC
- CD40L (T-cell) - CD40 (APC) interaction
- CD28 or CTLA4 (T cells) - CD80/CD86 (APC)
- The level of expression of MHC on antigen presenting cell
CD80/86
- On APCs
- Bind to CD28 (pos) or CTLA4 (neg) on T cells
PD-L1/2
“Programmed death ligand 1/2”
- On APCs
- Bind to PD-1 on T cells
- Inhibits TCR-mediated activation of IL-2 production and T cell proliferation
MHC receptor binding
- On APCs
- Bind to TCR, (Lag-3) and (CD160)
Ab blocking
- Kind of regulation by Ab’s
- Ab competes with B cells for Ag
- > B cell suppression
Receptor cross-linking
- Kind of regulation by Ab’s
- Ag-Ab complexes bind to Fc receptors and send inhibitory signal to B cell
- > B cell negative costimulation
B cell positive costimulation
- Kind of regulation by Ab’s
- Costimulation of B cells is by complement receptors
- B cells express CR2 which can bind C3d
Ag-Ab complexes bind C3d and localize to APC via CR2 -> positive costimulation
CD4+ further differentiation
In thymus
1) foxp3+ => Treg
2) foxp3- => Th
Features of Treg cells (Quantity, surface markers, cytokine expression/secretion, suppression mechanism)
- Quantity: 5-10 % of Th
- Surface markers: CD25, CD103, Foxp3 (!), GITR
- Cytokine: IL-10, IFN-γ, TGF-β (and CTLA-4?)
- Suppression:
a) contact with activated target CD8+/CD4+ T cells
b) secretion of cytokines: IL-10, IFN-γ, TGF-β
c) secretion of non-specific inhibition (“bystander effect”)
Treg’s inhibit initial T activation?
No, they inhibit sustained response, and thus prevent chronic and potentially damaging responses
- Suppress Th1 and Th2 responses
iNK T cell
“Invariant NK T cell”
- Express semi-invariant (semi-constant) TCR α chain (Vα14-Jα18)
- Recognize lipid (glycolipid) antigens presented by CD1d on APCs
- Cytokines: INFγ, IL-4, GMCSF ++
- Wiki: respond rapidly to danger signals and pro-inflammatory cytokines
Breg cells mechanism
Main mechanism: production of anti-inflammatory cytokine interleukin 10 (IL-10)
- Suppresses inflammatory reactions by T cells, especially Th1 reactions (maybe also Th17 and Treg)
- Promotes maturation to adaptive Treg cell?
Breg cell receptors
- TLR4 (binds to LPS)
- BCR (binds to antigen)
- CD80/86 (binds to CD28/CTLA4 on T cells)
- CD40 (binds to CD40L on T cells)
Types of cytokines
- Interleukins
- Chemokines
- Colony stimulating factors (CSF)
- Interferons
- Tumor necrosis factors
- Adipokines
Stimulatory cytokines
- Most cytokines can be both stim and inhib
- IL-1
- IL-2
- IL-4-6
- IL- 8
- IL-12
- IL-17
- IL-18
- IL-26
- IL-27
- IFNγ
Inhibitory cytokines
- Most cytokines can be both stim and inhib
- IL-4
- IL-10
- IL-11
- IL-13
- IL-22
- IL-23
- IL-33
- IL-35
- TGF-β
- IFN-α/β
- IFN-γ
Regulation by cytokines
- Can be positive or negative regulators
- Dependent on milieu (other cytokines+receptors)
- Regulate the type and extent of immune response generated
- Soluble cytokine receptors could be agonists and antagonists
Th1/Th2 paradigm
- Th1 secretes IFNγ which inhibits Th2
- Th2 secretes IL-4, IL-10, TGF-β which inhibits Th1
- Th1 has to do with cell-mediated immunity, Th2 has to do with humoral immunity
Peptide-binding groove of APC is formed by the most polymorphic residues in MHC molecules
Encoded by different alleles
What determines the accuracy of peptide binding/Ag presentation of APC
MHC dependent aminoacid sequences of the groove
MHC-linked genes
- Control response to several infections
- Influences susceptibility to autoimmune diseases (Non-MHC-linked genes also affect susceptibility to several diseases)
- Certain HLA haplotypes confer protection from malaria
- Control response to infection (certain HLA haplotypes are associated with responders/nonresponders, susceptibility/resistance)
Linkage disequilibrium
“Nonrandom association of alleles at different loci”
- Grouping of some genes that increase the risk of particular disease (ex: HLA-DR3/DR4 diabetes)
Regulation cytokine and chemokine
- Genetic polymorphism
- Primarily in receptor genes
Non-MHC genes
- E.g complement regulatory factors, regulation of macrophage activity
Telomeres
- Repeats of DNA sequence (GGGTTA) at end of chromosomes
- Regulation of cell senescence (aging) by shortening (50-100 bp every cell division)
- Provide stabilization and protect chromosomal ends from damage; regulate cell replication
Aging by telomere shortening
- When too short: Unstable chromosome -> DNA damage can occur -> cell die by apoptosis or enter cellular senescence (cell arrest)
- Shorter telomeres: elderly, males, people with ageing syndromes
Idiotype definition
Variations in variable region gives antibody/TCR its antigenic specificity
Public idiotypes
Those found on other cells
Private idiotypes
Unique for a given cell or cell clone
Jerne’s idiotypic network
“Immune system seen as a network, components connected by variable- variable region interactions” (google bilde :) )
- Idiotypic determinants are immunogenic
- Anti-idiotypic Ab’s are formed following an anti-Ag Ab
- Anti-idiotypic Ab induce anti-anti-idiotypic response (Ab3, bind to anti-idiotype Ab)
- This leads to gradual fading of immune response against given antigen (damped oscillary motion)
Anti-idiotypic antibodies (Ab2α)
May block antigen binding and thus regulate immune response (bind to variable region/Ag-binding region of Ab)
Neuroendocrine modulation of immune responses
- Lymphocytes express receptors for a variety of hormones, neurotransmitters and neuropeptides (steroids, catecholamines, encephalins, endorphins++)
- Most are immunosuppressive when released during stress
1) Sympatetic nervous system - NE to β2AR (on APC, B cell, Th1, naive T, CTL)
2) Hypothalamus-pituitary-adrenal axis - IL-1 and IL-6
IL-1 and IL-6 synthesis and function on neuroendocrine regulation
Synthesis: - Neurons and glial cells - Pituitary cells - Adrenal glands Function: - Stimulants of adrenal corticosteroid production
Dysbiosis
Microbial imbalance or maladaption on or inside body
Possible causes of dysbiosis
1) Host genetics (mutations in NOD2, IL23R, ATG16L, IGRM)
2) Lifestyle (diet, stress)
3) Early colonization (birth in hospitals, altered exposure to microbes)
4) Medical practices (vaccination, antibiotic, hygiene)
Possible consequences of dysbiosis
1) Disease (Increased Th1, Th2, Th17)
2) Health (Increased Treg)
Immune modulation
Manipulation of immune response
- Vaccination (active+passive)
- Cytokine application
- Monoclonal antibodies application (!)
- Suppression (by glucocorticoids or other immunosuppressive drugs)
- Immune cell infusion
- Extracellular vesicles-microvesicles (!)
- Gene therapy
Modification of monoclonal antibodies (Mabs)
V: varable part, C: constant part
- Chimeric Mabs (V: mice, C: human)
- Humanized Mabs (HyperV: mice, C: human)
- Human Mabs (Human Ig expression in various biological carriers - bact.phages, transgenic animals, bacteria, plants)
- Minibodies (mini-Mabs - better penetration)
- Bispecific Mabs (specificity for 2 antigens)
Examples of Mabs used in therapy + effect + disease
- Infliximab: anti TNF (RA, Crohn)
- Rytuksymab: anti CD20 (RA, B cell lymphomas/leukemias)
- Efalizumab: antiCD11a (psoriasis)
- Trastuzumab: anti-HER2/neu (breast carcinoma)
- Cetuksymab: anti-EGFR (large bowel carcinoma)
- Lambrolizumab: anti-PD-1 (melanoma?)
iDC derived vesicles
Immunosuppressive
mDC derived vesicles
Immunostimulant
Immunosuppressive parts of immune system (?)
1) Cells: Treg, Th2, Breg, DCreg, Mreg (M2)
2) Inhibitory receptors: e.g NKG2A
3) Inhibitory cytokines: IL10, TGFβ
4) Microvesicles
Immunogenic parts of immune system (?)
1) Cells: T cells (Th1, Th17), B cells, DC, Mφ, NK cell
2) Activating receptors: e.g NKG2D
3) Cytokines: e.g IFNγ
4) Microvesicles
