Immunology 3 Flashcards
Immune regulation
o Immune response is power + must be regulated to prevent unwanted effects
o Typically, at end of successful resolution of an infection but also to prevent reaction against self
o Failure to regulate responses leads to problems
o Achieved by complex interactive network of immune cells
o Required to:
§ Avoid excessive lymphocyte activation + tissue damage during normal protective responses against infections
§ To prevent inappropriate reactions against self-antigens
o Failure of control mechanisms is underlying cause of immune-mediated inflammatory disease
Autoimmunity
o immune response against self (auto-) antigen = pathologic
o Pathogenesis à susceptibility genes + environmental triggers
o Systemic or organ-specific
o E.g. Grave’s disease, Addison’s disease, myasthenia gravis, SLE, rheumatoid arthritis etc.
Allergy
o Harmful immune responses to non-infectious antigens that cause tissue damage and disease
o Can be mediated by antibody (IgE) and mast cells – acute anaphylactic shock
o Or by T cells – delayed type hypersensitivity
Hypercytokinemia and Seosis
o Too much immune response
o Often in +ve feedback loop
o Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level
· One way to regulate immune response and prevent accidental activation is requirement for 3 different signals to licence the cells to respond.
o 1. Antigen recognition
o 2. Co-stimulation
o 3. Cytokine release
o Antigen recognition + co-stimulation leads to cytokine release à licenses cell to respond
· Another way to regulate immune responses is to make them self-limiting – naturally decline over time, unless there is continued presence of antigen to stimulate the cells
o Immune response eliminates antigen that initiated the response
o So, first signal for lymphocyte activation is eliminated
o Overall decline in immune responses as amount of antigen decreases
Resolution and Repair
o Resolution and repair are the desired outcome of a successful immune response and the system returns to its resting state
o Failure to do this can lead to chronic inflammation and tissue damage e.g. TB, rheumatoid arthritis
o Resolution à no tissue damage, returns to normal. Phagocytosis of debris by macrophages
o Repair à healing w/scar tissue and regeneration. Fibroblasts and collagen synthesis
o Chronic inflammation à active inflammation and attempts to repair damage ongoing
Immunity needs antigen
o Responses against pathogens decline as the infection is eliminated
§ Apoptosis of lymphocytes that lose their survival signals (antigen etc.)
§ Memory cells are the survivors
o Active control mechanisms may function to limit responses to persistent antigens (self-antigens, possibly tumours and some chronic infections)
§ Often grouped under tolerance
§ Basis of cancer immunotherapy
Regulatory T Cells
o Phenotype à CD4, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers
o Mechanisms of action
§ Secretion of immune-suppressive cytokines à TGF-beta, IL-10, IL-35
§ Inactivation of dendritic cells or responding lymphocytes
o IL-10 è master regulator à blocks pro-inflammatory processes
§ Key anti-inflammatory cytokine
§ Multi-functional
§ Acts on range of cells
§ Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN gamma
§ Downregulates macrophages
§ Viral mimics
Central tolerance
From thymus and bone marrow
· Destruction of self-reactive T or B cells before they enter circulation
· Autoimmune regulator (AIRE) à transcription factor express proteins in other organs
B Cells
Does it recognise self antigens?
Yes - Apoptosis
No - Cell kept (-ve selection process)
T Cells Does it recognise self MHC? No - Death by neglect Yes - Is it self reactive? -- Yes -> Apoptosis -- No -> Cell kept (-ve selection proccess)
Peripheral tolereance
· In spleen and lymph nodes etc.
· Destruction of self-reactive lymphocytes once they enter body circulation
· Regulation by Treg which secrets TGF beta, IL-10, IL-35
o Inhibit T and B cells and DCs
o Natural Treg develops in thymus
o Inducible Treg develop from CD4+ in periphery
· 3 mechanisms:
o ANERGY è induced by absence of co-stimulation – not stimulated + need more signals to become stimulated
o IGNORANCE è low conc. of antigen to reach threshold for TCR triggering
o DELETION è expression of Fas ligand to trigger apoptosis
Hypersensitivity
A condition in which normally protective immune system has harmful effect on body
Has 4 different types
Type I Hypersensitivity
· Mediated by antigen specific IgE antibodies e.g. asthma, allergic rhinitis etc.
· 1. Allergen presented by B cell
· 2. Th2 cell binds to APC à releases IL-4, IL-13
· 3. Produces plasma cells + memory cells
· 4. Plasma cells à allergen specific IgE
· 5. IgE bonds to sensitised mast cells (becomes over sensitised)
· 6. Mast cell secretes histamines, heparin, proteases etc. after degranulation when exposed to allergen again
· 1st allergen exposure = sensitisation
· 2nd exposure = allergic reaction
· Early phase è only mast cells
· Later phase è recruitment of early inflammatory cells
· Late phase è recruitment of eosinophils and Th2 cells
Type 2 Hypersensitivity
· Destruction of cells by IgG or IgM bound to cell’s surface antigens à inflammation and tissue damage
· E.g. mismatching of blood transfusion, haemolytic disease of newborn, immune thrombocytopenia, Grave’s disease (overactivity of thyroid gland)
· Mechanism 1 è receptor blockage or activation
· Mechanism 2 è complement cascade activation à activates/attracts neutrophils + forms MAC which bursts cell
· Mechanism 3 è cell mediated cytotoxicity – antibody dependent
Type 3 Hypersensitivity
· Immune complex deposition promoting inflammation and tissue damage
· E.g. vasculitis, glomerulonephritis, arthritis
· Attracts neutrophils which degranulate if they can’t phagocytose
· Soluble antigen
Type 4 Hypersensitivity
· T cell mediated
· Sensitisation and effector phase
· Delayed type hypersensitivity (takes longer to develop)
· 1. Th cell binds to DC
· 2. DC secretes IL-12 which makes Th cell into Th1 cell
· 3. Th1 cell secretes IL-2, IFN gamma à results in Th cell proliferation and macrophages
· E.g. contact dermatitis, asthma (by Th2), graft tissue rejection (cytotoxic cells)
Examples for Immune Evasion - Evading antibody opsonisation
Expressing Capsules - S. aureus, E. coli (many K types, 80types), S.pyogenes, Pseudomonas aeruginosa, S.pneumonia (91 capsule type), S. agalactiae (9 capsule types)
Binding to antibody Fc region - S. aureus (SpA bind to IgG), Streptococcus dysgalactiae (Protein G bind IgG), Peptostreptococcus magnus (Protein L bind IgG), Streptococcus agalactiae (Protein Beta bind IgA)
S. aureus SSL10 bind IgG to inhibit detection
Proteases cleave antibody - Group B streptococcus (IdeS)
Antigenic Variation - N. gonorrhoeae (Opa and LOS antigens), S.pneumoniae (Cap)
Examples for Immune Evasion - Evading complement functions
S. aureus SCIN binds C3bBb and inhibits convertases
S. aureus Efb binds C3d and inhibits fB binding C3
Other bacteria release proteins binding C3:-
M. catarrhalis (UspAs)
Proteases cleave complement components - S. pyogenes (SpeB)
P. gingivalis (Kgp)
N. meningitidis (MalP)
P. aeruginosa (AprA)
Acquired host derived complement regulators - C3b is inactivated by fH on bacterial surface (S. aureus (Sbi) S. agalactiae (b) H. influenzae Salmonella spp (Rck) A. baumannii (Omp) N. meningitidis (factor H binding protein) )
Associated with fI and degrades C2a from C3 convertases (C4b2a) -B. pertussis N. gonorrhoeae (type IV pili) E. coli (OmpA) S. pneumoniae (PspC)
Immune receptors detect bacteria
Conserved microbial
structures - TLR receptors
Microbial
carbohydrates - CLEC receptors
Formylated peptides - FPR receptors
Immune receptors indirectly detect bacteria
Microbes can become opsonised
by antibodies or complement
Neutrophils detect opsonised microbes
through Fc receptors or complement
receptors
Antibody opsonised microbes - Fc receptors
Complement opsonised microbes - Complement receptors
Immune receptors modulate function
There is a diverse range of immune receptors involved in generating and modulating a balanced immune response
Activatory receptors enhance immune cell activity
Inhibitory receptors suppress immune cell activity
Cytokine rceptors Chemoattractant receptors LAIR receptors SIGLEC receptors LILR receptors CEACAM receptors
Examples for Immune Evasion - Evading neutrophil functions
S. aureus CHIPs inhibits chemotaxis & activation
- Chemotactic receptors
C5aR detects C5a
FPR1 detects formylated peptides (fMLP)
- S. aureus inhibits chemotactic receptors
CHIPs binds C5aR
CHIPs binds FPR1
- CHIPs binds C5aR and FPR1 and prevents binding of their agonists (C5a and formylated peptides)
Kill neutrophils - S. aureus (PVL), S. aureus (PSMs), B. pertussis (PT), S. pyogenes (SLS)
Bind inhibitory receptors
- S. agalactiae (b), N. gonorrhoeae (Opa), H. pylori (HopQ), E. coli
Inhibit effects of
antimicrobials - S. aureus (SPIN), S. pneumoniae (SP_1749), Y. pestis (YopE), P. aeruginosa (ExoS)
Modify bacterial surface -
N. meningitidis (Opa)
E. coli (O and K antigens)
S. pneumoniae (Cap)
TNF
Macrophages, Th1 cells
Distressed tissues
Targets and effects Endothelial cell activation (inflammation & coagulation) Neutrophil activation Hypothalamus: fever Liver: Acute phase reactants Muscle, fat: catabolism Many cell types: apoptosis Fibroblast: proliferation, collagen deposition
Chemokines
Macrophages, endothelial cells, T cells, fibroblasts, platelets
Targets and effects
Chemotaxis and activation of cells (to site of infection)
IL-1
Chemotaxis and activation of cells (to site of infection)
Targets and effects
Endothelial cell: activation, inflammation, coagulation
Hypothalamus: fever
Liver: acute phase reactants
IL-12
Macrophages, dendritic cells
Targets and effects
NK and T cells: IFN-gamma synthesis, increased cytolytic activity
T cells: Th1 differentiation
IFN-gamma
NK cells, Th1
Targets and effects
Activation of macrophages and DC to produce co-stimulators and cytokines esp IL-12
Stimulate some antibody responses – production of IgG antibodies in the interaction between a Th and B cell
Type 1 IFN
All nucleated, distressed cells
IFN-alpha: mainly macrophages
IFN-beta: mainly fibroblasts
Targets and effects
All cells: antiviral, increased MHCI expression
NK cells: activation
IL-6
Macrophages, endothelial cells, T cells
Targets and effects
Macrophages, endothelial cells, T cells
