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)
