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Basic mechanisms of immune defense
Associate Professor Susanne Brix PedersenSystems Biology of Immune Regulation , CBS, DTU Systems Biology
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Immunity?
Consists of the following activities:
– Defense against invading pathogens (viruses & bacteria)
– Removal of 'worn-out' cells (e.g. old RBCs) & tissue debris (e.g. from injury or disease)
– Identification & destruction of abnormal or mutant cells (primary defense against cancer)
– Rejection of 'foreign' cells (e.g. organ transplant)
– Inappropriate responses:
• Allergies - response to normally harmless substances
• Autoimmune diseases
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A delicate equilibrium
Challenges
• Discrimination between self and non-self
– bacteria
– fungi
– vira
– parasites
– (transplants)
• Evolution
• Dealing with non-pathogenic factors
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Lethality from pathogenic factors
- induce tissue damage & produce disease largely by releasing enzymes or toxins that physically injure or functionally disrupt affected cells & organs
- can only reproduce in host cells & cause cellular damage or death by:
– depleting essential cellular components
– causing cellular production of substances toxic to cells
– transforming normal cells into cancer cells
– inducing destruction of cells because infected cells is no longer recognized as 'normal-self' cell
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Immune cell subsets
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Characteristics of the two parts
T cells
B cells
Antibodies
Memory
MHC - HLA
Diversity
Somatic hypermutation
Polymorphism
Granulocytes
Monocytes
Macrophages
Dendritic cells
NK cells
NK T cells
Complement
Pattern recognition
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Characteristics of the two parts
T cells
B cells APC
Antibodies
Memory
MHC - HLA
Diversity
Somatic hypermutation
Polymorphism
Granulocytes APC
Monocytes APC
Macrophages APC
Dendritic cells APC
NK cells
NK T cells
Complement
Pattern recognition
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Innate and adaptive immune responses
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Immune cell locations
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Lymphoid organs and lymphatics
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Immune cell subsets
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Ideally, selected T cells contain TCRs with low affinity for self MHC in combination with “non-self” antigens, but usually auto-reactive T cells also exists in the periphery
Central T cell tolerance
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Discrimination between “self” and “non-self”
Every immune response depends on regulation at the single-cell level
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The phases of an adaptive immune response
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Antigen-presenting cells
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Immature DCs takes up antigen
Antigen processing pathways
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Antigen presentation pathways
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MHC class I and II
TH TC
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Antigen presentation – the 3 activating signals
3. Signal
Cytokines ↔ Cytokine receptors
Activation Proliferation Help or Killing
1. 2.
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MHC molecules
Length of peptides:MHC class I >10 aaMHC class II: 10–30 aa
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T cells
Helps:B cells
CD8+ T cellsMacrophages
Kills:Infected cellsTumour cells
Recognizes MHC II on APC
Recognizes MHC I on all cells
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Activation of CD4+ T cells
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Clonal expansion
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T cell receptor
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Timing in T cell activation
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Induction of immunity
Importance of CD4+ T cells:
CD4+ T cells are central in providing help for CD8+ T cell and B cell activation
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Activation of CD8+ T cells
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Killing of virus-infected cells
Apoptosis is induced due to the action of perforin (making pores), and the granule-containing granzyme B, a serine protease which activates a variety of caspases.
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CTLs in virus clearance
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Meeting places (T – APC)
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Antibodies
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B cells – plasma cells - antibodies
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T cell help for B cell activation
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B cells – memory cells
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Antibody classes
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Antibody-mediated bacteria killing
Preference for ”opsonized” bacteria
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Different biological effects of antibodies
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Activation of adaptive immunity
Christensen, HR (2003)
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The ”patterns” of microorganisms
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Pattern recognition in APC
Takeda & Akira, Int. Immunol. 2005
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Recognition of ”pathogenic” structures
• Direct recognition of pathogens – ”danger signals” (viral, bacterial, fungal, parasitic)
• Innate immune system alerts the adaptive immune system in parallel with antigen-presentation
• Must recognize vital structures!
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Cytokines are important polarizing agents
Zeuthen, LH (2006)
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Antigen presentation
3. Signal
Cytokines ↔ Cytokine receptors
Activation Proliferation Help or Killing
1. 2.
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Cytokines are important polarizing agents
Zeuthen, LH (2006)
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Activation of CD4+ T cells requires formation of the immunological synapse
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Activation or inhibition? Importance of co-stimulatory signals and cytokines
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Regulation of the immune response
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’Summing up’ questions
• What is the origin of the antigens presented on MHC I and MHC II?
• Which cell types display MHC I and MHC II, and to which type of T cells do they bind?
• How are a) bacteria, b) vira and c) cancer cells fought by the immune system?
• How is the human immune system dealing with the rapid evolution of microorganisms?
• What happens when an immune response is finishing and what happens if an immune response is not terminated upon elimination of the pathogen?