Basic mechanisms of immune defense
Susanne Brix PedersenMolecular Immune Regulation Group, CBS, DTU
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
A delicate equilbrium
Challenges
• Discrimination between self and non-self
– bacteria
– fungi
– vira– vira
– parasites
– (transplants)
• Evolution
• Dealing with non-pathogenic factors
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
Immune cell subsets
Characteristics of the two parts
T cells
B cells
Antibodies
Memory
Granulocytes
Monocytes
Macrophages
Dendritic cellsMemory
MHC - HLA
Diversity
Somatic hypermutation
Polymorphism
Dendritic cells
NK cells
NK T cells
Complement
Pattern recognition
Characteristics of the two parts
T cells
B cells APC
Antibodies
Memory
Granulocytes APC
Monocytes APC
Macrophages APC
Dendritic cells APCMemory
MHC - HLA
Diversity
Somatic hypermutation
Polymorphism
Dendritic cells APC
NK cells
NK T cells
Complement
Pattern recognition
Innate and adaptive immune responses
Immune cell locations
Lymphoid organs and lymphatics
Immune cell subsets
Ideally, selected T cells
contain TCRs with low
affinity for self MHC in
combination with “non-
self” antigens, but
Central T cell tolerance
self” antigens, but
usually auto-reactive T
cells also exists in the
periphery
Discrimination between “self” and “non-self”
Every immune response depends on regulation at the single-cell level
The phases of an adaptive immune response
Antigen-presenting cells
Immature DCs takes up antigen
Antigen processing pathways
Antigen presentation pathways
MHC I and II
Tc TH
Antigen presentation – the 3 activating signals
3. Signal
Cytokines ↔ Cytokine
receptors
1. 2.
Activation
Proliferation
Help or Killing
MHC molecules
Length of peptides:
MHC class I >10 aa
MHC class II: 10–30 aa
T cells
Helps:B cells
CD8+ T cellsMacrophages
Kills:Infected cellsTumour cells
Recognizes MHC II on APC
Recognizes MHC I on all cells
Activation of CD4+ T cells
Clonal expansion
T cell receptor
Timing in T cell activation
Induction of immunity
Importance of CD4+ T cells:
CD4+ T cells are central in providing help for CD8+ T cell and B cell activationfor CD8+ T cell and B cell activation
Activation of CD8+ T cells
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.
CTLs in virus clearance
Meeting places (T – APC)
Antibodies
B cells – plasma cells - antibodies
T cell help for B cell activation
B cells – memory cells
Antibody classes
Antibody-mediated bacteria killing
Preference for ”opsonized” bacteria
Different biological effects of antibodies
Activation of adaptive immunity
Christensen, HR (2003)
The ”patterns” of microorganisms
Pattern recognition in APC
Takeda & Akira, Int. Immunol. 2005
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!
Cytokines are important polarizing agents
Zeuthen, LH (2006)
Antigen presentation
3. Signal
Cytokines ↔ Cytokine
receptors
1. 2.
Activation
Proliferation
Help or Killing
Cytokines are important polarizing agents
Zeuthen, LH (2006)
Activation of CD4+ T cells requires formation of the immunological synapse
Activation or inhibition? Importance of co-stimulatory signals and cytokines
Regulation of the immune response
’Summing up’ questions
• What is the origin of the antigens presented onMHC 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• How are a) bacteria, b) vira and c) cancer cellsfought by the immune system?
• How is the human immune system dealing withthe 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?