Transcript Basic mechanisms of immune defense

Introduction to the immune system
Lisbeth N. Fink
Nutritional Immunology Group – CBS - DTU
Protecting borders to the outside world
Challenges
• Discrimination between self and non-self
–
–
–
–
–
bacteria
fungi
vira
parasites
(transplants)
• Evolution
• Dealing with non-pathogenic factors
Outline
1.
2.
3.
4.
Cells and tissues of the immune system
Innate and adaptive immunity
Antigen presentation
Immunity vs. tolerance
First lines of defense
Anatomical Physiological
Skin
Mucosae
Ciliae
Temperature
pH
Lysozyme
Lymphoid organs and lymphatics
Immunocompetent cells
Hæmatopoesis = creation of blood cells
Red blood cells
Leukocytes/
White blood cells
Lymphocytes
Adaptivt/Specifikt Medfødt/Uspecifikt
Second line of defense: Humoral factors
Humor = liquid
(From greek, 4 humors controlling health and mood: blood, phlegm, yellow and black bile)
Antibodies – specific
pathogen recognition
Complement system
– non-specific recognition
Reactive oxygen species
(ROS) – bactericidal activity
Third line of defense: Immune cells
Haematopoieisis
Red blood cells
Leukocytes/
White blood cells
Lymphocytes
Adaptive/Specific Innate/Non-specific
Outline
1.
2.
3.
4.
Cells and tissues of the immune system
Innate and adaptive immunity
Antigen presentation
Immunity vs. tolerance
Characteristics of the two parts
Adaptive/Specific
Innate/Non-specific
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
Characteristics of the two parts
Adaptive/Specific
Innate/Non-specific
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
Inflammation – recruitment of cells
What leads to an adaptive immune response
Antigen uptake - phagocytosis
Phagocytic cells:
Granulocytes
Monocytes
Macrophages
Dendritic cells
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!
Outline
1.
2.
3.
4.
Cells and tissues of the immune system
Innate and adaptive immunity
Antigen presentation
Immunity vs. tolerance
What leads to an adaptive immune response
T cells
Recognizes MHC I
on all cells
Recognizes MHC II
on APC
Kills:
Infected cells
Tumour cells
Helps:
B-cells
T cells
Macrophages
Activation of CD4+ T cells
T cell receptor
MHC molecules
Antigen-presenting cells
Antigen presentation pathways
MHC I and II
Tc
TH
Antigen presentation
1.
2.
3. Signal
Cytokines ↔ Cytokine
receptors
Activation
Proliferation
Help or Killing
Induction of immunity
Importance of CD4+ T cells:
CD4+ T cells are central in providing help
for 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)
Second line of defense: Humoral factors
Humor = liquid
(From greek, 4 humors controlling health and mood: blood, phlegm, yellow and black bile)
Antibodies – specific
pathogen recognition
Complement system
– non-specific recognition
Reactive oxygen species
(ROS) – bactericidal activity
Antibodies
B cells – plasma cells - antibodies
T cell help for B cell activation
B cells – memory cells
Antibody classes
Antigen uptake
Preference for ”opsonized” bacteria
Outline
1.
2.
3.
4.
Cells and tissues of the immune system
Innate and adaptive immunity
Antigen presentation
Immunity vs. tolerance
What about ’endogenous’ challenges?
Cancer cells – tumor antigens
Immune reactions within self-tissues: autoimmunity
Discontinuation of immune responses
…and reactions to harmless environmental factors:
allergy (to food, pollen, fur etc.)
Immunity vs. Tolerance
The central issue:
immunity versus tolerance
The immune system has the tremendous task to
eliminate pathogens and eradicate arising tumours,
while preventing auto-reactive responses that are
harmful to the host.
In keeping with balancing this dual task, a complex
interplay between immune cells exists and many
stimulatory and inhibitory circuits are in place.
Deregulation of this intricate balance is directly
associated with human diseases, ranging from
inflammatory and autoimmune disorders to
infection and cancer.
Definitions
Immunity:
Effective clearance of all infectious agents and
tumours by immune cells
Tolerance:
Hindering of autoimmunity, and downregulation of immune responses after clearing
of pathogens
Discrimination between “self” and “non-self”
Every immune response depends on
regulation at the single-cell level
Different lines of tolerance induction
Regulation of tolerance is
two-legged:
1) Central regulation
(thymus, bone marrow)
2) Peripheral regulation
Central T cell tolerance
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
Peripheral tolerance
Ways of down-regulating immune responses in the
periphery:
 Anergy – no co-stimulatory signal
 Deletion - by apoptosis
 Active suppression (by naturally-arising or
peripherally induced Tregs)
Antigen presentation
1.
2.
3. Signal
Cytokines ↔ Cytokine
receptors
Activation
Proliferation
Help or Killing
Activation of CD4+ T cells requires
formation of the immunological synapse
Activation or inhibition? Importance of
co-stimulatory signals and cytokines
Central regulation
(thymus)
Activation of naïve T
cells requires at least a
moderate signal
iDCs induces weak
signals, leading to anergy
Killing by CTLs requires
strong signals
Activation of B cells
requires strong signals
Polarisering af immunsystemet
Central generation of Tregs:
The naturally-arising Tregs
Different Treg populations
Akbar et al. Nature Reviews Immunology 7, 231–237 (March 2007) | doi:10.1038/nri2037
Treg-mediated suppression:
In case of auto-reactive T cell clones
Treg-mediated suppression: during downregulation of responses to pathogens