Download Effector mechanisms of immunity

Effector mechanisms of
immunity
Jan Żeromski
2013/2014
Nobel 2011 in physiology and medicine –
devoted to key findings in immunology
prof. Bruce Beutler
(USA)
prof. Jules A.
Hoffmann
(France)
They determined conditions of activation of
nonspecific (innate) immunity and detected
close links between the induction of infection
and the reactivity of Toll-like receptors at
molecular level
prof. Ralph Steinmann
(USA)
Detected dendritic cells and
determined their function as
antigen presenting cells (APC).
POINTS TO BE DISCUSSED
• Cytokines, their receptors and effector
function
• Macrophages
• Granulocyte effector functions
• Cytotoxic T cell function
• Natural killer cells and natural killer T cells
• Effector action of antibodies
• Antibody dependent cell mediated cytotoxicity
(ADCC)
• Complement functions
GENERAL PROPERTIES OF
CYTOKINES (CT)
• Production induced by: a) microbial products
in innate immunity, b) foreign antigens in
acquired immunity, c) own metabolites
• Short secretion – transient and unstable
activation of transcription
• Lack of stability of mRNA
• Pleiotropic action on various cells, organs
and systems
FEATURES OF ACTIVATED
MACROPHAGES
• Increased expression of MHC molecules
• Increased expression of costimulators (B7-1 and
B7-2, CD40)
• Secretion of cytokines (TNF, IL-1, IL-12, IL-18,
IFNγ, PDGF)
• Secretion of chemokines
• Expression of enzymes catalysing the production
of microbicidal substances in phagolysosomes
(ROI, nitric oxide, proteolytic enzymes)
POTENTIAL MECHANISMS OF
CYTOTOXICITY OF MYELOID CELLS
•
Cationic proteins (defensins): small
peptides, comprise up to 50% of the granule
proteins. Form ion-permeable channels in
lipid bilayers of bacteria
•
Lysozyme, C3a
•
BPI (bactericidal/permeability increasing
factor)
POTENTIAL MECHANISMS OF
CYTOTOXICITY OF MYELOID CELLS-2
•
Hydrolases
•
Reactive oxygen intermediates (ROIs)
•
NO and reactive nitrogen intermediates
(RNI)
•
Tumor necrosis factor-alpha (TNF-alpha)
NET-osis – novel mechanism of killing
bacteria by neutrophils
• Neutrophils form network-like structures, consisting of
nucleic acids, histones and enzymes,
These nets have the ability of
immobilizing and killing pathogens
• Neutrophils released from the net undergo apoptosis
• Net may be formed only by fully mature and intact cells
MAIN CYTOTOXIC AGENTS OF
LYMPHOCYTES
• Perforin, granzymes (fragmentins)
(induction of apoptosis)
• Lysosomal enzymes (proteolysis, induction
of apoptosis)
• Granulolysin (lipid binding protein,
membrane damage)
• Fas - FasL (induction of apoptosis)
MAIN CYTOTOXIC AGENTS OF
LYMPHOCYTES - 2
• TNF (tumor necrosis factor)
• LT-alpha (lymphotoxin alpha)
• TRAIL (TNF-related apoptosis inducing
ligand)
• Leukoregulin (sensitizer for cytotoxic
action)
• ATP, ROI, RNI (increased membrane
permeability)
CYTOTOXIC FACTORS OF LYMPHOCYTE
GRANULES
• Granzymes (fragmentins) – serine
proteases.Penetrate cell through perforin
channels. Induce apoptosis. Hydrolize
extracellular matrix components
• Granulolysin – belongs to saponins, lipid
binding proteins. Destroys cell and
mitochondrial membranes.
CTL EFFECTOR FUNCTIONS
1. Cytotoxicity
– Granule exocytosis pathway (perforin,
granzymes)
– Fas /FasL pathway, TNF/TNF-R (?)
2. Inflammation and immunity
–
–
–
–
Cytokine and chemokine production (IFN-,
TNF-, MIP1, MIP1, RANTES)
Macrophage activation
Direct antiviral effects
CYTOTOXIC FACTORS OF LYMPHOCYTE
GRANULES
• Cytolytic granules are the product of Golgi
apparatus
• Perforin – glycoprotein (555 aminoacids),
similar to C6-C9 complement components,
Ca ions dependent; its polymerization leads
to formation of channels in cell membrane
CYTOTOXIC T LYMPHOCYTES (1):
Provide partial protection from:
• Most viruses
• Some bacteria (e.g. Listeria monocytogenes,
Mycobacterium tuberculosis)
• Some protozoa (e.g. Trypanosoma cruzi,
Toxoplasma gondi, Plasmodium falciparum
• Tumors
CYTOTOXIC T LYMPHOCYTES (2):
Contribute to or cause:
1. Hypersensitivity reactions such as
tissue damage in several infectious
diseases,
2. Some autoimmune diseases,
3. Organ transplant rejection,
4. Graft-vs-host disease.
FEATURES OF NK CELLS
• Granular lymphocytes, express CD16 and
CD56, but NOT CD3
• Spontaneously cytotoxic to certain tumors
and virally infected cells
• Found in the blood, spleen, lung, liver, GI
tract and uterine decidua
• Activated by IL-2, IL-12, IL-15 or IL-18
FEATURES OF NK CELLS -2
• Subsets express killer immunoglobulin-like
receptors (KIR) for class I MHC antigens.
Long ones possess ITIM (immunoreceptor
tyrosine based inhibitory motif) domain
(inhibitory), while short ones – have ITAM
domain providing activatory (death) signal
• Target cell lysis via perforin/granzymes
pathways and receptor induced apoptosis
Mechanisms of NK cell cytotoxicity
• Release of cytokines (IFN gamma, TNF and
others)
• Release of cytolytic granules for lysis of
infected or transformed cells
• Induction of target cell death through cell
surface receptors
RECEPTORS AND LIGANDS OF
NK CELLS
Receptors
• immunoglobulin-like
receptors
Ligands
• Class I HLA-C alleles
• C-type lectins - CD94NKG2A-F in man
• HLA-E with HLA-A:C
leader peptide
• Natural cytototoxicity
receptors
• Influenza hemaglutinin,
C-type lectin
NKT (CD3+, CD56+) cells
• Recognize antigens in the context of CD1d (one of five
nonpolymorphic MHC class I glycoproteins (CD1a-e),
• CD1d molecules present nonprotein and glycolipid
antigens (components of mycobacterial walls)
• NKT cells are few in the blood (0,3%) but abundant in
liver (4% of all lymphocytes)
• They secrete IFN-γ, TNF, but may also IL-4, IL-10,IL-13
Cytotoxicity – CD1d restricted, either Fas mediated or
perforin dependent
EFFECTOR FUNCTIONS
OF ANTIBODIES
• Neutralization of microbes (bacteria and viruses)
• Inactivation of toxins
• Opsonization of microbes with subsequent
phagocytosis
• Antibody dependent cellular cytotoxicity (ADCC)
• Activation of classical pathway of complement
(IgG, IgM)
• Mast cell and basophil degranulation (IgE)
CLASS SWITCHING AND AFFINITY
MATURATION ENHANCE THE
PROTECTIVE FUNCTIONS OF ANTIBODIES
• Heavy chain class switching –cf. From IgM to
IgG or IgA – results in production of antibodies
with distinct Fc regions, ready to perform various
effector functions,
• Affinity maturation – prolonged antigen
stimulation leads the production of antibodies with
higher and higher affinities for the antigen. This
results in increased ability of antibodies to
neutralize or eliminate microbes,
• Avidity – the sum of affinity receptors
ANTIBODY DEPENDENT CELLMEDIATED CYTOTOXICITY (ADCC)
• Is due to Fc receptor for IgG (CD16) on effector cell
• Fc receptor on effector cell binds Fc fragment of
antibody bound to target cell, what enables direct
contact between effector and its target
• Cells possessing Fc receptor are called killer cells (Kcells).They include NK cells, T cells, monocytes,
eosinophils, some other myeloid cells (polymorphs?)
THANK YOU!