Transcript An Overview of Immune System

An Overview of Immune System
Swapan K. Ghosh
Professor of Immunology
BASIC TENETS OF VERTEBRATE
IMMUNE SYSTEM
• Sophisticated Innate or non-specific immune
apparatus
– Sophistication due to ability to serve as a liaison
between Innate & Adaptive immunity
– Molecular pillar: complements, cytokines
• Super-sophisticated Acquired or specific immune
Apparatus
– Unique ability to specifically recognize extra- &
Intracellular antigens (non-self Mol.)
– Exhibits D S M T S
– Molecular pillars: Ig, TCR, MHC, cytokines
Three aspects of immune activation
• For specific adaptive immunity: Clonal selection
theory: to explain - selection of specific B and T
lymphocytes (Burnet’s hypothesis): P L E A S E
• For innate immunity: leads to expression of TOLL
receptors & then co-stimulatory molecules
– Infectious Non-Self theory (Janeway) to stimulate costimulatory molecules against pathogens
– Danger Model (Madzinger) to stimulate against any
stressful exposure
Innate immunity’s Pattern
Recognition Receptors (PRR)
•Reflections on self : immunity and beyond in
Science Vol.296 12 April 2002
SNS=self-nonself structure
Infectious Non-self model
• Infectious nonself (INS), by Janeway : APCs have
their own form of self/nonself discrimination :
they do not co-stimulate unless activated via PRRs
(receptors for evolutionarily distant infectious
non-self, i.e. the immune system has a
phylogenetic memory of infectious organisms).
The universe of antigens is split into 2 sets :
noninfectious self (set a) and infectious nonself
(set f). It tends to ignore noninfectious nonself (set
b - f).
Limitations of INS model
• It does not explain why viruses that do not
generate dsRNA stimulate immunity, why
transplants are rejected, what induces
autoimmunity, why tumors are sometimes
spontaneously rejected, or how nonbacterial
adjuvants, such as alum, work.
Danger model
• APCs are activated by endogenous cellular alarm
signals from distressed or injured cells. The universe of
antigens is split into 2 sets :
- Those associated with dangerous entities or
harmless ones, defining as dangerous anything that
induces stress or nonphysiological (lytic) cell death.
Dangerous entities may be self (set c) such as
mutations that lead to stress or inappropriate cell death
or inefficient scavenging; or
-Nonself, such as pathogens (set e), environmental
toxins (set d), and such. Set f would contain fetuses
and evolutionarily distant organisms that have PAMPs,
but that are not dangerous (e.g. symbiotic organisms,
well-adapted viruses).
PAMP recognition Receptors
• Toll-like receptors (TLRs) are Type 1
transmembrane proteins with an
extracellular LEU-RICH REPEAT (LLR)
and an intracellular TOLL/IL1 RECEPTOR
(TIR) domain. The originally discovered
TOLL receptor in Drosophila Melanogaster
was considered a maternal-effect gene
controlling dorsoventral axis formation in
embryo
Different TOLL Receptors
• TLR1 (expressed constitutively on many cell
types) binds to ?
• TLR2 (highly expressed in APCs (monocytes,
DCs, ..) and endothelial cells
• TLR3 (expressed on DCs) binds to dsRNA and its
synthetic analogue polyinosine-polycytidylic acid
(poly(I:C)).
• TLR4 (highly expressed in monocytes; weakly
expressed in neutrophils and basophils)
TOLL R continued
• TLR5 (highly expressed in monocytes and on the basolateral side of
intestinal epithelium; weakly expressed in neutrophils and basophils)
binds to flagelin FliC protein.
• TLR6(expressed constitutively on many cell types) binds to ?
• TLR7 (expressed in B cells and PDCs) binds to imidazoquinoline
immunostimulants.
No natural ligand is known.
• TLR8 binds to ?
• TLR9 (highly expressed in B cells and PDCs; weakly expressed in
monocytes, NK cells and T cells) binds to unmethylated
R1pR2CpGpY1pY2 DNA sequences (where R1 is a purine with
preference for G, R2 is a purine or T, and Y1 and Y2 are pyrimidines).
• TLR10 (higly expressed in B cells)
Innate Vs. Adaptive
• APCs cannot distinguish self from non-self
• They capture normal tissue antigens as well as non
self-antigens and present both to passing T cells
• In self-nonself models, T cells must be trained to
tell the difference between these foreign and self
antigens. Thymus does it.
• Both APC & B, T cells undergo recognition,
activation and execution phases.
Activation of APC
• Triggering TLRs on specialized APCs induces the expression of
costimulatory molecules on the cell surface, which is necessary for
the activation of naive T cells specific for antigenic peptides
expressed on the same APC in complex with MHC molecules.
• Because the costimulators are induced by PAMPs, their expression
on APCs flags the antigenic peptides presented by the same APC
as being of microbial origin and activates antigen-specific T cells.
• Self-peptides expressed and presented by these APCs are not
recognized as nonself, because T cells specific for these peptides
are eliminated during negative selection in the thymus. Thus
negative selection and microbial induction of costimulatory
molecules together ensure that the adaptive immune response is
generated against infecting pathogens but not against self-antigens
• TLR-mediated recognition is vital for the generation of TH1, but not
TH2 effector responses.
Dawning of Adaptive immunity
• Adaptive or acquired or specific immune system,
together with lymphoid tissue (a particular kind of
connective tissue), appeared abruptly among Vertebrata at
some point in the divergence of the class Chondrichthyes
(cartilaginous fishes) from Hyperoartia (cyclostomes),
where it is completely absent. Members of the subclass
Elastobranchii (elasmobranchs) are the oldest organisms
with Ig-like genes.
• The evolution of adaptive immunity appears to have been
made possible by the invasion of a putative
immunoglobulin-like gene by a retrotransposon encoding a
gene able to catalyze gene rearrangement (eg, RAGs)
APC & T-lymphocytes
• In an immune system poised for danger, the T cells
need only to distinguish APCs from everything else
• Resting T cells need 2 signals to be activated; signal
A from TCR binding to MHC/peptide and signal B
(co-stimulation) from an APC. It states that T cells
die if they receive signal A without signal B (leading
to tolerance) and become activated if they receive
both.
• Resting T cells can receive signal B only from APCs.
Interdigitating DCs (and, perhaps, macrophages) can
serve as APCs for both virgin and experienced T
cells, and B cells can re-stimulate experienced but
not virgin T cells.
T-cells
• Thymus educated involving MHC class 1 and
class II molecules
• CD4+ T-cells: MHC class II-mediated: Th1
(CMI) & Th2 (Humoral)– cytokine difference
• CTL: CD8+ T cells: Killer
• Aberrant lymphocytes: non-thymus educated NK
cells
• MHC CD1allele presents non-protein Ag to T cells
B-lymphocytes & T cells
• B-cells see native antigen, produce IgM
• Memory B-cells require T-help; produce IgG, IgA,
IgE; APCs play little role
• Igs are antibodies secreted by PC as well as
receptors on B-cells
• Naïve B-cells express two Ig receptors: IgM, IgD
• Memory B-cells express one Ig receptor, IgG,
IgA, IgE
B-cell characteristics
• B-lymphocytes: B1 and B2 cells: humoral
response
– B1:in peritoneum and cavities. not recirculating, they
are absent from lymph nodes, spleen and peripheral
blood. Not much hypermutable. Lack interaction with
T cells
– B-2 cell (conventional B cell)
– BCR consists Ig (for Ag recognition) plus Ig & Ig
(for signal transduction); Ig has premonition of what Ag
to recognize at the germ line
X-Ray Crystallograph of Ig
Ig Domains
Ig Gene rearrangement in a B-cell
Ig class switches
TCR genes
• Similar to Ig gene rearrangement, but
different chromosomes, different, V, D, J
&C
• Two types:  and  (majority)
• TCR complex: CD3 & -CD3 (signal)
• No somatic mutation
• Both chains undergo N-nucleotide addition
by TdT
Summary
• Specific gene rearrangements of B and T-cell
genes occur initially before antigen interaction
• Antigen promotes further differentiation
• Allelic exclusion of inherited genes ensure
specificity
• Antibody engineering produces humanized Ab for
treatment against all kinds of diseases
• The cells of immune system are also models for
studies of stem cell biology, mitosis, apoptosis,
and of course immunodiagnosis and vaccines