Documente Academic
Documente Profesional
Documente Cultură
1. Autoimmune diseases
2. Increased susceptibility to infection
2. Toll-like receptors (TLR)
Identification Of The Invader
On the organism:
Pathogen associated molecular patterns (PAMPS),
On the effector cells:
Pattern recognition receptors
(PRR).
2. Toll-like receptors (TLR)
Toll-like receptors (TLRs) are transmembrane
proteins that serve as a key part of the innate
immune system considered pattern recognition
receptors (PRRs), binding to pathogen-associated
molecular patterns (PAMPs). Their function is the
recognition of pathogens and the activation of
immune responses directed against those pathogens.
PATHOGEN-ASSOCIATED MOLECULAR
PATTERNS (PAMPS)
1. Must be shared by large groups of pathogens and thus
must represent general patterns & non-specific structures.
2. Must be conserved products of microbial metabolism
which are not subject to antigenic variability.
3. pathogens cannot "change" them because they are essential
for the survival or pathogenicity of the microorganisms.
Any attempts to change them could be lethal to the
microbe or render it nonpathogenic.
4. The recognized structures must be absolutely distinct from
self-antigens. The major consequence of this requirement
is the ability of the innate immune system to discriminate
between self and non-self.
GRAM
POSITIVE
GRAM
NEGATIVE
PAMPS
PAMPS recognized by the innate immune system:
Cell wall constituents or microbial nucleic acids
1. Lipopolysaccharide (LPS) from the gram -ve cell wall.
2. Peptidoglycan found abundantly in the gram-positive cell wall and to a
lesser degree in the gram-negative cell wall .
3. Lipoteichoic acids in the gram +ve bacterial cell walls
4. Lipoarabinomannum (LAM) in mycobacterial wall
5. Mannose-rich glycans (common in microbial glycoproteins and
glycolipids but rare in those of humans).
6. Flagellin found in bacterial flagella.
7. Pilin from bacterial pili.
8. Bacterial and viral nucleic acid. Bacterial and viral genomes contain a
high frequency of unmethylated cytosine-guanine dinucleotide
sequences (a cytosine lacking a methyl or CH3 group and located
adjacent to a guanine). Mammalian DNA has a low frequency of
cytosine-guanine dinucleotides and most are methylated.
9. Double-stranded RNA unique to most viruses.
10. Lipoteichoic acids, glycolipids, and zymosan from yeast cell walls.
Pattern-recognition Receptors (PRR)
To recognize microbial molecules,
various body defense cells have on
their surface a variety of receptors
called
Pattern-recognition Receptors
capable of binding specifically to
PAMPS
CLASSIFICATION OF PRR
CLASSIFICATION OF PRR
ENDOCYTIC PRR
Found on the surface of phagocytes and
promote the attachment of microorganisms
to phagocytes and their subsequent
engulfment and destruction.
CLASSIFICATION OF PRR
Signaling PRR
Binding of microbial molecules to the
receptor promotes the synthesis and
secretion of intracellular regulatory
molecules such as cytokines that is crucial
to initiating innate immunity and adaptive
immunity.
1. Toll-like receptors
2. CD14.
3. NOD (nucleotide-binding oligomerization
domain proteins)
CLASSIFICATION OF PRR
Secreted PRR
Secreted pattern-recognition receptors. These
bind to microbial cell walls and enable them to
be recognized by the complement pathways
and phagocytes.
E.g. mannose-binding lectin is synthesized by
the liver and released into the bloodstream. MBL
recognizes carbohydrate patterns, found on the
surface of a large number of pathogenic micro-
organisms, including bacteria, viruses, protozoa
and fungi.
2. Toll-like receptors (TLR)
A series of Signaling PRR play a
major role in innate immunity and
the induction of adaptive immunity.
THE TOLL
Mammalian (homologues) TLRs owe their
name to a closely related receptor called
Toll receptor, first identified in Drosophila
in 1988.
TOLL: german word of fantastical or
strange.
They recognize and bind to PAMPS
TLR Responding to Lipopolysaccharide (LPS)
from the Gram-Negative Cell Wall
2. Toll like receptors (TLR)
TLRs belong to the IL-1 receptor family.
Linked to a signaling pathway that involves the
IL-1 receptor-associated kinase-4 (IRAK-4)
transcription NF-κB .
Upon binding of the extracellular ligand
recognition domain to PAMPs, changes in the
intracellular domain result in initiation of
signaling events leading to
Inflammatory responses and/or
Release of antimicrobial agents.
TLRs are found both on the surface and within the
phagolysosomes of phagocytes.
PAMPs Binding to TLRs on Macrophage
The TLRs found in the membranes of the phagosomes
Recognizing Viral Double-Stranded RNA after phagocytosis
2. Toll like receptors (TLR)
ROLE IN INNATE IMMUNITY
1.The binding of a microbial molecule to its TLR
transmits a signal to the cell's nucleus inducing the
expression of genes coding for the synthesis of
cytokines. Many of the TLRs, especially those that bind
to BACTERIAL AND FUNGAL cell wall components
stimulate IL -1, TNF-alpha, and IL-8. triggering innate
immune defenses such as inflammation, fever, and
phagocytosis in order to provide an immediate
response against the invading microorganism.
2.Most of the TLRs that bind to VIRAL components
trigger the synthesis of interferons via activation of
interferon regulatory factor 3 (IRF-3) that block viral
replication within infected host cells..
2. Toll like receptors (TLR)
ROLE IN ADAPTIVE IMMUNITY
4 Positive
chemotaxis
Inflammatory
chemicals
diffusing from
the inflamed
site act as
chemotactic
1 Neutrophils agents
enter blood
from bone 3 Diapedesis
marrow 2 Margination
Endothelium
Capillary wall
Basal lamina
INNATE IMMUNITY ADAPTIVE IMMUNITY
PAMP
Trigger (Pathogen-associated Specific antigens
molecular pattern)
Memory No Yes
Communication Cytokines
Complement
Complement
Antigen presentation
Effectors Antigen presentation
Antibodies
Phagocytosis
Cytotoxicity
References
Dr Samia Esmat Professor of Dermatology Cairo
University
Bolognia: Dermatology, 2nd &3rd ed.
Immense Immunology Insight
Immunity and the immune system Dr. Angelo Smith
WHPL