- Innate immunity relies on pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and Nod-like receptors (NLRs) to recognize pathogens. - TLRs and NLRs activate immune responses upon binding pathogen-associated molecular patterns. TLR4 recognizes LPS from gram-negative bacteria while TLR2 recognizes components from gram-positive bacteria. - Nod1 and Nod2 are intracellular NLRs. Nod1 detects peptidoglycan fragments from gram-negative bacteria containing meso-diaminopimelic acid while Nod2 detects muramyl dipeptide found in peptidoglycan of most bacteria. Binding of ligands activates NF-kB and MAPK

1. RECEPTOR
DIVERSITY OF
INNATE IMMUNITY
PRESENTOR :YVONNE WAITHERA MWAURA
SB11/JR/MN/14119/2022

2. Introduction
 Innate or non-specific immunity is the defense mechanism with which one is born with. They form the
first line of defense in immune response.
 Receptor is a protein molecule inside or on the surface of a cell that binds to a specific substance and
causes a specific effect in the cell.
 Although innate immunity lacks specificity, it can distinguish non-self from self. It has receptors that
activate immune response by both recognizing pathogens directly or signaling for a cellular response.
 These receptors are typically not clonally distributed; a given set of receptors will be present on all the
cells of the same type.
 The binding of pathogens to the receptors give rise to rapid response, which are put into effect without
delay imposed by clonal expansion of cells.

3. Differences between innate and adaptive immunity

4. Functions mediated by receptors of innate
immunity
 Receptors of the innate immune system mediate a number of different functions.
 Many are phagocytic receptors that stimulate ingestion of the pathogens they recognize.
 Some are chemotactic receptors, such as the f-Met-Leu-Phe receptor, which binds the N-formylated peptides
produced by bacteria and guides neutrophils to sites of infection.
 A third function, which may be mediated by some of the phagocytic receptors as well as by specialized signaling
receptors, is to induce effector molecules that contribute to the induced responses of innate immunity and
molecules that influence the initiation and nature of any subsequent adaptive immune response.

5. Receptors with specificity for pathogen surfaces
 The surfaces of microorganisms typically bear repeating patterns of molecular structure. The innate immune
system recognizes such pathogens by means of receptors that bind features of these regular patterns; these
receptors are sometimes known as pattern-recognition molecules.
 The mannan-binding lectin that initiates the MB-lectin pathway of complement activation is one such receptor, as
shown by structural studies of its binding. Pathogen recognition and discrimination from self is due to recognition
of a particular orientation of certain sugar residues, as well as their spacing, which is found only on pathogenic
microbes and not on host cells.
 Other members of the collectin family also bind pathogens directly and function in innate immunity. The collectin
C1q is able to bind directly to pathogen surfaces and initiate complement activation through the classical pathway.
In addition, other collectins are made in the liver as part of the acute-phase response, which will be described in
the last part of the chapter. The exact structures recognized by these other collectins have not yet been defined, but
all collectins have multiple carbohydrate-recognition domains attached to a collagen helix and are thought to bind
pathogen surfaces in a similar way to mannan-binding lectin.

7.  Phagocytes are also equipped with several cell-surface receptors that recognize pathogen surfaces directly. Among
these are the macrophage mannose receptor.
 This receptor is a cell-bound C-type lectin that binds certain sugar molecules found on the surface of
many bacteria and some viruses, including the human immunodeficiency virus (HIV).
 Its recognition properties are very similar to those of mannan-binding lectin and, like mannan-binding lectin, it is a
multipronged molecule with several carbohydrate-recognition domains. Because it is a transmembrane cell-surface
receptor, however, it can function directly as a phagocytic receptor.
 A second set of phagocytic receptors, called scavenger receptors, recognize certain anionic polymers and also
acetylated low-density lipoproteins. These receptors are a structurally heterogeneous set of molecules, existing in
at least six distinct molecular forms.
 Some scavenger receptors recognize structures that are shielded by sialic acid on normal host cells. These
receptors are involved in the removal of old red blood cells that have lost sialic acid, as well as in the recognition
and removal of pathogens. There are other recognition targets, many of which still need to be characterized.

8. Toll-like receptors
 The best-defined activation pathway of this type is triggered through a family of evolutionarily conserved
transmembrane receptors that appear to function exclusively as signaling receptors.
 These receptors, known as the Toll receptors, were first described in the fruit-fly. They appear not to recognize and
bind pathogens directly, but clearly are involved in signaling the appropriate response to different classes of
pathogen. In the fruit-fly, the Toll receptor itself triggers the production of antifungal peptides in response to
fungal infections, while a different member of the Toll family is involved in activating an antibacterial response.
 In mammals, a Toll-family protein, called Toll-like receptor 4, or TLR-4, signals the presence of LPS by
associating with CD14, the macrophage receptor for LPS.
 TLR-4 is also involved in the immune response to at least one virus, respiratory syncytial virus, although in this
case the nature of the stimulating ligand is not known.
 Another mammalian Toll-like receptor, TLR-2, signals the presence of a different set of microbial constituents,
which include the proteoglycans of gram-positive bacteria, although how it recognizes these is not known. TLR-4
and TLR-2 induce similar but distinct signals, as shown by the distinct responses resulting from LPS signaling
through TLR-4 and proteoglycan signaling through TLR-2.
 There are at least nine distinct proteins in this newly discovered family in mammals, and further functions of Toll-
like receptors may soon be revealed as mice lacking one or other of these proteins are produced and analyzed.

9. Nod-like receptors
 Nod1 and Nod2 were first discovered as mammalian members of the Ced4/Apaf-1 family of apoptosis
regulators .
 Nod1 and Nod2 are multi-domain proteins consisting of one or two CARD domains respectively, a centrally
located NOD domain followed by a number of C-terminal LRRs in contrast to apoptosis protease activating
factor-1 (Apaf-1), which contains C-terminal WD40 repeats.
 Nod1 and Nod2 orthologs are found across higher order vertebrates but are absent in insects or worms.
 Nod1 is widely expressed in many cell types and organs. Although Nod2 expression is believed to be more
restricted, it has been described in macrophages, dendritic cells, Paneth cells, keratinocytes, and epithelial
cells of the intestine, lung, and oral cavity .
 Both Nod1 and Nod2 are expressed in the cytosol, but more recently a fraction of Nod1 and Nod2 has been
shown to be associated with the plasma membrane.
 In the case of Nod2, point mutants that prevent membrane association exhibit a decreased ability to
activate downstream signaling. However, the same mutations are known to affect microbial recognition and
secondarily Nod2 activation, so the role of membrane localization in Nod2 signaling remains unclear.

10.  NLRs including Nod1 and Nod2 are thought to be kept in an inactive state by intra-molecular interactions.
 In the case of Nod2, a C-terminal fragment consisting of only the LRRs interacts with an N-terminal
fragment consisting of the CARD and NOD domains, when co-expressed in cells, an interaction which is
disrupted in the presence of the Nod2 bacterial ligand.
 Collectively, the results have suggested a model in which ligand recognition results in a conformation
change in the protein relieving these autoinhibitory intramolecular interactions and allowing NOD domain-
dependent nucleotide binding and oligomerization.
 However, evidence for a direct interaction between NLRs including Nod1 and Nod2 and their putative
ligands is still lacking, so it is possible that the activation of Nod1 and Nod2 by microbial stimulation is
indirect.

11. Mode of action
 Stimulation of Nod1 or Nod2 results in the activation of NF-κB and MAPKs, which drive the transcription of
numerous genes involved in both innate and adaptive immune responses.
 Both Nod1 and Nod2 sense bacterial molecules produced during the synthesis, degradation, and remodeling
of PGN, a major component of bacterial cell walls.
 PGN is a polymer composed of glycan chains of alternating N-acylglucosamine (GlcNAc) and N-
acetylmuramic acid (MurNAc) units cross-linked to each other by short peptides. The cross-linking of two
parallel glycan chains is mediated by stem peptides that can be further linked by bridging amino acids.
 Nod2 senses muramyl dipeptide (MDP), which is found in the PGN of nearly all Gram-positive and Gram-
negative organisms, whereas Nod1 recognizes meso-diaminopimelic acid (meso-DAP)-containing PGN
fragments. DAP is an usual amino acid residue that is unique to PGN from most Gram-negative bacteria and
certain Gram-positive bacteria, including the genus Listeria and Bacillus species.
 Analysis of synthetic compounds revealed the dipeptide γ-D-glutamyl-meso-DAP (iE-DAP) as the core motif
that is sufficient to trigger Nod1 activation. Nod1 and Nod2 null cells or mice are unable to activate NF-κB
and MAPKs as well as to produce cytokines and chemokine in response to ligand stimulation.

12.  Nod1 and Nod2 are involved in the sensing of numerous pathogenic bacteria. Nod1 detects the Gram-
negative Shigella flexneri, enteroinvasive Escherichia coli, Chlamydia, Pseudomonas
aeruginosa, Campylobacter jejuni , and Helicobacter pylori