THE INNATE IMMUNITY

The innate immunity is the first line of defence against antigens. It is found in all
multicellular organisms, it is phylogenetically very old, universal and evolutionarily
conserved. Its receptors are fixed in the genome, they do not undergo rearrangement.
Moreover, the innate immune system is not clonal, so its activation is linear. The cells
of the innate immunity recognise conserved molecular patterns are not antigen
specific.
Innate immunity can be divided into 3 components: barriers, molecules and cells.

Barriers can be mechanical, chemical or biological.

Molecules can be natural autoantibodies, soluble antimicrobials (e.g. defensis*),
or part of the complement system.
o Defensins are amphipathic molecules that have clusters of positively
charged aa side chains and hydrophobic aa side chains. They cause the
formation of membrane wormholes. Examples of defensins are lysozyme
(peptidoglycan N-acetylmuramylhydrolase) and lactoperoxidase in saliva.
o The complement system is a system of serine proteases present in
inactive form all over the body. Once they are activated, they initiate a
cascade by cleaving and activating other complement components.
CELLS> there are several types:
o Monocytes and mononuclear phagocyte system (MPS). Monocytes are
macrophages; they can be either tissue resident or recruited. Tissue
resident macrophages are part of the inherent cells of an organs
parenchyma; they have less flexible programming that is determined
during ontogenesis; they have a direct lineage commitment that is
determined by specific transcription factors and epigenetic
modifications. Recruited macrophages are patrolling cells that get
into the site of infection after they sense signals; they have flexibleprogramming, that is to say their phenotype is driven by
microenvironmental signals, which means that cytokines, transcription
factors and epigenetic changes modulate phenotypic and functional
plasticity.
o DCs are phagocytic cells found in peripheral tissues in an inactive form; in
this case theyre called immature. When they encounter a pathogen, they
migrate through lymph vessels to secondary lymphatic organs, where
they become mature DCs in the deep cortical regions. When they are
immature, they have high phagocytic activity, which they lose when they
mature. In the cortex of II lymph organs, they present antigens to T cells.
There are four main types: cDC 1, cDC 2, pDC, monocyte-derived DC.
Dendritic Cells can direct differentiation of T cells into their different
subsets.
o Innate Lymphoid Cells (ILCs) are cells of the lymphoid lineage. They have
receptors commonly found on lymphoid progenitors, but they lack
markers found in mature lymphoid cells. They are strategically placed in
the GI tract and represent an optimal early defence against bacteria,
parasites and viruses; they are characterised by plasticity and have the

ability of secreting large amounts of cytokines. Their plasticity can result

in distinct subsets of cells that derive from a common precursor, but the
ILCs themselves do not give rise to further progenitor (precursor) cells.
ILC subsets ally with T cell subsets in the immune system against
microbes; their diversity in cytokine production is comparable to that of T
cells, but they are independent of antigen-specific interactions. The ILCs
are divided into 3 subtypes (subsets): type (group) I, type (group) II, type
(group) III.
NATURAL KILLER CELLS (NKs) can be considered part of the ILCs.
They are large, granular lymphocytes that have neither B nor T cell
receptors, and whose function is to kill virus-infected and tumour
cells. They possess activating and inhibitory receptors; this is
important because if there were no inhibitory receptors, NKs might
bind to autosomal cells and kill them. However, thanks to these
receptors, NKs can discriminate the bodys own cells from harmful
ones, by recognizing MHC I molecules. These cells have mainly four
courses of action: 1) no response 1 > the target cell does not have
MHC nor activating ligands, so the NK doesnt act; 2) no response 2
> the target cell has MHC I, to which the NK inhibitory receptor
binds, so the NK is inhibited; 3) NK attacks target cell > the target
cell has no MHC I but possesses an activating ligand so it
stimulates the NK through activating receptors; 4) signal balance >
the target cell has both MHC I and activating ligands, so the action
of the NK will be determined by the sum of inhibitory and
stimulatory signals. Activating Receptor: NKG2D; Inhibitory
Receptor: NKG2A.
Neutrophil Granulocytes derive from CMP GMP Myeloblast
Promyelocyte Myelocyte Metamyelocyte Neutrophil. They have
mainly three courses of action/killing mechanisms: 1) phagocytosis
intravesical killing (O-dependent/-independent)/degradation by lysosomal
enzymes; 2) degranulation frustrated phagocytosis; 3) NETs neutrophil
extracellular traps: extracell DNA traps. When they invade a tissue PUS
will form, which consists of live and dead neutrophils and tissue debris.
1) INTRAVESICAL KILLING 1 (O-dependent): can be peroxidasedependent or, independent. In the peroxidase-dependent
pathway, lysosomes fuse with phagosomes and release their
contents (peroxidase) into the phagosome, which will degrade the
bacterium. In the independent path, an NADPH2 oxidase on the
phagosome membrane, forms a superoxide from O2, which will
degrade the bacterium. INTRAVESICAL KILLING 2 (Oindependent/NO-dependent): TNF and IFN-gamma will activate
pathways leading to activation of NOS (NO synthase) which
together with H4biopterin will transform O2 and L-arginine into
Citrulline and NO; NO will destroy the pathogen.
2)FRUSTRATED PHAGOCYTOSIS: macrophages and neutrophils, in
particular, play a central role in the inflammatory process by
releasing proteins and small molecules that are inflammatory
mediators that control infections, but can damage host tissue. In
general, phagocytes aim to destroy pathogens by engulfing them

and subjecting them to a battery of toxic chemicals present in

phagolysosomes. If a phagocyte fails to engulf its target, these
toxic chemicals can be released into the extracellular environment
(frustrated bitch). As these agents are also toxic to the cells, they
can cause extensive damage to host cells and tissues.
3) NETs: networks of extracellular fibres primarily composed of DNA
from neutrophils which bind pathogens. Neutrophils release
granule proteins and chromatin to form an extracellular fibril
matrix called through an active process, upon signalling of specific
pathogenic agents. NETs disarm pathogens through antimicrobial
proteins such as neutrophil elastase and histones, which are bound
to DNA.

SURFACE RECEPTORS OF PHAGOCYTES

They are divided into opsonic and pattern recognition receptors (PRRs). Opsonic
receptors are further divided into Fc and complement receptors.

Opsonic receptors: opsonisation is the process of facilitation of phagocytosis by

binding of either an antibody or a complement protein to the antigen.
Phagocytic cells can thus engulf the pathogen by binding to the antibody or the
complement protein through Fc and/or complement receptors. Fc receptors bind
to the Fc (fragment crystallisation) region of antibodies. There are several types
of Fc receptors:
o FcR: binds IgG, facilitates phagocytosis (e.g. FcRI), and may suppress
functions of B cells (FcRIIb).
o FcR: binds IgE, high affinity form (FcRI) is on mast cells and basophils,
plays a role in allergy.
o PolyIg Receptor: binds polymeric antibodies (IgA), it is expressed on
several glandular epithelia, and mediates transcytosis of polymeric Igs
through the epithelium of the mucous membrane.
o FcRn (neonatal): binds IgG, it is important in mediation of the passive
humoral immunity transfer from mother to fetus, also by protecting IgG
from degradation.
Pattern Recognition Receptors: they recognise determinate patterns in foreign
(pathogenic) molecules, called PAMP. There are three types: 1) membrane PRR;
2) secreted (soluble) PRR; 3) intracellular PRR.
o 1) They can be: lectin, NK cell, scavenger, complement, or toll-like
receptors. TLRs are particularly important; they have horse- shoe shape,
Leu-rich repeats, and are much conserved structures. Ligand binding
induces signal transduction: MyD88 adaptor binding, Ser/Thr kinase
cascade, phosphorylation of lkB, lkB degradation, lkB binds NFkB, NFkB
translocation to nucleus, expression of costimulatory molecules (B7) and
cytokines.
o 2) There are various types: C-type lectins (MBL, C1q, etc), lipocalin,
mindin, pentraxins (SAP, CRP), defensins, cationic peptides,
cathelicidines, and lipid transfer proteins.
o 3) Intracellular (cytosolic) PRRs, they can be Nod-like Receptors (NLRs),
for intracellular bacteria and PG recognition, or RIG-I-like Receptors
(RLRs), for intracellular viruses and foreign dsDNA/helicase domain

recognition. NLRs bind with pro-caspase 1 either through teir own

inherent CARDs (caspase activation and recruitment domain) or via the
CARDs of adaptor protein ASC and together form the INFLAMMASOME, a
multiprotein oligomer that promotes the maturation of inflammatory
cytokines IL-1beta and IL-18. Both PAMPs and DAMPs can induce
inflammasome activation.