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Doctoral Seminar
Title: Neuropeptide Y (NPY) and The Immune System
Presented by: M. Sh. Mojadadi
Advisor: Dr. A. Zavaran
Outline

Overview of the NPY family of peptides (NPY, PYY and PP) and their
receptors

Biological functions of the NPY family of peptides

Distribution of NPY family receptors

NPY and the immune system (the innate and adaptive immunity)

NPY in immune disorders (Autoimmunity and Allergy)
Overview of the NPY family of peptides (NPY, PYY and PP) and their receptors
The NPY family of peptides (NPY, PYY and PP)

NPY and its related peptides, peptide YY (PYY) and pancreatic polypeptide
(PP), are a highly conserved family of genes and proteins.

Chromosomal location: NPY: 7, PYY and PP:17

The NPY family of peptides consist in vertebrates of 36 amino acids.

All peptides have a carboxyterminal amide group.

These peptides regulate fundamental cellular processes of growth, metabolism
and cell-cell communication.
Overview of the NPY family of peptides (NPY, PYY and PP) and their receptors
The NPY family of peptides (NPY, PYY and PP)

Pancreatic polypeptide (PP) was initially discovered in the chicken in 1975.

NPY and peptide YY (PYY) were initially discovered in the pig in 1982.

NPY occurs predominantly in the central nervous system and in peripheral nerves,
primarily in blood vessels.

The most prominent effects of NPY in mammals are vasoconstriction, stimulation
of appetite, and influence on circadian rhythm, pain, and the release of pituitary
hormones.

PYY is primarily produced in gut endocrine cells and is released after meals
contributing to inhibition of gut motility and pancreatic secretion.

PP is released from pancreatic F cells after meals and shares the effects of PYY by
reducing pancreatic secretion and gut motility.
Overview of the NPY family of peptides (NPY, PYY and PP) and their receptors
The NPY family of peptide receptors

Five Y receptor subtypes exist in most mammals: Y1, Y2, Y4, Y5 and Y6.

They belong to G-protein-coupled receptors family and seem to function
primarily by inhibiting cAMP accumulation.

Chromosomal location: Y1, Y2 and Y5: 4, Y4: 10 and Y6: 5

In the periphery, Y1 mediates vasoconstriction, and in the hypothalamus, along
with Y5, it stimulates food intake.

In contrast to Y1 and Y5, the subtypes Y2 and Y4 inhibit food intake.

Subtype Y2 also stimulates angiogenesis.
Biological functions of the NPY family of peptides
Introduction

Pancreatic polypeptide (PP) was the first member of the NPY peptide family to
be discovered.

NPY was first isolated by Tatemoto and Mutt from pig brain.

The final member of these peptide family was isolated from preparations of
pig intestine and called peptide YY (PYY).

While NPY is primarily localized to neurons and PP is found mainly in
endocrine pancreas, PYY is found in both endocrine cells and neurons.

The hairpin-like three-dimensional structure has been called the PP-fold is
present in all three peptides.
Biological functions of the NPY family of peptides
Introduction

When comparing the amino acid sequences from a variety of mammals, only
two of the 36 amino acids of NPY are variable.

On the other hand, the PYY sequence exhibits eight variable amino acids
between different orders of mammals.

PP is the least conserved peptide of NPY family.

Despite the limited conservation observed in the PP and PYY amino acid
sequences, the general three-dimensional structure is maintained across a wide
variety of species indicating its potential importance in function.
Biological functions of the NPY family of peptides
NPY functions

The NPY gene is located on human chromosome 7 at the locus 7p15.1.

It is composed of four exons and results in the synthesis of a 97 amino acid prepro NPY.

Prepro NPY is proteolytically processed into the C-terminal peptide of NPY
(CPON) and NPY.
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The C-terminal amidation of NPY is essential for its biological activity.

NPY is further processed to NPY3-36 and NPY2-36 by two enzymes, dipeptidyl
peptidase IV (DPPIV) and aminopeptidase P, respectively.
Biological functions of the NPY family of peptides
NPY functions

In the rat brain, NPY is found in numerous brain regions including the
hypothalamus, amygdala, hippocampus, cerebral cortex.

The adrenal medulla is the primary source of circulating NPY.

NPY is abundant in peripheral neurons including sympathetic neurons where it is costored and co-released with norepinephrine (NE).
Biological functions of the NPY family of peptides
NPY functions

The biological functions of NPY include:
1: The most potent orexigenic peptides known. when injected ICV it induces food intake with
a preference for carbohydrate-rich food.
2: Other centrally mediated effects of NPY include decreased thermogenesis,
anti-convulsant activity, anxiolysis and modulation of cognition.
3: NPY deficient mice were found to have an impaired development of neurons in the olfactory
epithelium suggesting a role in neuronal development.
4: NPY is frequently co-localized with noradrenaline (NA) in sympathetic nerves and enhances
NA-mediated vasoconstriction, especially upon strong stimulation.
5: NPY can act as an antinociceptive peptide, probably through inhibition of substance P
release in the dorsal horn of the spinal cord.
Biological functions of the NPY family of peptides
PYY and PYY3-36 functions

The human PYY gene are found 10 kb apart from PP gene on chromosome 17q21.1.

Like NPY, the PYY gene is organized with four exons and three introns.

The rat preproPYY sequence is 98 amino acids.

Like NPY, PYY is cleaved by dipeptidyl peptidase to the 3–36 fragment that is thought
to be the principal active circulating peptide.

PYY is found primarily in the L cells of the gastrointestinal tract with the highest
concentrations found in the rectum followed by the ileum and the colon.
Biological functions of the NPY family of peptides
PYY and PYY3-36 functions

PYY is released in the gastrointestinal (GI) tract in response to meals. Its biological
effects include:
1: Inhibition of gut motility
2: Inhibition of fluid and electrolyte secretion in the intestinal tract.
3: Inhibition of pancreatic secretion
4: vasoconstriction
5: Peripherally administered PYY3-36 decreases food intake in both human and rodents.
Biological functions of the NPY family of peptides
PP functions

The human PP gene are found 10 kb apart from PYY gene on chromosome 17q21.1.

PP is almost exclusively expressed in endocrine pancreas and is released in response
to meals. produces its biological effects mainly in the gastrointestinal tract, including:
1: Inhibition of pancreatic secretion
2: Inhibition of intestinal motility
3: Inhibition of ileum contractions
4: Inhibition of gastric emptying
5: Peripherally administered PP inhibits food intake.
Distribution of NPY family receptors
Introduction

The human NPY-family peptides bind to four receptors, namely Y1, Y2, Y4 and Y5.

They all belong to the G-protein coupled receptor (GPCR) superfamily.

Some species including mouse have an additional receptor (y6) that is non-functional in
humans and absent in rats.

NPY and PYY bind Y1, Y2 and Y5 with similar high affinities.

On the other hand, Y2 binds truncated versions of NPY and PYY such as PYY3-36 and
NPY13-36 with similar affinity as the native peptides

PP binds to Y4 with higher affinity than NPY and PYY and has moderate affinity for Y5.
Distribution of NPY family receptors
Y1 receptor

The Y1 receptor was the first NPY receptor to be cloned.

The gene for Y1 is located in a cluster together with Y2 and Y5 on human
chromosome 4q31.

Full length NPY and PYY are potent agonists at Y1 whereas PP and C-terminally
truncated NPY/PYY fragments display lower affinity.

The Y1 receptor is involved in the feeding response of NPY.
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Most of the vascular effects of NPY and PYY are transduced via the Y1 receptor.

Antinociception of NPY through inhibition of substance P release are mediated by
Y1.
Distribution of NPY family receptors
Y1 receptor

This first indication for the expression of the Y1 receptor on immune cells was
further substantiated by De la Fuente et al (1993) who demonstrated binding sites
for radiolabeled NPY on peritoneal murine macrophages.

A more detailed investigation on this matter was conducted by Petitto et al.

They successfully cloned a Y1 receptor from human splenic lymphocytes, which
displayed a 100% sequence homology upon comparison to the Y1 receptor cloned
from the frontal cortex.

The Y1 receptor for NPY is widely expressed on leukocytes, including T, B cells
and APCs such as DCs and macrophages.
Distribution of NPY family receptors
Y2 receptor
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Originally, the Y2 receptor was identified using vascular preparations.

The Y2 receptor gene codes for a 381 amino acid protein that is located close to
the Y1 gene on chromosome 4.
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The Y2 receptor is mainly located presynaptically where it acts as an autoreceptor
inhibiting further release of neurotransmitter.

Y2 specific agonists increase blood pressure.
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In pig spleen, a Y2 specific agonist evoked potent vasoconstriction.
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The Y2 receptor is important in the feeding response to NPY.
Distribution of NPY family receptors
Y2 receptor
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The Y2 receptor is expressed on the surface membrane of neutrophils.

Nave et al. have found that NPY enhances the adherence of rat peritoneal
macrophages activated with LPS in vitro and in vivo, with NPY Y2 receptor
mediating this effect.
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Parallel activation of both the Y1 and the Y2 receptor modulates phagocytosis of
gram-negative bacteria.
Distribution of NPY family receptors
Y4 receptor
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The third Y receptor to be identified by cloning had high affinity for PP.
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The most interesting feature of the Y4 receptor may be the low degree of
sequence identity between species (only 75% homology when comparing the rat
and human sequences).
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Many of the GI effects produced by PP, like rabbit ileum contractions are
mediated by Y4 receptor.
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Y4 agonism (PP) may serve as a potential inhibitory signal on food intake.
Distribution of NPY family receptors
Y5 receptor
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the Y5 receptor is highly conserved (88–90%) between orders of mammals.
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The Y5 receptor mediates the NPY feeding effects.
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Other effect of NPY that is mediated by the Y5 receptor are reproduction through
inhibition of luteinizing hormone release.
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The Y5 receptor is expressed on the surface membrane of neutrophils.

The production and secretion of highly reactive oxygen species from neutrophil
can be inhibited by activating the Y5 receptor.
NPY and the immune system
Introduction

It is now well established that the immune system and the nervous system
communicate functionally with each other.
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A major pathway for this bidirectional interaction between the nervous and the
immune system is provided by the sympathetic nervous system (SNS).

Although earlier studies focused mostly on the catecholamines, more recent
work has established that other sympathetic transmitters, such as neuropeptide
Y (NPY), also play a significant role within the neuroimmune crosstalk.
NPY and the immune system
NPY containing nerves in lymphoid organs

For role of NPY in neuroimmune crosstalk it is necessary the presence of NPY
containing nerve fibers in primary and secondary lymphoid organs from which NPY
can be released within the local immunological microenvironment.
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The presence of sympathetic fibers innervating lymphoid organs is well documented.

Several of these not only contain catecholamines, but also store NPY.

NPY+ sympathetic nerves supply lymph nodes in a variety of mammalian species
(guinea pig, rat, cat, pig, mouse and human).
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NPY+ nerves also innervate other important lymphoid organs, such as the thymus
and the bone marrow.
NPY and the immune system
NPY containing nerves in lymphoid organs

Electron microscopy studies revealed that NPY+ nerve terminals form close contacts
with lymphocytes and macrophages in the marginal zone of the rat spleen.

Thus, the presence of NPY containing fibers in lymphoid organs and the release of
NPY within the local microenvironment allows for a direct interaction between NPY
and immune cells.
NPY and the immune system
NPY receptors in lymphoid organs

If NPY truly functions as a transmitter in the neuroimmune crosstalk, leukocytes
should be equipped with functional NPY receptors.
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Initial investigations have revealed a high density of the Y1 receptor for NPY on
immune cells of different species.
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Petitto et al. have cloned a Y1 receptor for NPY from human splenic lymphocytes.
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Furthermore the Y1 receptor for NPY is widely expressed on leukocytes, including
T, B cells and APCs such as DCs and macrophages.

Thus, the presence of NPY containing fibers in lymphoid organs and its receptors on
various immune cells provides a direct communication between NPY and the
immune system.
NPY and the innate immunity
NPY and the innate immunity

Immunity—the state of protection from infectious disease —has both a less specific
and more specific component.

The less specific component, innate immunity, provides the first line of defense
against infection.
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Phagocytic cells, such as macrophages and neutrophils, NK cells and a variety of
antimicrobial compounds synthesized by the host all play important roles in innate
immunity.

It has been shown that NPY could affect some functions of innate immunity such as
phagocytosis, NK cell activity and cytokine release.
NPY and the innate immunity
NPY and the innate immunity

Immunity—the state of protection from infectious disease —has both a less specific
and more specific component.

The less specific component, innate immunity, provides the first line of defense
against infection.

Phagocytic cells, such as macrophages and neutrophils, NK cells and a variety of
antimicrobial compounds synthesized by the host all play important roles in innate
immunity.

It has been shown that NPY could affect some functions of innate immunity such as
phagocytosis, NK cell activity and cytokine release.
NPY and the innate immunity
Phagocytosis
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Phagocytosis of extracellular particles and microorganisms represents a major
function of monocytes and neutrophils.

For this function, phagocytic cells carry out the phagocytic process. This process
involves several functions such as adherence to tissues, mobility to the infectious
focus (chemotaxis), ingestion of the foreign material (phagocytosis) and digestion
and destruction of this ingested material by respiratory burst.

There is convincing evidence that NPY profoundly interferes with phagocytosis of
both monocytes and neutrophils.
NPY and the innate immunity
Adherence

The first step of the phagocytic process involves the adherence of phagocytic cells to
tissue substrate before migration to the site of inflammation.

Nave et al. have found that NPY enhances the adherence of rat peritoneal macrophages
activated with LPS in vitro and in vivo.

Furthermore NPY Y2 receptor mediates this effect.
NPY and the innate immunity
Chemotaxis
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Phagocytes show great mobility, both spontaneous and directed towards a chemical
gradient (chemotaxis) produced from an infectious focus.
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NPY profoundly alters chemotaxis, a critical step of phagocytic cells, directly, and
additionally modulates the outcome of other chemotactic stimuli.
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It has been shown that NPY increases spontaneous mobility and chemotaxis of
peritoneal murine macrophages.

On the other hand, NPY inhibits the fMLP-induced chemotaxis of human monocytes.
NPY and the innate immunity
Ingestion
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The phagocytic capacity of macrophages and neutrophils are the most representative of
these cells.

There is convincing evidence that NPY profoundly interferes with phagocytosis of both
monocytes and neutrophils.

Notably, the effect of NPY on phagocytosis by monocytes depends on the type of
microorganism studied.

For example NPY increases phagocytosis of Candida albicans, whereas inhibits
engulfment of Leishmania major.
NPY and the innate immunity
Ingestion

NPY also potently modulates the ability of neutrophils to phagocytoze gram-negative
bacteria.

Studies using fluorescence-labeled Escherichia coli on human neutrophil phagocytosis
showed that NPY itself modulated phagocytosis in a bimodal manner.

When stimulated with low concentrations, NPY significantly inhibited phagocytosis
of E. coli. However, with increasing concentrations of NPY this effect changed,
eventually resulting in a significant enhancement of phagocytosis.

Furthermore The results demonstrated that NPY-mediated modulation of phagocytosis
is mediated via the Y5 receptor subtype.
NPY and the innate immunity
Respiratory burst


A remarkable feature of the host defense apparatus is its ability to produce highly
reactive oxidizing reagents, including oxidizing radicals and singlet oxygen.
The importance of this so called “respiratory burst (RB)” became obvious when the
syndrome chronic granulomatous disease (CGD), characterized by predisposition to
bacterial and fungal infections, was shown to be associated with decreased oxygen
consumption.

It has been shown that mediators of the SNS are the potent modulators of the RB.

Studies show whereas NPY has no influence on the respiratory burst of resting murine
peritoneal monocytes, the stimulation of the respiratory burst resulting from activation of
phagocytosis is directly increased by NPY.
NPY and the innate immunity
Respiratory burst

Moreover studies have been shown that the RB of rat peritoneal macrophages induced
PMA stimulation is potentiated not only by NPY, but also by NPY13-36, a selective Y2
receptor agonist.

This supports the role of Y2 receptors in PMA-induced RB.
NPY and the innate immunity
Summary
NPY and the innate immunity
NK cell activity

NK cells control host response to viruses and tumors.

NK cell activity is modulated, among several other mechanisms, by physical and
psychological stress, such as exercise or mood disorders.
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Most likely these alterations are mediated via the SNS.

Interestingly, a growing number of studies indicate that sympathetic control on NK cell
activity also involves NPY.
NPY and the innate immunity
NK cell activity

The first detailed study on the association of NPY levels and NK activity was performed
in patients undergoing bereavement or other severely threatening life events.

It was found that the decrease in NK activity resulting from such events is inversely
correlated with NPY plasma levels.

Increased NPY levels result in decreased NK cell activity, and vice versa.

Moreover the peripheral distribution of NK cells is also modulated by NPY.

It has been shown that intravenous application of NPY dose-dependently alters NK cell
distribution in the blood.
NPY and the innate immunity
Mast cells
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Another innate branch of the immune system is formed by mast cells.

It has been shown that NPY can induce releasing of histamine from murine connective
tissue mast cells in receptor-independent manner.

In contrast NPY has no effect on human mucosa mast cells.
NPY and the adaptive immunity
NPY and the adaptive immunity

The induction of an adaptive immune response is a complex process involving the
coordination of a number cell types and molecules.

Macrophages and dendritic cells (DCs) act as APCs, taking up antigen and presenting it
to naive CD8+ and CD4+ T cells respectively. which then differentiate into antigenspecific effector cells.

Newly activated T cells can differentiate into T helper (Th) 1 or 2 cells, depending on the
cytokine environment.

The interaction between T cells and APCs is a fundamental step in the induction of an
adaptive immune response.

It has been shown that NPY can modulate components of the adaptive immune system.
NPY and the adaptive immunity
Th1/Th2 balance

The differentiation into Th1 or Th2 cells is a crucial step in the development of immune
responses and diseases, such as autoimmunity or allergy.

Using lymhocytes isolated from BALB/c spleens, it was demonstrated that NPY elevates
IL-4 production and decreases IFN-γ production upon stimulation with a plate-bound
anti-CD 3 antibody.

To confirm these findings, several different Th1 and Th2 clones were stimulated with
their specific antigens in the presence or absence of NPY.

These results showed that NPY suppresses differentiated Th1 cells in their production of
IFN-γ and stimulates the production of IL-4 by Th2 cells.

Thus, a typical Th2 shift is induced by NPY in vitro.
NPY and the adaptive immunity
Th1/Th2 balance

On the other hand, intraperitoneal application of NPY significantly inhibits the exvivo
production of IFN-γ in antigen-specific murine lymphocytes.

The induction of a Th2 shift in vivo is further substantiated by the observation that NPY
also selectively inhibits the production of antigen-specific IgG2a.
NPY and the adaptive immunity
A bimodal role for neuropeptide Y1 receptor

Two studies have described a novel role for NPY via its Y1 receptor in regulating the
induction Th1 responses.

In the first study, treatment of mice with NPY or an agonist to the Y1 receptor
suppressed experimental autoimmune encephalomyelitis (EAE), a Th1 T cell-driven
autoimmunity model.
Suggesting suppressive role for NPY, via signaling
through its Y1 receptor on T cells.

The second study using another Th1-mediated model of inflammatory colitis, the
dextran sodium salt (DSS)-induced colitis. In this model, Y1-deficient mice or those
treated with a Y1 receptor antagonist were protected against weight loss and disease
activity induced by DSS.
Suggesting this time that an absence of Y1 receptor
signaling has a protective effect in this model.
NPY and the adaptive immunity
A bimodal role for neuropeptide Y1 receptor

Why Y1 signaling protected in some Th1-mediated settings and yet participated in
inflammation in some others?

Julie Wheway et al. using Y1 deficient mice (Y1-/-) answered to this question.

They found that Y1-/- mice were resistant against DSS-induced colitis.

In this case, the data suggests that Y1 is an important inflammatory mediator.

On the other hand, Both male and female C57/B6 WT mice injected daily with
50 mg/kg NPY were protected against DTH compared to the PBS-treated control mice.

In this case the result suggests that NPY signaling on T cells inhibits the Th1 T cell
response that drives DTH.
NPY and the adaptive immunity
A bimodal role for neuropeptide Y1 receptor

To examine which defective immune cell type contributed to the reduction in Th1mediated inflammation in Y1-/- mice, they decided to examine Y1-/- T cells and APCs
separately.

The results showed:
1: Y1-/- T cells were hyper-responsive to activation and normally differentiated into Th1
cells in vitro and in vivo.
2: Y1-/- APCs were functionally impaired.
NPY and the adaptive immunity
A bimodal role for neuropeptide Y1 receptor
NPY and the adaptive immunity
B cells

Intravenous infusion of a low-dose of NPY results in a significant decrease in the
number of circulating IgM+ B cells.

Moreover this work revealed the dose-dependent mobilization of a previously ndetected
B cell subpopulation in the rat, referred to as B-1-like B cells.


Intraperitoneal application of NPY in rats results in a dose-dependent inhibition of IgM
and IgG antibody responses against keyhole limpet hemocyanine (KLH).
Direct antimicrobi alactivity of NPY
Direct antimicrobial activity of NPY

In vitro, NPY has potent antifungal activity against C. albicans, C. neoformans and
Arthroderma simii and probably has activity against Gram-negative and Gram-positive
microbes.

The expression of NPY by non-neuronal cells, sustentacular cells and olfactory
ensheathing cells may create a local antimicrobial barrier protecting the projecting
axons, discouraging microbial invasion along the axonal tract and suppressing a need
for the assistance of tissue destructive inflammatory cells in the clearance of microbes.
Direct antimicrobi alactivity of NPY
Direct antimicrobial activity of NPY
NPY in immune disorders: Autoimmunity
Autoimmunity





An important feature of T cells is their ability to develop into distinct subtypes that are
characterized by specific cytokine patterns.
The Th1 phenotype predominantly secretes cytokines, such as IL-2 and IFN-γ, whereas
the production of IL-4 is an important feature of T cells biased towards a Th2 subtype.
This Th1/Th2 balance is of critical significance for autoimmune disorders, such as
multiple sclerosis (MS), and systemic lupus erythematosus (SLE).
In MS Th1 cells predominate and in SLE a Th2 bias is present.
It has been shown that NPY can modulate Th1/Th2 balance in some autoimmune
disorders.
NPY in immune disorders: Autoimmunity
Multiple Sclerosis

In MS, a disease characterized by the destruction of myelin sheaths, impaired
sympathetic functions are indicated both experimentally and clinically.

The course of EAE, an animal model for MS, is much more severe when sympathetic
nerves are chemically disrupted by the application of 6-hydroxydopamine (6-OHDA).

Conversely, clinical signs and the pathology of EAE can be significantly reduced by
treating the animals with β-adrenergic agonists.

In support of the concept that the sympathetic influence on the immune system is
alleviated, decreased concentrations of NPY in the cerebrospinal fluid and plasma of
MS patients have been documented.
NPY in immune disorders: Autoimmunity
Multiple Sclerosis

Moreover it has been shown that administration of exogenous NPY can suppress
actively and also passively-induced EAE in a dose-dependent manner.

Pharmacological assessment of the involved receptor revealed that the suppression is
due to a Y1 receptor-mediated induction of a Th2 shift of autoreactive lymphocytes in
vivo.
NPY in immune disorders: Autoimmunity
Systemic Lupus Erythematous

SLE is driven by autoreactive T cells that are biased towards the Th2 subtype.

Contrasting sympathetic dysfunctions in Th1 driven autoimmune disorders, such as
MS, observations in SLE patients indicate increased sympathetic activity.

For example prolonged pupillary reaction and increased maximal pupillary areas, as
well as increases in blood pressure and heart rate are found in SLE patients.

Jacobs et al. compared stress-induced alterations in the composition of leukocytes in
the peripheral blood of SLE patients and healthy controls.

They found whereas in the control group the number of both IFN-γ (Th1) and IL-4
(Th2) producing cells increased upon stress, in SLE patients only IL-4 producing cells
increased, suggesting a selective inhibition of stress-induced Th1 responses in SLE
patients.
NPY in immune disorders: Autoimmunity
Systemic Lupus Erythematous

Ericsson et al. compared the expression of NPY mRNA in the spleen, the bone marrow
and the peripheral blood in different mouse strains and found largely elevated NPY
levels in mice that develop SLE.

Furthermore, it was demonstrated that the onset of glomerulonephritis in lupus-prone
mice is accompanied by increased quantities of NPY in the kidney.
NPY in immune disorders: Allergy
Allergy

In the nasal mucosa, co-existence of NA and NPY immunoreactivity was observed in
sympathetic nerves present around both resistance and capacitance vessels of most
species including mankind.

Presence of NPY was also demonstrated in adrenergic nerves found in both lower
airway and vascular smooth muscle of the respiratory tract in several different species.

The predominant NPY receptor type in nasal mucosa blood vessels is of the Y1 type.
However, the presence of Y2 receptors is strongly suggested by in vivo studies with Y2
agonists.
NPY in immune disorders: Allergy
Allergy

In the pig nasal mucosa, local intra-arterial injections of NPY as well as sympathetic
nerve stimulation (SNS) were shown to produce long lasting vasoconstriction.

In humans, exogenous NPY is a powerful vasoconstrictor of the nasal mucosa vascular
bed in both control subjects and patients with perennial rhinitis.

In one study was shown that pretreatment with exogenous NPY significantly reduces
both nasal obstruction and mucus secretion induced by allergen challenge.

Intranasal or intrabronchial pretreatment with TASP-V, a potent NPY Y2 receptor
agonist reduces both nasal obstruction and bronchoconstriction produced by histamine
challenge in the pig.
Thank you for attention