Download Autoimmunity - Egyptian Society of Pediatric Allergy and Immunology

Autoimmunity and Malignant Diseases
Zeinab Awad
Professor of Pediatrics
Ain Shams University- Cairo – Egypt
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Manifestations of malignancies mimicking autoimmune diseases
Actual autoimmune diseases associating malignancies.
Anticancer therapy & transplantation causing autoimmune problems.
Autoimmune diseases culminating in malignancy
1. Manifestations of malignancies mimicking autoimmune diseases:
Lymphoproliferative disorders and autoimmune diseases have some common aspects in
their clinical appearance such as:
a- Musculoskeletal complaints
Several malignancies in children can present with musculoskeletal involvement,
mimicking JRA:
Acute leukemia:
“Osteoarticular manifestations as initial presentation of acute leukemias in children and
adolescents in Bahia, Brazil.”
[Robazzi et al., 2007]
• 54.7% of the patients with AL have joint tenderness and arthritis. More in ALL than in
AML
• Predilection for large joints manly knee
• Conclusion: “AL should be considered in the differential diagnosis of osteoarticular
symptoms of unknown etiology in children.”
In ALL musculoskeletal concerns appear even before appearance of blasts in the
peripheral blood. Such presentation may lead to the misdiagnosis of JRA. To
differentiate:
The 3 best predictors of the diagnosis of ALL:
• Low white blood cell count (< 4 x 109/L),
• Low-normal platelet count (150 - 250 x 109/L), and
• History of night time pain.
In the presence of all 3, sensitivity was 100%, specificity was 85%. [Jones et al., 2006]
ANA, Rash, Objective signs of arthritis were not helpful in differentiating between these
diagnoses.
Hence when a child develops new-onset bone-joint complaints, the presence of subtle
CBC changes combined with nighttime pain should lead to consideration of leukemia as
the underlying cause. In that case, primary care physicians should seek oncology
consultation before rheumatology consultation for consideration of additional workup."
[Barclay and Murata, 2007]
However, there are few reports of misdiagnosis of a case of ALL as systemic JRA
because of daily fever peaks & polyarthritis in the presence of Normal blood counts at
presentation
Thus, ALL should always be considered in the differential diagnosis in children with
musculoskeletal pain and fever, even in the face of a normal blood count. Close follow up
and perhaps a bone-marrow examination may be done before steroid treatment is given
[controversial].
Non-Hodgkin's lymphoma (NHL).
• Reports of children presenting with fever, adenopathy, myalgia and arthralgia with
rash in some. This led to the diagnosis of systemic onset JRA and steroid therapy was
strarted with delay of diagnosis of NHL.
When to suspect?
Large LN, significant hepatosplenomegaly, increase in size of or appearance of other
groups of LN in spite of steroid therapy for JRA.
Synovial Immunocytology: The few studies on synovial fluids in leukaemia/lymphoma
and arthritis have shown variable leucocyte counts and cytologic characteristics, with
questionable results in terms of specificity and sensitivity
Neurofibromatosis masquerading as monoarticular JRA.
A 3-yr-old boy presented with monoarthritis. Persistence of the condition and some
unusual features led to re-evaluation of the original investigations.
Osteosarcoma: In the presence of musculoskeletal complaints, the presence of
radiolucent bands, lytic lesions, and sclerotic lesions should alert the clinician to consider
malignancy until proven otherwise.
b- Lupus-Like Syndrome
ALL presenting as lupus-like syndrome with pleurisy, leukopenia, thrombocytopenia,
fever, weight loss, arthralgia and +ve ANA
has been reported in children.
2. Actual autoimmune diseases associating childhood malignancies:
a- Autoimmune hemolytic anemia (AIHA):
• AIHA presented either prior to, simultaneously with, or years after the diagnosis of
Hodgkin’ disease (HD).
AIHA should be considered in any child with HD who develops anemia and HD should
also be considered in the differential diagnosis in any child with chronic AIHA.

NHL also may exhibit AIHA
• A 5-year-old girl developed T-ALL 15 months after being diagnosed with autoimmune
hemolytic anemia mediated by warm antibodies.
[Olcay & Koç, 2005].
b- Evan’s Syndrome
A 6.5-year-old boy presented with thrombocytopenia, Coombs' +ve hemolytic anemia &
multiple small posterior cervical LN.
High-dose methylprednisolone therapy for a diagnosis of Evans syndrome.
Six weeks later: sudden increase in size of left posterior cervical LN and a biopsy was
compatible with HD, mixed cellularity type.
[Ertem et al., 2000]
c. Other associated autoimmune diseases
• Of 421 NHL patients, 32 (7.6%) had an autoimmune disease.
The most common diagnosis was Sjِogren's syndrome. The other cases were
autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), RA (1),
vasculitis (1), undifferentiated collagenosis (1), autoimmune hepatitis (1), Addison's
disease (1), and AIHA (1).
• Of 519 HL patients, an associated autoimmune disease occurred in 45 (8.6%).
In 31 cases, they found autoimmune thyroid disorders, then came glomerulonephritis (3),
immune thrombocytopenia (3), IDDM (2), AIHA (1), seronegative spondylarthritis (1),
SLE (1), MCTD (1), scleroderma (1), and vasculitis (1).
Another difference:
• In NHL autoimmunity preceded the lymphoma diagnosis
• In Hodgkin's autoimmunity developed mainly after the treatment of malignancy.
d. Renal Paraneoplastic Syndromes
Among 661 children with HD, 1.2% had biopsy proven nephropathy:
- amyloidosis (AA type),
- membranoproliferative GN,
- minimal change glomerulopathy
- IgAnephropathy was reported with HD in a 14-year-old boy.
[Khositseth et al.,
2007]
A 7-year-old girl with membranous nephropathy is reported who suffered 16 months later
from an orbital rhabdomyosarcoma
e. Catastrophic Antiphospholipid (Asherson's) Syndrome
• Malignancy may be an important risk factor for CAPS.
• 9% of patients with CAPS presented with an underlying malignancy:
- hematologic,
- lung,
- colon
- Childhood AML-M4
f. Psoriasis was positively associated with leukemia and non-Hodgkin's lymphoma.
g. Other autoimmune paraneoplastic syndromes: refer to Prof Azza AbdelGawwad’s talk
h. Autoantibodies in association with malignancy
• Autoantibodies against actin, intermediate filaments, single stranded DNA and
histones were found in the sera of Burkitt's lymphoma (BL) patients.
• Autoantibodies were also found in other malignancies such as nasopharyngeal
carcinoma
•
Increased prevalence of autoimmune disorders [thyroid & rheumatic] and
autoantibodies in parents and patients with opsoclonus-myoclonus syndrome (OMS).
[Krasenbrink et al., 2007]
3. Anticancer Therapy and Autoimmunity
• Cisplatin induces hemolytic a. with +ve antiglobulin test.
• Autologous graft followed by a persistent thrombocytopenia and the presence of high
levels of antiplatelet antibodies.
• Autoimmune hepatitis in the late post-transplant phase.
• Sclerodermoid variant of chronic GVHD
• Membranous glomerulopathy as a rare manifestation of chronic GVHD in 2 pts with
hematopoietic stem cell transpl.
N.B. Immunosuppressive therapy for autoimmune disorders may in turn induce
malignancy:
A patient was diagnosed with ALL seven months after the initial diagnosis of FSGS and
immunosuppressive therapy with CsA and tacrolimus.
5. Autoimmune diseases culminating in malignancy:
The overall risk of malignancy was increased by 25 and lymphomas constituted the major
excess risk. The risk of non-Hodgkin's lymphoma (NHL) was nearly 3-fold increased.
There was also an increased risk of lung cancer and squamous cell skin cancer most
pronounced at more than 15 years of follow-up.
• SLE is associated with a lower risk of all cancers compared with RA and SS, but an
increased risk for non-Hodgkin's lymphoma compared with the general population. Li
et al., 2006 reported 3 patients with SLE and prolactinomas.
• Dermatomyositis/Polymyositis has a strong association with the development of
cancer in adulthood, particularly gastric carcinoma, in Japan.
• Close temporal relationship between the onset of SS and hematologic disease,
especially a lymphoproliferative process
The ↑ risk of hematologic malignancies in autoimmune rheumatologic disorders
suggest chronic immune stimulation as a mechanism contributing to the
development of these malignancies. Immunosuppressive therapy may also induce
malignancy.
Epidemiology of Pediatric Asthma in Egypt: Recent Data 2008
Professor Tharwat Deraz
Professor of Pediatrics and Pediatric Pulmonology
Ain Shams University- Cairo – Egypt
Asthma is one of the most common chronic diseases in children all over the world.
Despite significant advances in the understanding of the pathophysiology, course and
management of asthma, its prevalence, morbidity and mortality appears to be on the rise
and the reasons are not entirely clear. Interaction between genetic factors and
environmental factors play a major role in the pathogenesis and evolution of asthma.
Most of the previous studies about asthma prevalence in Egyptian children were either
old studies or studies included small sample size on certain or localized areas. The
previous studies showed that the prevalence of asthma in Egyptian school children ranged
from 8.2-9.4%.
In order to study the recent prevalence of asthma in Egypt, a large epidemiological study
was conducted on school children aged 6-15 years. The study was conducted on the
following governorates which are representative of Cairo and most of the Nile delta
regions: Cairo metropolitan which represents Cairo governorate and adjacent areas of
Giza and Kalioubia, Sharkia, Dakahlia and El- Behira governorates. The study was
conducted using a written questionnaire which was adopted from ISAAC project and
many other questions were added to study the risk factors underlying the epidemiology of
asthma in Egyptian children. The study was conducted in the period from 2006 to 2008.
The study included 5128 children; there were 2549 males and 2534 females.
The result of the study showed that asthma prevalence in the studied governorate was:
16.8% in Cairo metropolitan, 10.9% in Sharkia, 14.1% in Dakahlia and 18.7% in ElBehira governorate. So the prevalence of asthma in Egyptian school children ranged from
10.9 to 18.7 with a mean of 15.1%. The study showed that asthma prevalence was
significantly higher in children in urban areas compared to those in rural areas (P<0.05).
The study showed significantly higher prevalence of asthma in school children exposed
to smoking compared with those not exposed to smoking (P<0.001). Exposure to nearby
sources of pollution is an important risk factor for asthma as significantly higher
percentage of asthmatic children gave history of exposure to sources of pollution
compared with those not exposed to pollution (P<0.05). The crowding index, which is an
index of socioeconomic standard at home, was significantly higher in asthmatic children
compared to non asthmatic children (P<0.5). While history of breast feeding showed no
protective effect on asthma.
From the results of this study we can conclude that asthma prevalence is increasing in
Egyptian children during the last few years. The increase in asthma prevalence is more
evident in urban areas compared to rural areas. Exposure to environmental tobacco
smoke, air pollution and bad housing conditions are important determinants of asthma
and may explain the trend of increased asthma in Egyptian school children.
Primary Immunodeficiency: Ain Shams University Experience
Prof. Shereen Reda
Professor of Pediatrics
Ain Shams University- Cairo – Egypt
Primary immunodeficiency diseases (PIDs) are genetic disorders that affect the immune
system. Affected individuals are predisposed to increased rate of severe infections,
allergy, autoimmunity and malignancy. During the last decade, advances in medical
research have led to the identification of 206 different subtypes of PID. Of these diseases,
110 gene defects have been identified. Based on the International Union of
Immunological Societies Primary Immunodeficiency Diseases Classification Committee,
primary immunodeficiency diseases are classified into 8 categories:
1) Combined T-and B-cell imunodeficiencies.
2) Predominantly antibody deficiencies.
3) Other well-defined immunodeficiency syndromes.
4) Diseases of immune dysregulation.
5) Congenital defects of phagocyte number, function or both.
6) Defects in innate immunity
7) Autoinflammatory disorders.
8) Complement deficiencies.
Physicians and general practitioners have little knowledge about the clinical presentation,
diagnostic approach, and health impact of PID. Consequently, affected persons may
either die or remain undiagnosed for several years and eventually suffer from long term
morbidity.
The Pediatric Allergy & Immunology Unit, Children's Hospital, Ain Shams University is
the main referral center of PID in Egypt and is the only center in the country that is
authenticated to register Egyptian PID patients in the Online registry system of the
European society for immunodeficiency (ESID). The spectrum of PID in terms of the
clinical features, treatment, and outcome of 64 Egyptian PID patients diagnosed in the
past 5 years will be demonstrated. The aim is to increase to increase the awareness of
general practitioners and pediatricians about when to suspect PID, how to proceed in the
diagnosis, and when to refer to an immunology specialist
The On-line ESID Registry
• Multi-center data collection system that is accessible via standard internet
browsers in EU and non-EU centers for patients with PID.
• The purpose of the system is to provide a multi-center clinical research.
• The central data storage is in The University Medical Center Freiburg
(Universitätsklinikum Freiburg), Germany, which holds data-subsets of every
participating center and presents these data to authenticated users (user password
authentication).
• Access rights are precisely restricted to the head administrator of the system and
the administrators of individual centers.
The Egyptian data vs. the ESID registry and others: These comparisons focus on
similarities and differences in the frequency of PID categories, consanguinity rate,
diagnosis lag, and the mortality rate.
Future Perspectives
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Increase the awareness of PID (pediatricians & publics).
Advanced diagnostic procedures are required (genetic studies).
National registry is vital.
BMT for SCID should be a priority.
A national stem cell bank.
Research funding, support of families of PID cases (genetic counseling).
Neurogenic Inflammation in Allergy
By
Dr. Gehan Ahmed Mostafa, MD
Assistant Prof. of Pediatrics
Ain Shams Universitry
Cairo, Egypt
The concept of neurogenic inflammation
Neurogenic inflammation encompasses a series of vascular and non-vascular
inflammatory responses, triggered by the activation of primary sensory neurons with a
subsequent release of inflammatory neuromediators, resulting in a neurally mediated
immune inflammation. Neuromediators are mainly released from neurons. Immune
and/or structural cells are secondary sources of neuromediators during immune
inflammation.
Mediators of neurogenic inflammation (neuromediators) include:
Neurotrophins
-Nerve growth factor (NGF).
-Brain-derived neurotrophic factor (BDNF).
-Neurotrophin-3 (NT-3).
-Neurotrophin-4/5 (NT-4/5) and NT-6.
Neuropeptides
-Tachykinins family (substance P, neurokinin A & B).
-Calcitonin gene-related peptide (CGRP).
-Vasoactive intestinal peptide (VIP).
-Neuropeptide Y (NPY).
1- Neurotrophins:
Neurotrophins are target-derived autocrine and paracrine protein family of neuronal
growth factors that regulate neuronal outgrowth toward their place of synthesis. They
control the survival, differentiation, and maintenance of neurons in the peripheral as well
as in the central nervous system in the embryonic and postnatal stages. They induce a
variety of responses in peripheral sensory and sympathetic neurons. These effects include
regulation of neurotransmitter production, establishment of synapses, control of
metabolic functions and peripheral axonal branching. Members of the neurotrophin
family bind to ligand-specific (high affinity) Trk receptors. In addition, all neurotrophins
bind to the common pan-neurotrophin (low affinity) receptor p75NTR. The high affinity
receptors mediate trophic effects, whereas the low affinity receptor may be involved in
induction of apoptosis.
2-Neurotropeptides;
The biological activity of tachykinins, the neurotransmitters of the excitatory part of the
nonadrenergic, noncholinergic (NANC) nervous system, depends on their interaction
with three specific tachykinin receptors, NK1, NK2 and NK3 receptors. The adequate
stimuli for tachykinin release from the sensory nerves in the airways are of chemical
nature, especially those chemicals that are produced during inflammation and tissue
damage. VIP, an anti-inflammatory neuropeptide, is a neurotransmitter of the inhibitory
part of the NANC nervous system. Peptidases are involved in the breakdown of
neuropeptides. Both neural endopeptidase (NEP), the main regulator of tachykinins in the
airway, and angiotensin converting enzyme (ACE) are involved in tachykinin breakdown.
A decrease in NEP activity has been observed in response to substances which exacerbate
asthma, such as smoking which upregulates tachykinin activity and production. NEP is
upregulated by steroid use.
Neuroimmune interaction in allergic inflammation
Understanding the complex pathophysiology of allergic diseases has been a main
challenge of clinical and experimental research for many years. During allergic
inflammation, a bidirectional regulation of neuronal stimulation and allergic
inflammation has been prospected. Neuromediators represent the key factors of this
process, working on immune and structural cells and exerting
neuroimmunomodulatory functions. Recent studies have demonstrated that in allergic
inflammation, various cytokines, such as IL-1, mediate signals from the immune to the
nervous system and stimulate neuromediators synthesis. Vice versa, evidence has
emerged that allergic inflammatory responses are controlled by neurons. Therefore,
signaling molecules that mediate inflammatory interactions among immune, neuronal,
and structural cells (neuromediators) are becoming a focus of allergy research. Because
neuropeptides are short-lived signaling molecules that are rapidly degraded, their action
is temporally limited and mainly restricted to the site of synthesis. The neuropeptides are
considered to be the major initiators of allergic inflammation. Neurotrophins,
however, were found to be produced continuously during allergic inflammation. Thus,
neurotrophins might act as long-term modulators, amplifying inflammatory signals
between the nervous and immune systems during allergic inflammation.
 Sources of neuromediators in allergic inflammation:
Under physiological conditions, the primary sources of neuromediators are
neuronal cells. During allergic inflammation, cells of the immune system and structural
cells are able to express both the neuromediators and their corresponding receptors.
Neuromediators and immune cells:
- Monocytes/macrophages:
Alveolar macrophages produce neurotrophins after allergen challenge. Monocytes
isolated from human peripheral blood show a constitutive expression of neurotrophins in
patients with allergy compared with those obtained from healthy donors.
- Eosinophils:
In one study, circulating blood eosinophils from patients with allergy did not show
any Trk expression, but more importantly, eosinophils obtained from the BALF after
allergen provocation expressed all neurotrophin receptors.
- Lymphocytes:
T lymphocytes have been shown to produce neuromediators, but the amount of
synthesis depends on the activation level..
Neurotrophins and structural cells:
Constitutive expression of some neuromediators in mouse lung epithelial cells is
markedly upregulated after repeated allergen challenges in a murine model of
experimental allergic asthma. This finding indicates that the airway epithelium may be an
important source for increased expression of some neuromediators in the allergic lung. In
the skin, keratinocytes are recognized as a primary source of some neuromediators
during allergic inflammation.
 Mechanisms of action of neuromediators in allergic inflammation:
A-Neuronal plasticity:
Although immunoregulation of neuropeptides has been intensively studied, one important
question is related to the mechanism of induction of their release during the allergic
inflammation. Various cytokines (eg, IL-1) mediate signals from the immune to the
nervous system and activate tachykinin synthesis. However, the communication between
neurons and immune cells is not restricted to these classical cytokines. Local
overproduction of neurotrophins during allergic inflammation results in increased
neuronal release of neuropeptides such as tachykinin, exhibiting a great degree of
functional plasticity defined as neuronal plasticity. Immune cells contribute to this
process by virtue of their neurotrophin expression. Neuropeptides released by sensory
neurons then modulate a broad range of functional responses of immune cells including
lymphocytes, eosinophils, mast cells, and macrophages, leading to activation and
differentiation of these cells. Thus, neurogenic inflammation describes a vicious cycle of
neuroimmune interactions that amplify allergic inflammation and neurotrophins are
cross talks between immune and nervous systems in allergic inflammation.
B- Immunological plasticity:
There is a growing evidence that neuromediators released by activated immune and
structural tissue cells trigger the allergic inflammation through direct interplay with
resident or invading immune cells. Because the pathophysiology of allergic diseases is
characterized by the progression of allergic inflammation, the potential role of
neurotrophins in progression and amplification of allergic inflammation is of great
interest. This has led to the concept that neurotrophins act in autocrine as well as
paracrine signaling, which results in various biological effects. These effects are
described by the term immunological plasticity and include survival, differentiation,
and/or proliferation of immune cells, in addition to selective functional aspects such as
activation or release of cytokines or mediators.
Neuromediators might influence allergic immune inflammation at different levels:
 Local recruitment of effector cells (eg, mast cells and eosinophils).
 Maintenance, support, and activation of these cells in the tissue.
 Direction of the immune response toward a TH2-specific phenotype.
How neuromediators result in progression and amplification of allergic inflammation?
1- In allergic inflamed tissues, mast cell numbers are increased. Mast cells are mainly
recognized to depend on NGF for homing, survival, and differentiation. NGF is a
chemoattractant for mast cells and acts as a cofactor, together with stem cell factor, to
prevent apoptosis. The combination of NGF and stem cell factor increased or induced
expression of typical mast cell markers. In addition, neuromediators upregulate mast cell
degranulation and serotonin release. Asthmatic airways are characterized by an increased
number of mast cells together with elevated concentrations of NGF in the BALF.
Abrogation of NGF signaling by inhibits allergen induced early phase reaction, which is
mediated by mast cell degranulation.
2- In vitro studies showing prolonged survival of BALF but not blood eosinophils by all
members of mammalian neurotrophins due to their antiapoptotic effects. Thus,
neurotrophin mediated survival of eosinophils might cause the massive eosinophilia
observed during asthma and also contributes to increased airway inflammation. In
addition, some neuromediators are eosinophil chemo-attractants.
3-Neurotrophins can directly stimulate lymphocytes to produce Th2 cytokines, going in
line with the Th2 type shifted immune response. Studies in murine asthma models
showing that treatment of mice with anti-NGF antibodies decreases Th2 cytokine levels.
4- There is also a growing evidence that neurotrophins influence the developing immune
response by acting as cytokines.
5- Tachykinins, through interaction with their receptors in airways, elicit
bronchconstriction, plasma protein extravasation, increase mucus secretion and attract
and activate immune cells.
C-Angiogenesis and microvascular remodeling:
Both angiogenesis and microvascular remodeling mainly result from endothelial cell
proliferation and often occur simultaneously. It has been recognized that neurotrophins
and tachykinins are vasoactive factors elicit angiogenesis and survival of endothelial
cells. Moreover, it has been shown that NGF induces matrix metalloproteinase
expression in vascular smooth muscle cells which contributes to the migratory response
of smooth muscle cells by releasing them from their surrounding extracellular matrix.
Thus, enhanced neuromediators synthesis may represent one important mechanism
triggering neoangiogenesis in chronic allergic inflammatory diseases.
Is there a role for neurogenic inflammation in allergy?
Whilst there is a convincing evidence of neurogenic inflammation in various animal
models of allergic diseases such as asthma, the evidence in humans is less clear and
replicating the experimental approaches in humans has proven difficult with different
studies producing conflicting results. In terms of human studies, the three main
investigative approaches of neuromediators in some allergic diseases (eg, bronchial
asthma, atopic dermatitis, allergic rhinosinusitis and ocular allergy) include;
1. Studies to determine if pro-inflammatory neurotrophins and neuropeptides are
elevated.
2. Studies to examine different functional effects of neurotrophins and neuropeptides.
3. Studies using inhibitors of pro-inflammatory neurotrophins and neuropeptides.
The importance of neurogenic inflammation in allergy in clinical
practice
1-Assessment of the severity of some allergic diseases:
The expression of neuromediators and their receptors is highly upregulated during
allergic inflammation. Their levels in BAL, sputum and peripheral blood samples in
bronchial asthma and in peripheral blood samples in atopic dermatitis) may have a role in
the objective assessment of the severity of inflammation for better management of
these diseases.
2-Therapeutic approach:
 Neurotrophin antagonism:
Neurotrophin antagonism for asthma therapy has not been tested in humans so far.
However, there are now a number of highly specific antagonists under development so
far only tested in animal models of asthma. Several pharmacological strategies were
used in animal models of asthma include:
1. Direct blocking of neurotrophins by antibodies.
2. Blocking the high affinity receptors Trks by decoy or antibodies.
3. blocking the low affinity panneurotrophin receptor p75NTR by antibodies.
4. blocking neurotrophin signal transduction by tyrosin kinase inhibitors.
These experiments demonstrated that blocking of neurotrophins or their receptors is able
to inhibit the development of the key characteristics of asthma in animal models (mouse,
rat and guinea pig). A careful balance with respect to the expected beneficial
pharmacological actions in comparison to the possible side effects is essential.
 Neuropeptide antagonism including:
1-Depletion of neuropeptides within nerves (e.g. by the neurotoxin capsaicin).
2-Inhibition of the release of sensory neuropeptides [e.g. by β2-adrenoceptor agonist,
theophylline, cromoglycate or phosphodiesterase inhibitors].
3-Inhibition of tachykinin receptors by receptor antagonists. A number of receptor
antagonists have been administered, but they seem unlikely to confer any additional
benefit to inhaled steroid therapy in human.
The Key Messages of the article
Tissue and immune cells produce and respond to neuromediators. Studies of various
allergic diseases performed over the period of the last 2 decades indicate that
neuromediators are upregulated in allergic diseases such as asthma and atopic
dermatitis and may act as inflammatory cytokines. There is a growing evidence that
neuromediators are part of an integrated adaptive response to several offending stimuli
that connect cells of the immune and nervous system together with structural cells.
On the basis of these observations, a more intense investigation of the complex biological
functions of neuromediators might open new opportunities for the development of novel
therapeutic intervention strategies beyond the currently available anti-inflammatory
drugs.