Role of Selenium in Pathogenesis and Treatment of the Autoimmune Diseases Authors

Full text

Role of Selenium in Pathogenesis
and Treatment of the Autoimmune
Diseases
Authors:
Erfan Rahmani
Tehran University of Medical Sciences
Atousa Moghadam Fard
Iran University of Medical Sciences
Hediyeh Baghsheikhi
Shahid Beheshti University of Medical Sciences
Zahrasadat Hosseini
Islamic Azad University of Tehran Medical Sciences
Branch
Amirhesam Mashaollahi
Tehran Medical Sciences, Islamic Azad University
Javaneh Atighi
Qazvin University of Medical Sciences
Negar Baharlouei
Isfahan University of Medical Sciences
Delaram Naderi
Iran University of Medical Sciences
Soroush Shahraki Zahedani
Islamic Azad University Zahedan
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Mohsen Motavaselian
Kerman University of Medical Sciences
Peyman Mazaheri
Isfahan University of Medical Sciences
Roozbeh Roohinezhad
Iran University of Medical Sciences
Seyed Saied Rajaei Ramsheh
Shahrekord University of Medical Sciences
Ashkan Shagh
Tabriz University of Medical Sciences
Fatemeh Taheri
Islamic Azad University Pharmaceutical Sciences
Branch
Mehrdad Farrokhi
ERIS Research Institute
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BOOK DETAILS:
Publisher: Kindle
Publication Date: December 2022
Language: English
Dimensions: 5 x 0.39 x 8 inches
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CONTENTS
Chapters:
1- Pathophysiology of Multiple Sclerosis
2- Role of Selenium in Multiple Sclerosis
3- Pathophysiology of Oral Lichen Planus
4- Role of Selenium in Oral Lichen Planus
5- Pathophysiology of Psoriasis
6- Role of Selenium in Psoriasis
7- Pathophysiology of Rheumatoid Arthritis
8- Role of Selenium in Rheumatoid Arthritis
9- Pathophysiology of Crohn's Disease
10- Role of Selenium in Crohn's Disease
11- Role of Selenium in Other Autoimmune Diseases
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1-PATHOPHYSIOLOGY
OF MULTIPLE SCLEROSIS
Neuronal injury, leading to characteristic
multifocal plaques apparent on magnetic
resonance imaging and a wide variety of
neurologic symptoms. The disease pathology is
known by multifocal plaques within the central
nervous system (CNS), in both the white matter
and gray matter, with perivenular inammatory
cell inltrates, demyelination, axonal transection,
neuronal degeneration, and gliosis. MS pathogenesis
is complex, as it aects both T- and B-cell processes
and is heterogeneous in appearance. Relatively
recently, the historical 4 core clinical categories
of MS were dened in an eort to improve
classication of the clinical course, better detect
where a given case is positioned in the disease
spectrum, and to guide clinical investigations.
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In young and middle-aged subjects, MS is one
of the most frequent contributors to neurologic
disability, and it acts detrimental eects on a
patient’s productivity and health-related quality of
life. Commonly, cases with MS have a long life
span, although healthcare utilization increases over
time. Consequently, the disease places a substantial
burden on cases and their caregivers/families, as
well as employers, and the healthcare system.
Risk Factors
The pathogenesis of MS is complex, as both genetic
factors and environmental exposures have role.
Both ethnicity and geography aect the prevalence
of MS, proposing that heritable factors have role
in MS pathogenesis, as well.The relatives of
cases with MS have greater risk for the disease;
however, the genetic basis of MS is complex and
heterogeneous. Multiple genes have cumulatively
role in disease risk and disease behavior, and the
genes and alleles involved are dierent from patient
to patient. Genes encoded in the class II region
of the major histocompatibility complex (MHC) on
chromosome, specically the HLA-DR2 haplotype
DRB1*1501-DQB1*0602 have been proposed. It
is known that the MHC-disease correlation
results from eects on antigen-presenting cells,
which change immune reactivity to auto-antigens,
possibly myelin-related auto-antigens.A number of
epidemiologic investigations have shown unequal
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geographic distribution of MS; the disease is
relatively rare in the tropics and increases in rate
with increasing latitude in both the northern and
southern hemispheres. Compared with other ethnic
groups residing at the same regions, those with
northern European ancestry have higher risk for
MS; however, more recently, an increasing incidence
of MS has been shown in southern Europe. There is
also evidence of tempering of the latitude gradient
in MS incidence during the past years.This may be
in part be claried by the increased incidence of MS
in geographic regions closer to the equator and to
an increase in the female-to-male ratio of MS with
time. Migration ndings propose that the risk of
developing MS is determined at the time of puberty
or before.
Other putative risk factors include infectious
factors, a diet high in salt and low in long-chain fatty
acids, environmental risk factors, and low exposure
to sunlight, although none have been denitively
correlated.Taken together, 3 major epidemiologic
shifts in MS have been found in recent years:
(1) an increased rate of MS, mostly because of
longer survival; (2) a possible true increase in the
incidence of MS in many countries, particularly
in women, resulting in higher female-to-male sex
ratios; and (3) a lessening of the idea of a latitudinal
gradient in Europe and North America regions. The
increase in the female-to-male sex ratio proposes
an environmental aect on the risk of MS; however,
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environmental variants may be exerting at the
population level rather than at the individual level.
Clinical Presentations
The broad range of signs and manifestations of MS
show multifocal plaques in the CNS, including the
aerent visual mechanisms, cerebrum, brainstem,
cerebellum, and spinal cord. Taken together, the
range and severity of symptoms in a case at
a particular time shows the extent of plaques,
their location, the severity of tissue injury, and
the rate of accumulation. However, the association
between plaques (as seen on standard magnetic
resonance imaging) and clinical symptoms is only
approximate. This may be due to the recovery
and neural plasticity compensate for injury, and
residual function may not parallel alterations in
MRI. Moreover, recent work has approved that
there are pathological characteristics in both
white and gray matter not visible on standard
MRI. MS manifestations caused by interruption
of myelinated tracts in the CNS. The initial
manifestations often include 1 or more of the
following: weakness or reduced dexterity in 1
or more limbs, a sensory disturbance, monocular
visual loss (optic neuritis), double vision (diplopia),
gait instability, and ataxia. As MS ensues, bladder
dysfunction, fatigue, and heat sensitivity are found
in many cases.
Additional manifestations include Lhermitte’s sign,
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facial weakness or pain, vertigo, brief tonic spasms,
and other paroxysmal presentations, which are
thought to represent discharges along demyelinated
axons. Cognitive decits are frequent, particularly
in advanced patients, and include memory loss,
impaired attention, problem-solving diculties,
slowed data processing, and diculties in shifting
between cognitive tasks.
Diagnosis
Clinically, MS is known by discrete episodes
(“attacks” or “exacerbations” or “relapses”) of
neurologic dysfunction. The type and severity
of manifestations created by these episodes vary
signicantly between cases and depend upon the
site of neurologic involvement. Frequently, cases
may experience numbness, tingling, weakness,
vision loss, gait impairment, incoordination,
imbalance, and bladder disturbances. In between
these attacks, at least during the remitting periods
of the illness, cases have fairly stable neurologic
activity. Nevertheless, residual manifestations may
persist and many cases have fatigue or heat
sensitivity in the interval between attacks. Over
several years to decades, many cases who present
with relapsing-remitting MS (RRMS) evolve to the
secondary progressive characteristics of illness,
in which they show an insidious worsening
of function and the accumulation of neurologic
disability unrelated to any acute attacks that may or
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may not appear. This is especially true in untreated
cases.
MS diagnosis is considerably aected by clinical
judgement.The diagnosis of MS is primarily clinical
and relies on the approval of manifestations and
signs attributable to white matter plaques on MRI
that are disseminated in time and space, along
with the exclusion of other disorders that may
mimic MS. There is no single laboratory evaluation
diagnostic for MS.In addition to a thorough history
and physical evaluation, diagnostic tools needed to
diagnose MS and exclude other diagnoses include
MRI, CSF analysis, and evoked potential testing.
CSF analysis reveals increased immunoglobulin
levels and 2 or more oligoclonal bands (OCBs)
in more than 90% of cases. Delayed latencies of
the visual, somatosensory, and auditory evoked
potentials on electrophysiological investigations, as
well as prolonged central motor conduction times,
are hallmark of demyelination; this may represent
clinically silent plaques. Blood tests are commonly
used to rule out other disorders that mimic MS.
Differential Diagnosis
Another critical component of MS diagnosis
is the exclusion of alternate causes. The list
of conditions that mimic MS clinically or
radiologically is extensive; however, in clinical
practice, there are few causes that truly mimic
MS on both fronts. In MS, dierential diagnosis
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must be guided by clinical manifestation and
neurologic evaluation. Some of the diseases that
are often mistaken for MS include nonspecic
neurologic manifestations (eg, migraine, functional
neurologic disorders, bromyalgia, and small
vessel ischemic disease alone or in combination),
other demyelinating diseases (eg, neuromyelitis
optica, idiopathic transverse myelitis, and
acute disseminated encephalomyelitis), systemic
inammatory disorders with CNS presentations
(eg, sarcoidosis, CNS commonly includes a vitamin
B12 level (for vitamin B12 deciency causing the
syndrome of subacute combined degeneration),
treponemal antibody testing (for syphilis), Borrelia
serologies (for Lyme disease, depending on
geography, local epidemiology, and season), and
antiphospholipid antibody syndrome evaluation.
Aquaporin-4 antibody evaluation for neuromyelitis
optica should be carried out in any case with a
longitudinally extensive myelitis, and in all cases
who experience a rst episode of acute optic
neuritis. Although erythrocyte sedimentation rate
may provide evidence of a systemic inammatory
cascade, it is extremely nonspecic. Antinuclear
antibody evaluation is a pivotal serologic
marker of a number of systemic inammatory
(rheumatologic) syndromes, but false positives
occur in otherwise healthy subjects at rates of more
than 30% at the 1:40 dilution and 5% at the 1:160
dilution (using human epithelial type 2 cells as
the antinuclear antibody test substrate). A positive
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result for a putative MS “mimic” does not itself
exclude the diagnosis of MS (ie, a case with MS can be
vitamin-B12 decient and still have MS).
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2- ROLE OF SELENIUM IN
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a chronic and
inammatory disorder of the central
nervous system (CNS) whose rate is clearly
increasing in many regions. Symptomatology and
patient’s disability are outcomes of the presence
of demyelinating plaques in the CNS and include
weakness, fatigue, incontinence and paralysis. The
immunopathogenesis of these plaques is complex
and aects the interplay of distinct subsets of T
lymphocytes.
Autoreactive T cells specic for myelin peptides,
probably triggered in the peripheral lymphoid
organs by molecular mimicry or bystander
stimulation, migrate toward the CNS and target
the myelin sheath-producing oligodendrocytes,
stimulating a local inammatory and injurious
mechanism. Classically, Th1 and Th17 cells, locally
stimulated by myelin presented by microglia act
mainly by releasing pro-inammatory mediators
as IFN-γ, TNF-α, IL-6 and IL-17. Th17 cells have
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also being correlated with blood-brain barrier
(BBB) disruption, facilitating therefore lymphocyte
transmigration to the CNS. Local antigen
presentation, that is carried out in the presence
of MHCII and co-stimulatory molecules, allows T
cell stimulation in the CNS and is viewed as
a critical event for disease evolution. Dierent
cell types as peripheral dendritic cells (DCs),
inltrating macrophages, CNS-resident microglia,
and T lymphocytes (Th1, Th17, and Tregs) have
been extensively assessed concerning their role in
this neuroinammatory mechanism.
This orchestrated cell interplay will,
ultimately, produce inammation and subsequent
neurodegeneration. Strong ndings show that
oxidative stress is a dominant stimulant for
inammation and vice versa and that this cyclical
mechanism is implicated in both, demyelination
and axonal injury cascade. A close association
between the oxidative stress and the stimulation
of the inammasome platform has been reported.
CNS reactive species of oxygen (ROS) are mostly
synthesized by inltrating macrophages and
stimulated microglia. In addition to direct injury
to the BBB and myelin sheath, ROS are also
known as the main inammasome stimulators.
The inammasomes are innate system receptors
that perceive inammatory messages coming
from infections or from host derived mediators.
Several inammasomes have been found so far
but NOD-like receptor pyrin/domain-containing-3
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(NLRP3) inammasome is currently the best
known complex involved in the pathogenesis
of chronic inammatory and autoimmune
conditions including MS. Briey, pathogen-
associated molecular patterns (PAMPs) or damage-
associated molecular patterns (DAMPs) interaction
with Toll-like receptors (TLRs) stimulates NF-κB
function, promoting the transcription of NLRP3,
pro-IL-1β, and pro-IL-18. Subsequent trigger as
presence of ROS, potassium eux, calcium inux or
mitochondrial injury, allows oligomerization of the
inammasome complex and subsequent secretion
of active IL-1β and IL-18. In addition of being crucial
mediators of innate immunity, IL-1β and IL-18 play
critical roles instructing Th1 and Th17-types of
polarization.
Although there is no treatment for MS yet,
the current treatment, which is essentially based
on the usage of immunomodulatory agents, can
decrease the intensity and number of disease
relapses. Alternative and adjunct treatments have
been largely assessed, including compounds derived
from helminths, medical cannabis and vitamin
D. In the last few years, investigations used
experimental autoimmune encephalomyelitis (EAE)
to assess alternative or adjunct treatments for
MS. EAE is applied worldwide as an investigation
method to allow a deeper comprehension of
MS immunopathogenesis. C57BL/6 mice develop a
chronic type of disease known by only one peak
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of CNS inammation and demyelination, whereas
SJL/J mice resembles the relapsing-remitting MS
(RRMS), presented by periods of stability in between
relapses. Considerably, around 85% of the cases
develop this type of disease. Both murine models
are largely used to investigate new prophylactic and
therapeutic approaches, but SJL/J mice also has role
in the development of treatments to decrease the
intensity or rate of relapses.
Many of the treatments currently elected for MS
treatment were assayed and validated by pre-clinical
assessments carried out with the EAE model.
Despite the variety of treatments, some cases do
not respond to available treatments and the global
inhibition of the immune system can stimulate
collateral eects as increased susceptibility to
infections.
In the view of MS immunopathogenesis, a product
with the potential to control ROS synthesis and/
or inammasome stimulation and capable of
reaching the CNS are thought logical to be
tested. From this perspective, selenium (Se) is
a micronutrient crucial for normal physiological
mechanisms that is endowed with antioxidant and
anti-inammatory characteristics. It is involved in
the mitochondrial dynamics, calcium channels and
free radical regulation, that are all mechanisms
implicated in MS pathogenesis. Moreover, Se usage
can make a regulatory phenotype in Th cells,
decrease the expression of adhesion factors as E-
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selectin and polarize macrophages to an anti-
inammatory function. Se usage has already been
eective in the control of Parkinson and other
possible autoimmune disorders. Its positive eects
depend mainly on its incorporation into proteins
that will mediate the stimulation, proliferation
and dierentiation of innate and adaptative
immune components. Se-containing amino acids,
such as selenocysteine and selenium-methionine,
can provide direct antioxidant eects and can also
be incorporated into the production of antioxidant
enzymes, as glutathione peroxidase, thioredoxin
reductases and methionine sulfoxide reductases.
Synthetic compounds containing organic Se
resemble the eects of human selenized proteins,
including antioxidant function.
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3- PATHOPHYSIOLOGY
OF ORAL LICHEN
PLANUS
The mouth is a representor of health or
disease, a sentinel or early warning
system. The oral cavity may well be
thought as a window to the body because oral
presentations accompany many systemic disorders.
In many instances, oral involvement precedes the
appearance of other manifestations or plaques
at other areas. Most of the oral mucosa is
derived embryologically from an assessment of the
ectoderm and perhaps not surprisingly, this, like
other similar orices, may become involved in
diseases that are primarily correlated with the skin.
Lichen planus (LP) is a chronic mucocutaneous
disease of the stratied squamous epithelium that
involves oral and genital mucous membranes, skin,
nails, and scalp. Oral lichen planus (OLP) is known
as the mucosal counterpart of cutaneous LP. It is
constructed from the Greek word “leichen” means
tree moss and Latin word “planus” means at.
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Historical Background
The designation and description of the pathology
were rst reported by the English physician
Erasmus Wilson in 1866. He reported this to
be the same disease as “lichen ruber,” previously
reported by Hebra and described the disease as “an
eruption of pimples remarkable for their color, their
gure, their structure, their habits of isolated and
aggregated development.” In 1892, Kaposi stated
the rst clinical variant of the disease, lichen ruber
pemphigoides. In 1895, Wickham reported the
characteristic reticulate white lines on the surface
of LP papules, today known as Wickham striae.
Darier is credited with the rst formal report of the
histopathological alterations related to LP.
Epidemiology
The exact incidence and prevalence of LP is
unclear. In 1895, Kaposi reported the disease as
“rather frequent” with 25 to 30 patients presenting
annually. In the United States, the incidence of LP is
indicated to be approximately 1% of all new cases
seen at health care clinics. The Indian subcontinent
has an especially high incidence of disease. LP is
estimated to involve 0.5% to 2.0% of the general
population, the prevalence being ranging from 0.5%
selectively in Japanese people, 1.9% in Swedish
population, 2.6% in Indian population and 0.38%
in Malaysia (relatively uncommon). The relative risk
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is 3.7% in subjects with mixed oral habits, lowest
(0.3%) in non-users of tobacco and highest (13.7%)
among those who smoked and chewed tobacco. This
disease has most often been shown in middle-aged
cases with 30-60 years of age and is more frequent
in females than in males. OLP is also reported in
children, although it is rare. It aects all racial
population. However, according to some literature
white subjects are ve and a half time more likely
to develop this disease compared to other races. OLP
occurs more commonly than the cutaneous form
and tends to be more persistent and more resistant
to therapies.
Etiology
Although the exact etiology of this disease is still
unclear, but some factors are correlated with it.
These are as follows:
Genetic Factors
Familial patients are rare. A correlation has been
found with HLA-A3, A11, A26, A28, B3, B5, B7, B8,
DR1, and DRW9. In Chinese cases, an increase in
HLA-DR9 and Te 22 antigens has also been repotted.
Dental Materials
A great many materials frequently used in
restoration managements in the oral cavity have
been found as triggering elements for OLP,
including silver amalgam, gold, cobalt, palladium,
chromium and even non-metals such as epoxy
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resins (composite) and prolonged application of
denture wear.
Pharmaceutical Factors
Oral lichenoid drug reactions may be stimulated
by systemic agents including NSAIDs, beta blockers,
sulfonylureas, some angiotensin-converting
enzyme (ACE) inhibitors, and some antimalarials,
contact allergens including toothpaste avorings,
particularly cinnamates.
Infectious Factors
OLP has been proposed to be associated with
bacteria such as a Gram-negative anaerobic
bacillus and spirochetes but this has not been
approved. Some of the investigations show the
role of Helicobacter pylori (HP) in the etiology
of OLP. However, no evidence of its role has
been found in OLP in some recent investigations.
Recently, it has been shown in some studies that
few periodontopathogenic microorganisms are also
correlated with the cases of OLP. Role of candida
infection is conicting in OLP. Several investigations
have revealed an increased rate of candida species.
However, some investigations show that there is an
insignicant correlation between candida infection
and OLP. OLP has been shown to be correlated
with dierent viral agents such as human papilloma
virus (HPV), Epstein Barr virus (EBV), human herpes
virus 6 (HHV-6) and human immunodeciency
virus (HIV). Epidemiological ndings from dierent
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investigations worldwide strongly propose that
hepatitis C virus (HCV) may be an etiologic factor
in OLP. In OLP, HCV replication has been shown
in the epithelial cells from mucosa of LP plaques
by reverse transcription/polymerase chain reaction
orin-situhybridization; also, HCV-specic CD4 and
CD8 lymphocytes were shown in the subepithelial
band. These probably propose that HCV-specic T
lymphocytes may have a role in the pathogenesis of
OLP. The putative pathogenetic association between
OLP and HCV still remains conicting and requires a
lot of prospective and interventional investigations
for a better clarication.
Autoimmunity
OLP may occasionally be correlated with
autoimmune diseases such as primary biliary
cirrhosis, chronic active hepatitis, ulcerative colitis,
myasthenia gravis, and thymoma.
Bowel Disease
Bowel disorders occasionally reported concomitant
with OLP include coeliac disease, ulcerative colitis
and Crohn's disease.
Food Allergies
Food and some of food additives such as cinnamon
aldehyde have been shown to be correlated with
OLP.
Stress
One of the most important factors responsible for
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the development of OLP is anxiety and stress. Some
of the investigations in literature show the role of
the psychological stress in the etiology of OLP.
Habits
Although most cases with OLP have no increased
rate of cigarette smoking, it has been proposed to
be an etiological factor in some Indian populations.
Betel nut chewing is also more common in Indian
cases with OLP than in those without.
Trauma
Trauma as such has not been reported as an
etiological factor in LP, although it may be the
mechanism by which other etiological factors act
their roles.
Diabetes and Hypertension
Investigations have shown that both diabetes
mellitus (DM) and high blood pressure are correlated
with OLP.
Malignant Neoplasms
LP has been found on the skin and/or mucosae of
cases aected by a range of dierent neoplasms
such as with breast cancer and metastatic
adenocarcinoma.
Miscellaneous Correlations
OLP has occasionally been correlated with other
disorders such as psoriasis, lichen sclerosis,
urolithiasis, agents used to treat gall stones,
DR. ERFAN RAHMANI
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Turner's syndrome.
Pathogenesis
OLP is a T-cell mediated autoimmune disorder in
which the auto-cytotoxic CD8 + T cells stimulate
apoptosis of the basal cells of the oral epithelium.
An early cause in the disease mechanism aects
keratinocyte antigen expression or unmasking of
an antigen that may be a self-peptide or a heat
shock protein. Following this, T cells (mostly CD8+,
and some CD4 + cells) migrate into the epithelium
either due to random encounter of antigen
during common surveillance or a chemokine-
mediated migration toward basal keratinocytes.
These migrated CD8 + cells are stimulated directly
by an antigen binding to major histocompatibility
complex (MHC)-1 on keratinocyte or through
activated CD4 + lymphocytes. Moreover, the number
of Langerhans cells in OLP plaques is enhanced
along with upregulation of MHC-II expression;
subsequent antigen presentation to CD4 + cells and
interleukin (IL)-12 stimulates CD4 + T helper cells
which stimulate CD8 + T cells through receptor
interaction, interferon γ (INF-γ) and IL-2. The
stimulated CD8 + T cells in turn kill the basal
keratinocytes through tumor necrosis factor (TNF)-
α, Fas-FasL-mediated or granzyme B-stimulated
apoptosis.
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A Cytokine-Mediated
Lymphocyte Homing
Mechanism
In OLP, there is enhanced expression of the
vascular adhesion molecules (VAM), that is, CD62E,
CD54, and CD106, by the endothelial cells of
the sub-epithelial vascular plexus. The inltrating
lymphocytes produce reciprocal receptors (CD11a)
to these VAM. Some of the mediators that are
responsible for the upregulation of the VAM are:
TNF-α, IFN-γ and IL-1.
Nonspecic mechanisms like mast cell
degranulation and MMP-1 stimulation more
aggravate the T-cell accumulation, BM disruption by
mast cell proteases and keratinocyte apoptosis. The
normal integrity of the BM is conducted by a living
basal keratinocyte due to its production of collagen
4 and laminin 5 into the epithelial BM zone. In turn,
keratinocytes need a BM-derived cell survival signal
to prevent the initiation of its apoptosis. Apoptotic
keratinocytes are no longer able to conduct this
activity, which leads to disruption of the BM. Again,
a non-intact BM cannot send a cell survival message.
This sets in a vicious cycle which associates with the
chronic nature of the disease.
The matrix metalloproteinase (MMP) have
principally role in tissue matrix protein
degradation. MMP-9, which cleaves collagen 4, along
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with its activators is upregulated in OLP lesional T
cells, leading to increased BM disruption.
RANTES (Regulated on Activation, Normal T-cell
Expressed and Secreted) is a member of the CC
chemokine family which has a crucial role in the
recruitment of lymphocytes and mast cells in OLP.
The recruited mast cell undergoes degranulation
under the inuence of RANTES, which secretes
chymase and TNF-α. These substances upregulate
RANTES release by OLP lesional T cells.
Weak production of transforming growth factor
(TGF)-β1 has been shown in OLP. TGF-β1 deciency
may increase the risk of autoimmune lymphocytic
inammation. The balance between TGF-β1 and
IFN-γ determines the level of immunological
function in OLP plaques. Local overproduction of
IFN-γ by CD4 + T cells in OLP plaques reduces the
immunosuppressive eect of TGF-β1 and increases
keratinocyte MHC class II expression and CD8 +
cytotoxic T-cell function.
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4- ROLE OF SELENIUM IN
ORAL LICHEN PLANUS
Oral lichen planus (OLP), one of the mixed red
and white plaques aecting the oral
mucosa, is a chronic inammatory
mucocutaneous disorder with immune-mediated
pathogenesis that can involve extraoral areas. The
overall incidence of OLP was shown to be up to 2.2%
worldwide. There are six clinical types of OLP that
can occur individually or combined together:
reticular, plaque-like, atrophic, erosive/ulcerative,
papular, and bullous. Clinical manifestations of OLP
range from totally asymptomatic plaques to very
painful ones, depending on the clinical variant(s)
encountered in each case; cases with non-erosive
variants (reticular, papular, and plaque subtypes)
are commonly asymptomatic, whereas those
suering from atrophic, erosive, and bullous
subtypes of OLP commonly suer from variable
degrees of pain and need treatment. Besides pain
and debilitating outcomes on quality of life
encountered in OLP cases due to erosions and
38
ulcerations, the development of oral squamous cell
carcinoma is the most important complication of
OLP. The management of symptomatic OLP
(atrophic, erosive, and ulcerative lesions) is
essential, to alleviate pain and improve the quality
of life. A state of oxidative stress (OS) has been
proposed to have role in the pathogenesis of OLP and
its malignant transformation potential risk.
However, a cause–eect association between
oxidative stress and appearance of OLP has not been
well approved till now. OS plays a pivotal role in the
appearance of the common histopathologic features
of OLP by mediating basal keratinocyte apoptosis
and recruitment of T lymphocytes and other
inammatory cells to the OLP plaques. This could be
associated with the ability of reactive oxygen species
(ROS) to maintain an inammatory condition in
OLP plaques by upregulating pro-inammatory
mediators (tumor necrosis factor α [TNF-α]) which
play a critical role in recruitment of T lymphocytes,
activating members of the matrix
metalloproteinase (MMP) family that degrade the
basement membrane, and changing intracellular
signaling molecules that are responsible for
apoptosis. On the other hand, in OLP, the
inammatory cellular inltrate, which has mainly
CD4+ lymphocytes, is a well-known source of ROS.
In high levels, ROS intensify the inammatory
mechanisms in the presence of T lymphocytes and
destroy the lipid membrane of keratinocytes,
resulting in more local tissue destruction and more
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39

production of ROS, that is, a vicious cycle. Many
antioxidants have been assessed for the
management of OLP, in order to counteract the
increased levels of ROS detected in OLP plaques,
introduce a denitive treatment for OLP plaques,
and reduce side eects of corticosteroids, which are
the 1st line of management for OLP. However, more
randomized clinical trials on larger sample sizes of
patients should be carried out to investigate clinical
ecacy. Selenium (Se), a crucial trace element, is a
well-known potent antioxidant that is identied
naturally in the human body. Se derives its
nutritional health eects from 25 selenoproteins
that have selenocysteine (SeC) at their active center,
with glutathione peroxidase and thioredoxin being
the most common. Through selenoproteins, Se
activities against oxidative stress, slows down the
aging process, reduces viral infections, plays critical
roles in chemoprevention through its involvement
in DNA modulation, and has metabolic
characteristics in the human body along with
thyroid hormone metabolism, and immune system
change. An investigation performed in 2011 on Iraqi
cases reported that levels of serum Se were
negatively associated with OLP disease chronicity
and severity.
Selenium has been previously suggested as an
alternative therapy for OLP in two clinical trials,
but to date its ecacy has never been investigated
as a single treatment in the management of
OLP cases. In 2011, a study assessed the ecacy
DR. ERFAN RAHMANI
40
of IMOD, an Iranian immunomodulator drug
consisting of selenium, carotene, and avonoids, in
the management of 30 cases suering from OLP.
This Iranian immunomodulator drug was shown
to be eective in the management of OLP plaques.
Another clinical trial performed on 30 cases with
erosive OLP in 2015 assessed the eectiveness
of selenium ACE (selenium plus vitamins A,
C, and E) as an adjunctive treatment to the
conventional management modality of OLP (topical
corticosteroids and antifungal). Selenium ACE was
shown to be successful as an adjunctive treatment
in OLP cases.
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DR. ERFAN RAHMANI
42
5- PATHOPHYSIOLOGY
OF PSORIASIS
Psoriasis is a chronic and relapsing disease
involving 1–3 % of the world’s population. It
results from the interaction between genetic
factors and a large spectrum of environmental
factors that stimulate the development of skin
plaques. The role of lifestyle habits, such as
smoking, diet, and alcohol usage, has been given
signicant attention in recent years. Alcohol
consumption is proposed to be one of the risk
factors for the disease and also may be correlated
with the course of psoriasis and aect its treatment.
The metabolism of ethanol has role in lipid
peroxidation and decrease of natural antioxidants,
therefore increasing the toxic eects of free radicals.
An impaired antioxidant skin barrier may lead to an
increase of free oxygen radicals in psoriatic lesions.
Some oxygen metabolites are highly reactive,
whereas others, such as hydrogen peroxide, are less
reactive and have the potential to diuse easily
across the cell membranes.
43

They may, therefore, impose oxidative changes
upon the membrane. After reaching the inside of
the cells, they will stimulate the cellular antioxidant
defense barriers. Oxidative stress develops within
the cells after its defenses are depleted, and
oxidative changes will be evident. Increased reactive
oxygen species (ROS) and lipid peroxidation have
a critical role in the inammatory mechanisms.
As such, they are reported in many dermatologic
diseases, for example, atopic dermatitis, psoriasis,
vitiligo, acne vulgaris, pemphigus vulgaris, and
alopecia areata. Selenium is considered to
have immune-modulating and antiproliferative
characteristics. It can aect immune response
by altering the expression of mediators and
their receptors or making immune cells more
resistant to oxidative stress. The antiproliferative
characteristics of selenium compounds are related
directly to their toxicity. As an integral part
of thioredoxin reductases and other antioxidant
enzymes, such as glutathione peroxidases, selenium
has role in protection of the skin against harmful
environmental factors, e.g., in the prevention of
ultraviolet-induced cell injury and death. On the
other hand, it has been shown that selenite
and selenocystamine could trigger apoptosis in
keratinocytes because of their prooxidant catalytic
function. Current ndings about changes of
selenium level and activity of selenium-dependent
enzymes in blood of cases with psoriasis are
conicting.
DR. ERFAN RAHMANI
44
Psoriasis and
Oxidative Stress
The human body is equipped with a complete
arsenal of barriers against external and internal
invasions. Those against ROS, such as superoxide,
peroxide, and hydroxyl radical, are essential in
inammatory processes, where they participate in
physiological mechanisms, such as the arachidonic
acid cascade and phagocytosis. The levels of ROS are
kept under strict control by the function of a
complex defense system including antioxidant
enzymes, such as superoxide dismutase and GSH-
Px, and by nonenzymatic species such as vitamins C,
E, A, or βcarotene. There is a large body of ndings
that poly- and mononuclear phagocytes are
essentially involved in host defense. In addition to
removing circulating immune complexes, debris,
and necrotic cells, they eectively attack invading
microorganisms. Monocytes and macrophages have
additional important activities as antigen-
presenting and cytokine-releasing cells, whereas
polymorphonuclear phagocytes are noted to
represent the rst line of defense in terms of
ingesting and killing potential risk factors. During
particle ingestion, granulocytes and macrophages
synthesize large amounts of highly reactive
molecules, mainly oxygen radicals, therefore
resulting in a considerable increase in energy and
oxygen usage. The sharp increase in usage of
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45

molecular oxygen during phagocyte stimulation
does not reect an increase in aerobic energy
synthesis as primarily assumed (a “respiratory
burst”), but is the result of an increased production
of highly reactive oxygen species. Neutrophils and
other phagocytes manufacture superoxide by the
one-electron decrease of oxygen at the expense of
NADPH. Most of the superoxide radical reacts with
itself to produce hydrogen peroxide. From these
factors, a large number of highly reactive
antimicrobial oxidants are produced, including
hypochlorous acid, which is synthesized by the
myeloperoxidase-catalyzed oxidation of Cl− by
H2O2; hydroxyl radical (OH· ), synthesized by the
decrease of H2O2 by Fe2+ or Cu+ ; peroxynitrite
(ONOO− ), formed by the reaction between O2− and
NO− ; and many others. These reactive oxidants are
produced for the aim of killing invading
microorganisms, but they also inict injury on
nearby tissues and seem to be of pathogenic
importance in a large number of disorders including
psoriasis. The skin conducts its role as an interface
between the human body and its surrounding
environment, therefore the skin is constantly
exposed to both endo- and exogenous prooxidants,
resulting in the production of harmful oxidant
species. Oxidative stress and the production of
excessive free radicals have been associated with
skin inammation in psoriasis. Cases with this
condition have decreased plasma levels of β-
carotene and α-tocopherol as well as a decrease in
DR. ERFAN RAHMANI
46
serum selenium and high levels of
malondialdehyde, a marker of lipid peroxidation in
the plasma and red blood cells. There are literature
results that propose that topical usage or oral
consumption of antioxidants, such as vitamin E and
selenium, is proposed as preventive treatment for
the psoriasis.
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DR. ERFAN RAHMANI
48
6- ROLE OF SELENIUM
IN PSORIASIS
Selenium Deficiency
and Psoriasis
The selenium level in psoriasis cases is lower
than that of healthy subjects, but there
are few investigations on its role in
the pathogenesis of the disease. An impaired
antioxidant barrier in skin may lead to a rise of
free oxygen radicals in psoriatic lesions. Thionine
may regulate immunologic mechanisms of the
disease by increasing the number of CD4+ T
cells in reticular dermis within psoriatic lesions.
Previously published preliminary ndings revealed
that selenium level and selenium-dependent GSH-
Px function in erythrocytes are higher in males
with psoriasis, lasting no longer than 10 years
than in those with the disease lasting 3 years or
more. Kadry and Rashed, using plasma and tissue
samples from 20 cases with psoriasis and 10 healthy
subjects, assessed the levels of overexpression of
49

osteopontin and selenium in psoriasis, and their
association with metabolic condition in cases to
nd a possible association between these markers
and comorbidities found. They found that the
plasma selenium levels were lower in cases with
psoriasis than in healthy subjects and showed
that overproduction of osteopontin and low
plasma selenium levels are predictable factors for
occurrence of psoriasis. Another study evaluated
the eect of selenium usage on the ecacy of
narrowband ultraviolet B (UVB) management in
cases with psoriasis and assessed the association
between serum levels of selenium, sTNF-R1, and C-
reactive protein (CRP) during management in these
cases. They managed 37 cases by administering 200
μg Se/day as thionine or placebo in addition to
UVB radiation ve times a week. The cases were
assessed by evaluating the psoriasis area, severity
index, and serum levels of selenium (in micrograms
per liter), sTNF-R1 (in nanograms per milliliter),
and CRP (in milligrams per liter) at the initiation
of treatment and at 2 and 4 weeks of treatment as
well as 1 month after the end of management. Their
ndings approve that the sTNF-R1 and CRP levels
were increased in active psoriasis, and that 1-month
usage with thionine does not help as adjuvant
treatment in cases with psoriasis.
Low serum selenium levels in cases with psoriasis,
and that management with thionine for 4 weeks
failed to give a positive clinical result to topical
treatment in these cases have been recently
DR. ERFAN RAHMANI
50
reported. There have been ndings indicating the
association between plasma selenium level acute-
phase response marker in cases with dierent
inammatory diseases, including psoriasis, and
malignancies. Ultraviolet B irradiation is a potent
trigger of TNF-α synthesis and secretion by human
keratinocytes in vitro. However, UVB can reach the
upper dermis and stop endothelial cells. Selenium
compounds prevent in vitro the secretion of UV-
induced proinammatory mediators (interleukin-6,
interleukin-8, and TNF-α) by inhibition of mRNA
for these mediators in human keratinocytes. It
also has been revealed that preincubation of
murine keratinocytes for 24 h with thionine or
sodium selenite (thionine is more eective) leads to
inhibition of UV-induced interleukin-10 expression
in these cells. In contrast, an investigation showed
no signicant alterations in serum levels of
interleukin-10 and TNF-α after three irradiations
with narrow-band ultraviolet in ve cases with
psoriasis. Another investigation showed selenium
levels in plasma and whole blood of 64
cases with psoriasis and in agematched healthy
subjects and showed no signicant dierences
between these study groups. British investigators
found no dierences in selenium absorption or
atopic dermatitis and healthy subjects, but the
exchangeable total body selenium was lower in
psoriasis cases than in healthy controls. Findings
of case–control investigations showed that low
selenium level can be a risk factor for some
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51

types of neoplasm and, therefore, proposed that
depressed selenium condition also can be a
risk factor for psoriasis, a disease known by
cell hyperproliferation. As it was reported above,
experiments on selenium usage in psoriatic cases
revealed that selenium in inorganic forms, but
not as thionine can achieve clinical improvement.
Another study assessed the immunological and
redox markers in a group of psoriatic cases
managed with efalizumab. They showed that the
activities of GSH-Px and glutathione-s-transferase
in granulocytes were considerably increased, and
catalase was reduced exclusively in nonresponders
vs complete or partial responders.
Role of Selenium
Supplementation on
Treatment of Psoriasis
As stated before, TNF-α is a mediator critical
for stimulating and maintaining psoriatic plaques.
A recent study assessed the eect of selenium
consumption on soluble TNF-α receptor type 1
and topical treatment in psoriasis cases. They
showed that 4-week consumption of thionine was
ineective in the acceleration of remission of
psoriatic plaques. Previous investigations showed
no signicant dierences in selenium absorption
or excretion between psoriasis cases and controls
after intravenous and oral consumption of SeMet,
but the total exchangeable body selenium was lower
DR. ERFAN RAHMANI
52
in psoriasis cases. Another investigation proposed
that insucient dietary intake of selenium in a
Polish population and in psoriasis cases, together
with excessive desquamation or poor selenium
absorption, may be additional causes for low plasma
selen level. Consumption of thionin in a Finnish
case with high baseline serum selenium level led
to a signicant increase in the number of CD4+ T
cells and in nonsignicant enhancements in CD11c
+ and CD1+ cells within the reticular dermis of
psoriatic plaques. In an investigation, 69 cases were
supplemented daily with either 600 μg of selenium-
enriched yeast, 600 μg of selenium-enriched yeast
plus 600 IU of vitamin E, or placebo for 12
weeks. They showed that neither supplementation
regimen decreased the severity of psoriasis or
made side eects. A recent study evaluated the
eects of oral selenium (400 μg) on expression
of phosphorylated p53, Fas, Bcl-2, Bax, and
oxidized guanosine and Langerhans and sunburn
cells counts. They showed that oral consumption
of sodium selenite did not signicantly protect
human skin against alterations in marker proteins
correlated with ultravioletinduced injury during
TL01 phototherapy. Another study showed for the
rst time that the combination of conventional
treatment and consumption of vitamin E, coenzyme
Q10, and selenium led to an improvement
in the clinical condition of cases with severe
psoriasis as well as a decrease in oxidative stress.
Supplementation using inorganic forms of selenium
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53

(sodium selenite and selenate) is also shown
to result in clinical improvement in cases with
psoriasis.
DR. ERFAN RAHMANI
54
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7- PATHOPHYSIOLOGY
OF RHEUMATOID
ARTHRITIS
Rheumatoid arthritis (RA) is a systemic
inammatory disease that mainly aects
articular inammation. Approximately
0.5% to 1% of the population worldwide is aected
by the disease, which may lead to joint damage
and disability. Moreover, approximately 40% of
cases present with extra-articular presentations,
complicating disease progression and mortality.
Autoantibodies isolated from patient serum and
synovial uid play important roles in the
pathogenesis of RA. According to the literature, 70–
80% of cases with RA are positive for autoantibodies
(autoAbs), such as rheumatoid factors (RFs)
and anti-citrullinated protein antibodies (ACPAs).
Although they are not essentially present in
all cases, antibodies reacting with self-antigens,
including immunoglobulins and posttranslational
modied (PTM) protein epitopes, have been shown
for over 80 years to exist in RA.
56
RFs were the rst auto-Ab found in RA. They
were reported by Waaler in 1940 as factors with
hemagglutinating function in the serum of a case
with RA and named by Pike in 1949 for their
correlations with RA. Subsequent investigations
have shown that the presence of RF is correlated
with a more severe and erosive RA phenotype.
Compellingly, using an analytical ultracentrifuge
method, Kunkel and his colleagues later found
that RF is an antibody to antigen–antibody
complexes. Furthermore, scientists reported that RF
targets antigenic epitopes within the crystallizable
fragment (Fc) region of immunoglobulin G (IgG)
and is found in dierent isotypes. Although the
specicity of RF for RA is only about 60–70% and
the conditions needed to break tolerance to IgG are
not yet fully known, RF was included in the 1987
ACR classication criteria for RA and noted as the
paradigm of auto-Ab clinical importance in RA.
The detection of ACPAs can be traced back
to 1964, when Nienhuis and Mandema showed
anti-perinuclear factors within the sera of RA
cases. Approximately 30 years later, Hoet and
colleagues reported them with regard to their
reactivity toward citrullinated peptides. Following
the discovery of multiple protein candidates eligible
for peptidyl arginine deiminase (PAD) citrullination,
“RA citrullinome”, referring to the collection of
hundreds of citrullinated proteins found in the
serum and synovial uid of RA cases, was
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57

reported to the eld of RA investigation in recent
decades. With its superb diagnostic specicity,
immunopathogenic relevance and excellent clinical
associations, ACPAs were considered in the
2010 American College of Rheumatology (ACR)/
European League Against Rheumatism (EULAR) RA
classication criteria. Alongside the classical RA
auto-Ab RF, ACPA was also noted as a pivotal
hallmark of the disease in the past decade.
In recent years, growing studies has approved
that proteins resulting from PTMs, other than
citrullination, are also capable of stimulating
autoimmune reactions important for the
development of RA. Indeed, autoantibodies against
carbamylated protein (anti-CarP Ab), acetylated
proteins, malondialdehyde, malondialdehyde-
acetaldehyde and other posttranslated modied
epitopes, such as anti-hinge antibodies, have
attracted considerations due to their clinical
importance and their potential application in
rening RA diagnosis and treatment. Among them,
anti-CarP Ab, reported in 2011, is maybe one of the
best assessed anti-PTM autoantibodies.
Genetic Risk Factors
Genetic background is a critical factor aecting
the development of RA. There is an estimated 40–
50% familial risk among seropositive RA cases
with strong risk noted in rst-degree relatives. In
addition to the high association for RF reported
DR. ERFAN RAHMANI
58
among identical twins with RA, a number of
investigations have shown dierences in genetic
components between RA cases positive or negative
for RF. However, controversies were reported,
as some investigations showed that RA cases,
regardless of the presence of RF, may harbor similar
human leukocyte antigen (HLA) susceptibility
alleles.
A conserved amino acid sequence at positions 70
and 74 within the HLA-DRB1 molecule, namely, the
“shared epitope (SE)”, is a pivotal genetic risk factor
for ACPA-positive RA. Moreover, a dose eect of
SE alleles on risk of RA among ACPA-positive RA
cases was also reported in literature. Utilizing paired
samples of presymptomatic subjects, Kissel and
others recently showed that SE alleles are correlated
with ACPA Fab glycosylation in the predisease phase.
In addition to SE, the protein tyrosine phosphatase
nonreceptor type 22 risk allele shows a synergistic
action along with the SE alleles. In addition, single-
nucleotide polymorphisms and long noncoding
RNAs are correlated with the presence of ACPAs
in RA cases. Tumor necrosis factor (TNF) receptor-
associated factor 1 C5 region, TNF-α-induced
protein, CD40, C-C motif chemokine ligand 2,
antisense noncoding RNA in the INK4 locus, and
peptidyl arginine-deiminase 4 are some of the well-
documented genetic factors associated with ACPA-
seropositive RA.
In contrast, the genetic risk for anti-CarP Ab is less
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59

reported in literature. While HLA-DR3 is shown
more commonly in subjects with ACPA-negative
RA than in the healthy subjects, HLA-DR3 is also
correlated with RA patients positive for anti-CarP Ab
and negative for ACPA.
Tobacco Smoking
The importance of tobacco smoking as a risk factor
for RA has been well established. Interestingly,
although smoking has been correlated with all
seropositive RA, it is approved to be correlated with
the presence of RF, even in the absence of RA. Large
population investigations and twin reports have
shown the correlation between smoking and ACPA
positivity, with a dominant risk being in subjects
positive for SE. Aside from the inammatory
alterations in the lungs subsequently causing
activation of PADs, in the setting of SE, smoking
creates a risk of high ACPA levels and proposes
a distinct mechanism of ACPA synthesis dierent
from that of RF.
Furthermore, smoking is known to promote
carbamylation in cases with RA. While smoking has
been shown to promote MPO-mediated conversion
of thiocyanate to cyanate, the level of anti-
CarP Ab, however, was not considerably higher.
Perhaps critical factors (genetic or environmental
exposures) other than carbamylation alone are
needed for the stimulation of anti-CarP Ab.
DR. ERFAN RAHMANI
60
Microbial Triggers
As RF is physiologically critical to increase immune
complex clearance, to assist B cell uptake for
antigen presentation and to facilitate complement
xation, an increased level of RF has been found
in subjects with chronic or indolent infection,
including hepatitis B or C virus infection or
infective endocarditis. Nonetheless, the synthesis
of RF under such conditions commonly stops
following resolution of the infection. Due to
the action of bacterial pore-forming virulence
and calcium ionophores in stimulating calcium
inux and producing nontolerized neocitrullinated
epitopes, the role of periodontitis-causing bacteria
and intestinal microbiota in ACPA-related RA was
recently reported. Although infection is likely
to stimulate the release of MPO from activated
neutrophils during infection episodes, no direct
evidence has linked acute infection to anti-CarP
Ab-positive RA, and the risk of infection in
autoantibody-mediated RA is still under evaluation.
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DR. ERFAN RAHMANI
62
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8- ROLE OF SELENIUM IN
RHEUMATOID ARTHRITIS
RA is a chronic disease with systemic
inammatory condition that primarily
aects the small diarthrodial joints of the
hands and feet, which may result in disability.
Increased levels of oxidative stress biomarkers and
decreased levels of blood antioxidants in cases with
RA corroborate the fact that oxidative stress and
Reactive Oxygen Species (ROS) play a critical role in
the physiopathology of RA. Due to the crucial role
of selenium in the endogenous antioxidant enzyme
glutathione peroxidase, selenium deciency is
proposed to be critical in the pathogenesis of RA.
A low selenium concentration has been shown in
RA, which results in increased levels of peroxidation
products in serum and synovial uid.
Investigators assume that reduced levels of
selenium in RA may be associated with the
redistribution of selenium from plasma into tissues
as a defense mechanism in severe inammatory
disorders. Another study reported that the function
64
of glutathione peroxidase was considerably lower in
RA cases compared to that in controls. Therefore,
with regard to the crucial role of selenium
as a major component of glutathione peroxidase
enzyme, the lower function of this enzyme may
be due to selenium deciency. A preliminary
investigation revealed that selenium consumption
for three months considerably decreased pain
and joint involvement in RA. The consumption
of sodium selenite for RA cases alleviates some
manifestations of the disease and results in
the improvement of immunological markers. The
decreased inammatory response in cases who
received selenium also improved swelling and
stiness of the joints, as well as the severity of pain.
Another investigation suggested the consumption
of sodium selenite in the treatment of RA, especially
in cases with subclinical hypothyroidism. Evidence
proposes that sodium selenite usage could be an
eective method for the management of articular
syndrome and could decrease inammation and
autoimmune presentations of RA, which is
important to prevent RA progression. Although
several investigations propose that selenium is
an eective nutrient for treatment of RA, some
investigations propose that selenium does not
considerably aect RA, and alters in rheumatoid
severity or disease progression occur independently
from selenium level. These conicting results could
be attributed to dierences in the investigation
design or the chemical form of selenium (e.g.,
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65

selenomethionine, selenite, selenite). Therefore, it
is thought that more investigations concerning the
eects of selenium consumption on RA activity
should be carried out to investigate the exact
responses of the disease to dierent types of
supplements.
A low plasma selenium content has been shown
amongst cases with any of a variety of disorders,
including rheumatoid arthritis, although neither
the reason for this anomaly nor its possible
functional importance are known. The seleno-
enzyme glutathione peroxidase has role in the
antioxidant defence by reacting with hydrogen
peroxide and related compounds. Dierent oxygen
radicals may have role in the pathogenesis of
rheumatoid arthritis, and the accumulation of lipid
peroxidation products in synovial uid has been
shown. In mammals, selenium is covalently bound
commonly in selenocysteine moieties in proteins,
and in human tissue glutathione peroxidase is the
only selenoprotein hitherto found. In a previous
investigation, most of the selenium in human
plasma was shown to be located in selenoproteins
other than glutathione peroxidase. Few other
investigations on selenium loc a I' Ization in human
tissue have been carried out, one reason probably
being the diculty in indicating the low selenium
levels present in biological material.
DR. ERFAN RAHMANI
66
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DR. ERFAN RAHMANI
68
9- PATHOPHYSIOLOGY
OF CROHN'S DISEASE
Crohn disease (CD) was rst reported by Dr
Burrill B. Crohn and colleagues in 1932.1
Along with ulcerative colitis (UC), it
is considered under the spectrum of chronic
idiopathic inammatory bowel disease (IBD). A
recent estimate proposes that 1.3% (3 million
subjects) of the US population has a diagnosis of IBD.
Crohn disease is a chronic disorder with an annual
incidence ranging from 3 to 20 cases per 100,000.
The median initiation of disease is age 30 years and
it has 2 peaks, rst between age 20 and 30 years and
then a smaller peak around age 50 years.
Crohn disease is known by discontinuous skip
plaques involving any part of the gastrointestinal
tract from the mouth to the anus. The
inammation is commonly transmural and on
pathology granulomas may be present on biopsies.
Presenting manifestations are variable but can
include diarrhea, abdominal pain, weight loss,
nausea, vomiting, and sometimes fevers or chills.
69

The natural process of the disease is one of
periods of remission and ares. There are multiple
dierent types of disease including inammatory,
stricturing, and penetrating. Cases can have 1
or more of these disease phenotypes during the
process of their disease, and cases often progress
from inammatory to stricturing or penetrating.
Unfortunately, there is no treatment for CD and
most cases need at least 1 surgical resection. The
aim of medical treatment is to achieve a steroid-
free clinical and endoscopic remission with the
hopes of preventing complications and surgery.
Until recently, treatment options were limited to
thiopurines, methotrexate (MTX), natalizumab, and
antietumor necrosis factor (anti-TNF) agents. Of
late, treatments with novel processes of action
have been approved including a gut-selective anti-
integrin (a4b7) inhibitor and a monoclonal antibody
to IL-12/IL-23.
Environmental Risk Factors
Crohn disease seems to be initiated by changes in
the gut microbiome or disruption in the intestinal
mucosa. Cases with IBD often Crohn disease seems
to be stimulated by changes in the gut microbiome
or disruption in the intestinal mucosa. Cases with
IBD often have a dysbiosis that leads to a decrease
in the diversity of the gut microbiome. Although
the literature surrounding the specics is evolving,
the exact process by which changes in the gut
DR. ERFAN RAHMANI
70
microbiome predispose to CD is still not fully
known. Gastrointestinal infections, nonsteroidal
anti-inammatory drugs, and antibiotics have all
participated in the development of IBD. However,
none of these correlations has been substantiated
with large epidemiological investigations. In one
investigation, cases with enteric infections from
salmonella or campylobacter had an increased risk
of developing IBD within the rst year of their
disease. Furthermore, sustained consumption of
nonsteroidal anti-inammatory drugs, especially in
women, may increase the risk of IBD. Antibiotic
exposure early in life has also been correlated with
an increased risk of developing CD. In women,
both hormone replacement treatment and oral
contraceptives may increase the risk of IBD. The
best-assessed environmental risk factor, cigarette
smoking, doubles the risk of developing CD. This
risk is enhanced in both current and former
smokers. Investigations have also proposed that
appendectomy may increase the risk of CD but this
may be due to exact classication of appendicitis
which in truth was actually CD. The role of diet
in the development of CD also remains unknown.
Some investigations have proposed that diets high
in sugar, omega-6 fatty acids, polyunsaturated fatty
acids, total fat, oil, and meat increase the risk of CD
whereas a diet high in ber and fruit reduced the
risk of CD. However, more investigations are still
required to clarify the role of diet and the risk of
developing CD.
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Genetic Risk Factors
Although family history does portend an increased
risk, only 10% to 25% of cases with IBD
have a rst-degree relative with the disease. In
twin investigations, concordance rates for CD in
monozygotic twins range from 20% to 50%
compared with 10% in dizygotic twins. Crohn
disease is more frequent in cases of Ashkenazi
Jewish origin than in non-Jews and is less
commonly reported in African Americans or
Hispanics. Although genetic risk factors are still
being claried, there are more than 200 genes that
have been correlated with the development of IBD.
The rst gene reported was the NOD2 locus on
chromosome 16. Homozygotic alterations at NOD2
have a 20 to 40 times higher risk of developing CD,
while being heterozygous increases the risk by 2 to
4 times. A number of other genetic foci aecting
multiple dierent mechanisms (eg, autophagy,
adaptive immunity, and epithelial activity) have
also been correlated with CD.
Laboratory Testing
Although there is no laboratory assessment that
denitely rules out CD or is diagnostic of CD,
results on serum and stool assessments can assist
with making a diagnosis. Stool investigations
should be obtained to rule out other diseases
of gastrointestinal manifestations and diarrhea.
DR. ERFAN RAHMANI
72
Laboratory abnormalities are seen more commonly
with a longer duration and more severe disease.
Cases may have an anemia from iron deciency
anemia, chronic inammation, and B12 deciency.
Inammatory mediators including erythrocyte
sedimentation rate and/ or c-reactive protein may
be assessed, but normal levels do not rule out CD
activity. Multiple evaluations have been assessed
to investigate inammation in the gastrointestinal
tract including fecal calprotectin or fecal lactoferrin.
However, none of these evaluations is unique to IBD
and can be assessed with any intestinal infection or
inammatory condition.
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73

DR. ERFAN RAHMANI
74
10- ROLE OF SELENIUM
IN CROHN'S DISEASE
Inammatory bowel disease (IBD) primarily
includes Crohn’s disease (CD) and ulcerative
colitis (UC), which are known by chronic
and relapsing intestinal inammation. In newly
industrialized regions, the prevalence of IBD
is continuously increasing. Except for chronic
intestinal inammation, these two disorder
present with distinct clinical and histopathological
characteristics. The pathogenesis of IBD has not
been assessed in depth. Multiple factors, such
as genetic mutations, diet, disordered intestinal
microbes, and hyperactivation of immunity, have
role in initiation of IBD.
Among these factors, dysfunction of the mucosal
immune system is the most crucial in the
pathogenesis of CD and UC. Some previous studies
has shown some obvious dierences in the
immune microenvironment, particularly in the T
cell dierentiation mechanisms, between these two
types of IBDs. However, the subjects included in
75

the distinct investigations have been administered
various treatments, such as amino salicylates,
steroids, immune modulators or biologic agents,
which would have aected their pathological
immune mechanisms. Therefore, the pathological
characteristics of immune responses in naive IBD
remain poorly assessed. The increasing prevalence
of IBD in newly industrialized regions is likely
correlated with the progress of urbanization
and structural alterations in the diet. Current
investigations have shown that short-chain fatty
acids, tryptophan, and bile acids have role in
mucosal immune homeostasis and initiation of
IBD. Metabolites are crucial mediators in regulating
T cell activity. Metabolic mechanisms synthesize
abundant intermediate metabolites and byproducts,
such as reactive oxygen species (ROS), which have
an critical role in modulating T cell activities and
metabolic shifts. ROS level is tightly controlled by
the antioxidant system, which includes superoxide
dismutases (SODs), catalase (CAT), glutathione
peroxidases (GPxs), thioredoxin reductases (TrxRs),
and glutathione reductase (GR). Considerably,
several nonenzymatic molecules, such as reduced
glutathione (GSH), uric acid, and ascorbate, can also
have reactions with ROS. However, the correlation
of ROS and antioxidant molecules with distinct
T cell dierentiation and the initiation of IBD
remains unknown. Selenium is a crucial trace
mineral that is incorporated into proteins to form
selenoproteins, which have indispensable roles in
DR. ERFAN RAHMANI
76
ROS scavenging and redox alterations. Among the
25 selenoproteins found in humans, GPxs and TrxRs
are well-known antioxidant enzymes, whereas the
physiological activities of other selenoproteins (e.g.,
selenoprotein W [SELW], SelT, and SelH) remain
incompletely known. A few investigations have
shown selenium deciency in subjects with IBD, as
shown by reduced selenoprotein P (SePP1) in serum.
In a mouse colitis models, selenium deciency
exacerbates intestinal damage and promotes
inammatory mechanisms. However, the specic
selenoproteins that change T cell activity in IBD
remain poorly evaluated.
Dietary Supplementation
with Selenite Alleviates
Colitis in Animal Models
and Individuals with IBD
In vitro investigations have revealed that
consumption of selenium can considerably decrease
the expression of IFN-g in Th1 cells. To nd out
whether selenium has role in Th1 dierentiation in
vivo, an adoptive T cell transfer-induced colitis
model was performed that typically shows
predominant Th1 and Th17 cell responses.
Recipient Rag1–/– mice were fed a selenium-
decient diet for 4 weeks and then adoptively
transferred CD45RBhi CD4+ T cells. During colitis
establishment, the recipient mice were fed a
ROLE OF SELENIUM IN PATHOGENESIS AND TREATMENT O...
77

common diet, a selenium-decient diet, or a sodium
selenite-supplemented diet (8 ppm). The selenium-
decient diet clearly stimulated more serious colon
inammation correlated with higher body weight
loss. The mice in the selenium-supplemented group
revealed the least weight loss and longest colon
length among the three groups. Consistently,
selenium deciency resulted in epithelial
denudation, and this eect could be rescued by
selenium usage. Consistent with the in vitro
phenotype, reductions in the total colonic CD4+ T
cell population were found and rate of IFN-g+ CD4+
T cells in the selenium-supplemented group.
Conversely, selenium deciency aggravated colitis
and enhanced the number of inltrating Th1 cells in
the colon. To evaluate the in vivo activity of SELW in
inammatory disorders, WT and Selenow–/–
eector T cells were transferred into Rag1–/– mice
that were fed a selenium supplement. The
transferred Selenow–/– CD4+ T cells clearly
stimulated severe body weight loss and reduced the
colon length to the same extent as that in the WT
controls. Increased rate of Selenow–/– cells and Th1
cells were found in the colon. These ndings more
showed the importance that selenium alleviated the
initiation of T cell-mediated colitis via SELW.
Clinical evidence has shown that subjects with CD
also show a low serum selenium level. Therefore, a
pilot investigation in subjects with CD and low level
of serum selenium was carried out. They were orally
used sodium selenite at a dose of 360 mg per day for
DR. ERFAN RAHMANI
78
8–10 weeks and were followed up weekly by
telephone visit. As expected, consumption of
selenite partially relieved the clinical
manifestations of CD, as indicated by a rapid decline
and lower scores in disease function compared with
the NT control groups. Colonoscopy revealed
improvement of the plaque at the same segment of
the colon in subjects with CD after selenite
management. The endoscopy score and biomarker
ndings, including the amounts of calprotectin, C-
reactive protein (CRP), and erythrocyte
sedimentation rate (ESR), also showed that selenite
supplementation clearly improved the clinical
manifestations of subjects with CD. CD4+ IFN-g+
cells were also reduced after selenium consumption
compared with those in subjects who did not receive
sodium selenite. These results revealed that
consumption of selenium improved the colitis
outcomes in subjects with CD by inhibiting an
excessive Th1 cell-mediated immune response in
the colon.
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DR. ERFAN RAHMANI
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DR. ERFAN RAHMANI
82
11- ROLE OF SELENIUM
IN OTHER AUTOIMMUNE
DISEASES
Selenium and Systemic
Lupus Erythematosus (SLE)
SLE is a multi-organ autoimmune disorder known
by general systemic inammation with specic
physical presentations and increased titer of
autoantibodies against double-stranded DNA and
other nuclear components. High antibody levels and
inammation lead to tissue injury and involvement
of the heart, skin, joints, lungs, blood vessels,
kidneys, liver, and nervous system. The exact
eect of selenium on SLE cases has not yet been
explained. Another study proposed that selenium
supplementation has signicant eects on natural
killer cells function in murine SLE. Moreover,
serum levels of selenium in SLE cases have been
shown to be lower compared to healthy subjects.
It has been shown that increased selenium intake
may be eective for SLE cases, however, there
is no report about its eects on autoantibody
synthesis and disease progression. Based on the
investigations presented here, it is thought that
83

a positive association may exist between serum
selenium deciency and higher titers of SLE-
specic antibodies. However, due to insucient
evidence about selenium usage in SLE cases, the
possible therapeutic role of selenium is unclear.
More detailed investigations in the future could
show the eect of selenium usage to alleviate SLE
presentations.
Selenium and Sjögren
Syndrome
Sjögren syndrome is a systemic disease with an
autoimmune nature. The lymphocytic inltration
of the exocrine glands is an important presentation
of the disease. This results in dryness of the eyes
and mouth due to inammation and resultant
pathology of the lacrimal and salivary glands.
Investigations about the eect of selenium on
Sjögren syndrome reveal that serum selenium value
is low in untreated cases, especially in older
cases. Moreover, a former investigation showed
that the management of Sjögren syndrome cases
with selenium in combination with vitamin E
halted disease progression for several years in
some patients, but not in all cases. Although
investigations showed that selenium level is low in
these cases, there is insucient evidence regarding
the eect of selenium on this syndrome. Therefore,
an exact conclusion cannot be made at the moment.
More investigation regarding the probable anti-
DR. ERFAN RAHMANI
84
inammatory eect of selenium in preventing the
progression of this condition are needed.
Selenium and
Behçet's Disease
Behçet's Disease (BD) is a chronic, sever, and
inammatory disorder known by recurrent oral
aphthous ulcers, genital ulcers, uveitis, and skin
plaques. For the rst time, it has been shown
that selenium deciency impedes the humoral
immune mechanism in BD. Investigations showed
that serum selenium level in BD cases was lower
compared to healthy subjects. In contrast, it has
been reported that levels of selenium in BD cases
with ocular involvement is higher than healthy
subjects. A proteomic analysis of autoimmunity in
BD revealed that 16% of cases with uveitis were
positive for the anti-selenium binding protein (SBP)
antibody. It has been reported that autoimmunity
reaction against the retinal SBP may have role in
the pathogenesis of uveitis in these cases. Therefore,
it is thought that higher levels of selenium in BD
cases with ocular involvement is associated with
autoimmunity against the retinal SBP. Although
serum selenium level has been assessed, the eect of
selenium administration in the management of BD
cases is not clear. More investigations on the eect of
selenium supplement in these cases could increase
our knowledge about BD treatment strategies.
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Selenium and Scleroderma
(Systemic Sclerosis)
Scleroderma is a rare connective tissue disease with
unclear pathogenesis. It presents by autoimmunity
mechanisms and excessive evidence of collagen and
extracellular matrix components. The early phase of
the disease is known by active inammation and is
potentially reversible. Micronutrient antioxidants’
level reveals reduced levels of scleroderma, which
is commonly associated with low selenium level.
In support of this results, some studies revealed
low levels of glutathione peroxidase in cases with
scleroderma. In another investigation, treatment
of cases with 0.2 mg of selenium as Na2SeO3
and 10 mg of tocopheryl succinate enhanced
glutathione peroxidase levels and resulted in
desired clinical outcomes. Therefore, investigations
propose a positive association between disease
activity and serum selenium level. Accordingly,
it could be found that sucient selenium may
be eective for the attenuation of scleroderma
progression. Low serum levels of selenium in some
autoimmune disorders was reported. Selenium
supplementation has positive eects in the
treatment of RA, and scleroderma. Selenium usage
decreases the incidence and severity of certain
autoimmune disorders through the maintenance
of thyroid activity and the anti-inammatory
eect of selenium. Since this issue is of clinical
DR. ERFAN RAHMANI
86
signicance, it can be noted in potential nutrition
interventions and have a positive eect on some
autoimmune disorders. One of the main limitations
of this investigation was the lack of ecient
clinical evidence to evaluate the eect of selenium
supplementation on autoimmune disorders. Despite
the fact that the included papers were assessed
by one reviewer and cross-checked by another
investigator, still, publication bias could be another
limitation of this investigation. Although there is
strong evidence on the eectiveness of selenium
usage on RA, more strong clinical ndings are
needed to establish the eect of this substance
on autoimmune musculoskeletal disorders, Sjögren
syndrome, Behcet's disease, and scleroderma. On
the other hand, no evidence was reported regarding
the role of selenium in some autoimmune
disorders like vasculitis, seronegative arthritis, and
antiphospholipid antibody syndrome. We suggested
more investigations evaluating the level of selenium
in these cases and addressing the eect of selenium
supplementation on their treatment.
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DR. ERFAN RAHMANI
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DR. ERFAN RAHMANI
90
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Proof