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Effects of Hyperbaric Oxygen on T helper 17/regulatory T Polarization in Antigen and Collagen-induced Arthritis: Hypoxia-inducible Factor-1α as a Target

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Objectives: We sought to investigate and prove the effect of hyperbaric oxygen therapy (HBOT) on T helper 17 (Th17)/regulatory T (Treg) cell polarization through changes in the expression of hypoxia-inducible factor-1 alpha (HIF-1α) in rheumatoid arthritis (RA) animal model. Methods: We used antigen and collagen-induced arthritis (ACIA) as a RA animal model. Sixteen male BALB/c models of ACIA mice were divided into two groups, the non-HBOT group as the control group and the HBOT group as the treatment group. Expression of HIF-1α, Th17 anti-cluster differentiation 196 (CD196), and Treg anti-interleukine 2 receptor β-chain cells (IL-2Rβ) in tissue from the left knee joint tissue were determined histologically. Oxidative stress and systemic inflammation were assessed by levels of superoxide dismutase (SOD), interleukin 17a (IL-17a), C-reactive protein (CRP), and rheumatoid factor (RF) using the enzyme-linked immune-sorbent assay. The degree of arthritis was assessed by clinical scoring of paw swelling and the diameter of paw swelling. Results: We found a significant decrease (p < 0.050) in the expression of HIF-1α, Th17 (CD196), IL-17a, RF levels, and the clinical scores and the diameter of paw swelling when comparing both groups. There was no significant decrease in the level of CRP in the treatment group compared to the control group. The expression of Treg (IL-2Rβ) increased significantly (p < 0.050) and the level of SOD increased but not significantly (p > 0.050) in the treatment group compared to the control group. Conclusions: HBOT has effects on the polarization of Th17 to Treg through a decrease in expression of HIF-1α in mice with ACIA. HBOT is recommended for use as a support therapy for RA in combination with drug therapy.
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*Corresponding author: titut.harnanik1972@gmail.com
Rheumatoid arthritis (RA) is a chronic
systemic musculoskeletal disease in
which various joints in the body are
inflamed, leading to swelling, pain,
stiness, and a possible loss of function.1,2 RA is
caused by an imbalance in the number or function
of T helper 17 (Th17) cells and regulatory T
(Treg) cells.3,4 Increased oxidative stress also
participates in the pathogenesis and severity of
the disease.5,6
Oxidative stress in RA can be caused by
deteriorating oxygen supply to the joint tissues
thereby supporting increased reactive oxygen species
(ROS), causing oxidative damage that further
promotes inflammation. Hence, oxidative stress
and inammation are inseparably connected.7,8
Hypoxia-inducible factor-1 alpha (HIF-1α) is a
key transcriptional regulator that enables cellular
metabolic adaptation to low levels of oxygen.9 As
a transcription factor, it inuences and regulates
the expression of dozens of genes involved in
maintaining homeostasis such as changes in oxygen
concentration (oxygen-dependent) and independent
signals.10,11 Superoxide dismutase (SOD) antioxidant
is a protein that functions as important defense
mechanisms for oxidative stress and acts as a rst-
original article O M J [2020], V. 35, N. 1: e90
Eects of Hyperbaric Oxygen on T helper
17/regulatory T Polarization in Antigen
and Collagen-induced Arthritis: Hypoxia-
inducible Factor-1α as a Target
Titut Harnanik
1,2,3*, Joewono Soeroso3, Mohammad Guritno Suryokusumo4
and Tedy Juliandhy5
1Department of Hyperbaric, Drs. Med. R. Rijadi S., Phys. Naval Health Institute, Surabaya, Indonesia
2Department of Physiology, Hang Tuah University, Surabaya, Indonesia
3Department of Biochemistry, Unit of the Experimental Animal, Airlangga University, Surabaya, Indonesia
4Department of Hyperbaric, Pembangunan Nasional University, Jakarta, Indonesia
5Department of Electrical Engineering, Hang Tuah University, Surabaya, Indonesia
ARTICLE INFO
Article history:
Received: 1 January 2019
Accepted: 2 May 2019
Online:
DOI 10.5001/omj.2020.08
Keywords:
Hyperbaric Oxygenation;
Hypoxia-Inducible Factor 1;
T-Lymphocytes, Regulator y;
Rheumatoid Factor; Arthritis,
Experimental.
ABSTRACT
Objectives: We sought to investigate and prove the eect of hyperbaric oxygen therapy
(HBOT) on T helper 17 (17)/regulatory T (Treg) cell polarization through changes
in the expression of hypoxia-inducible factor-1 alpha (HIF-1α) in rheumatoid arthritis
(RA) animal model. Methods: We used antigen and collagen-induced arthritis (ACIA)
as a RA animal model. Sixteen male BALB/c models of ACIA mice were divided
into two groups, the non-HBOT group as the control group and the HBOT group
as the treatment group. Expression of HIF-1α, 17 anti-cluster dierentiation 196
(CD196), and Treg anti-interleukine 2 receptor β-chain cells (IL-2Rβ) in tissue from
the le knee joint tissue were determined histologically. Oxidative stress and systemic
inammation were assessed by levels of superoxide dismutase (SOD), interleukin 17a
(IL-17a), C-reactive protein (CRP), and rheumatoid factor (RF) using the enzyme-
linked immune-sorbent assay. e degree of arthritis was assessed by clinical scoring of
paw swelling and the diameter of paw swelling. Results: We found a signicant decrease
(p < 0.050) in the expression of HIF-1α, 17 (CD196), IL-17a, RF levels, and the
clinical scores and the diameter of paw swelling when comparing both groups. ere
was no signicant decrease in the level of CRP in the treatment group compared to
the control group. e expression of Treg (IL-2Rβ) increased signicantly (p < 0.050)
and the level of SOD increased but not signicantly (p > 0.050) in the treatment group
compared to the control group. Conclusions: HBOT has eects on the polarization
of 17 to Treg through a decrease in expression of HIF-1α in mice with ACIA.
HBOT is recommended for use as a support therapy for RA in combination with
drug therapy.
OMAN MED J, VOL 35, NO 1, JANUARY 2020
*Corresponding author: titut.harnanik1972@gmail.com
T H,  .
line component of the defense system against free
radicals or reactive species.12
Interleukin 17a (IL-17a) is an inflammatory
biomarker for RA, which has a strong association
with C-reactive protein (CRP).13 CRP is a member
of the pentraxins protein family, which is composed
of ve 23-kDa subunits and its levels can increase
by 1000-fold or more with infection, inammation,
and tissue injury. CRP levels correlate with morning
stiness, pain, fatigue, grip strength, articular index,
and disability.14
Rheumatoid factor (RF) is the most common
laboratory serologic marker for the diagnosis of
RA.15 Although RF can be detected in patients
with other connective tissue diseases, RF isotypes
are helpful in the management of RA patients
from the time of diagnosis until deciding on the
choice of therapeutic strategy. RF testing in RA
patients has a sensitivity of 60% to 90% and a
specicity of 85%.16
RA causes high-intensity pain and severe
suering because it is oen not diagnosed or treated
quickly enough.17 Joint destruction occurs in the rst
six months aer illness, and permanent defects occur
two to three years later if le untreated.18 Extra-
articular manifestations of RA occur in 17.8–40.9%
of RA patients and 1.5–21.5% are usually associated
with increased morbidity and mortality such as
cardiopulmonary and kidney due to developing the
disease itself or the eects of the drugs given.19,20
Years of aggressive treatment are needed to control
symptoms, manage pain, and stop the development
of RA. Standard therapy in the form of drugs and
even surgery has not provided optimal results.21
Hyperbaric oxygen therapy (HBOT) is based
on administering pure oxygen to the patient while
undergoing increased ambient pressure.22 HBOT
can be a new breakthrough for creating appropriate
treatment strategies and reducing the adverse eects
of the drugs used, so HBOT research on RA needs
to be developed again. e Naval Health Institute
of the Indonesian Navy has used HBOT to treat
diving cases of decompression sickness, arterial gas
embolism, and gas poisoning, and even as an adjunct
therapy in some cases of clinical diseases such as
wound healing, diabetes mellitus with gangrene gas,
and osteomyelitis. Several studies have shown that
HBOT has a specic mechanism that can reduce
inflammation, but the mechanism of reducing
arthritis in RA is still unclear.
METHODS
We conducted a randomized, control study between
January and April 2018. We used BALB/c mice, male,
weighing 20–30 grams, aged 10–14 weeks, healthy
during the adaptation phase with the characteristics
of clear-eyed, shiny fur, agile movements, and
good feces.
e nature of this experiment was invasive and
fatal to the experimental animals. Random sampling
was used to select 16 mice with collagen-induced
antigen and arthritis (ACIA) from a total of 20. e
selected mice were divided into two groups with
each group consisting of eight mice. e rst group
was the control group (non-HBOT) and the second
group was the treatment group (HBOT).
We used ACIA as an animal model of RA
because ACIA is an animal model that is very similar
to RA in humans. Mice were injected with 100 g
of methylated bovine serum albumin (mBSA) in
50 L phosphate buffer saline (PBS), which was
emulsied with 50 L complete Freund adjuvant
subcutaneously and 200 ng of Bordetella pertussis
toxin (PTx) intraperitoneally.
Seven days later, mice were injected with 50 g
mBSA and 100 g collagen type II (CI I) in 50 L PBS
were emulsied with 50 L of incomplete Freund
adjuvant (IFA) and 200 ng PTx subcutaneously.
On day 14 of the study, mice were injected with 50
g mBSA and 100 g CII in 50 L PBS emulsied
with 50 L IFA subcutaneously and 200 ng PTx
intraperitoneally. On day 28 of the study, mice were
induced with 50 g mBSA dissolved in 20 µL PBS
into the le cavity of the knee joint intra-articular
(ipsilateral) and the right knee cavity (contralateral)
was injected with 20 L PBS intraarticularly.
Twenty-one days later (day 49 of the study), we
got research animals with the characteristics of RA
disease (ACIA animal models).
We used Treatment Table 9 (USN TT9), the
hyperbaric oxygen table dosing protocol developed
by the United States Navy (USN). e treatment
group was given normal air exposure for 10 minutes
at 2.4 atmospheres absolute (ATA) pressure. en
given oxygen exposure of 100% 3–4 L/min for
90 minutes divided by 3 × 30 minutes intervals 2
× 5 minutes breathing with normal air at 2.4 ATA
pressure. After that, the pressure was reduced to
1 ATA while breathing normal air without using
oxygen for 10 minutes. e treatment group received
HBOT for 10 consecutive days.
T H,  .
All mice were anesthetized with ketamine (300
mg/kg body weight + xylazine 40 mg/kg body
weight) intraperitoneally aer 30 minutes of exposure
to HBO. Blood and joint tissue samples were taken
aer 10 minutes to ensure no pain response. Blood
was taken using a syringe on the heart ventricle for
enzyme-linked immune-sorbent assay (ELISA)
examination, and synovial tissue was taken by using a
scalpel for immunohistochemical examination. e
mice were killed by neck dislocation.
The expression of HIF-1α was determined
using the anti-HIF-1α mouse monoclonal
immunoglobulin G1 (IgG1) antibody, the anti-
cluster differentiation 196 (CD196) mouse
monoclonal IgG1 antibody for the expression of
17, and anti-interleukine 2 receptor β-chain cells
(IL-2Rβ) mouse monoclonal IgG2b antibody (all
from Santa Cruz Biotechnology, Inc., Santa Cruz,
CA) for expression of Treg. We used the avidin-
biotin complex for staining. Immunoexpression was
calculated from the average number of brown cells
in ve large visual elds at 400 × magnication on a
light microscope.
e level of serum RF was measured using IgG
RF Mouse ELISA kit (LifeSpan BioSciences, Inc.,
USA). e level of serum CRP was measured using
mouse CRP antibody kit (LifeSpan BioSciences,
Inc., USA), and level of IL-17a in plasma was
measured using mouse IL-17a antibody (Bioassay
Technology Laboratory system, Korain Biotech
Co., Ltd, Shanghai, China) with an enzyme-linked
immunosorbent assays (ELISA) reader (Zenix-320
microplate reader). e examination of plasma SOD
levels was measured using a mouse SOD ELISA kit
(LifeSpan BioSciences, Inc., USA) with an ELISA
reader (Spectrophotometer Zhimadzu) analyzers.
e concentrations of RF (IU/mL), CRP (g/mL),
IL-17a (ng/mL), and SOD (L/mL) captured were


Figure 1: Immunohistochemical staining of hypoxia-inducible factor-1α (HIF-1α) in the (G1) non-
hyperbaric oxygen therapy (HBOT) and (G2) HBOT groups. Living cells that expressed the HIF-1α protein
(positive cells) were stained brown and blue cells (hematoxylin stain) showed no expression of the HIF-1α
protein. Magnication (a) = 50 ×, (b) = 400 ×.
OMAN MED J, VOL 35, NO 1, JANUARY 2020
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determined by measuring absorbance at 450 nm
using a spectrophotometer.
e degree of arthritis was assessed by clinical
scoring of paw swelling and the diameter of the paw
was measured by digital calliper (Mitutoyo, Japan).
e clinical scoring of the paw was graded as follows:
0 = normal and no swelling; 1 = erythema and mild
edema; 2 = erythema and moderate edema; 3 =
erythema and severe edema; 4 = maximal swelling
and deformation leading to incapacitated limb. e
calliper was placed across the paw at widest point
with a level of accuracy up to 0.05 mm (the number
of strips on the slider scale was 20 so that 1 mm: 20
= 0.05 mm). e values were expressed as the mean
of the two paw diameters of mice.
All data were analyzed using SPSS Statistics
(IBM Corp. Released 2013. IBM SPSS Statistics
for Windows, Version 22.0. Armonk, NY: IBM
Corp.). All values were expressed as mean±standard
deviations (SD). A value of p < 0.050 was considered
statistically signicant.
RESULTS
e normality test, using the Shapiro-Wilk test showed
the expression of HIF-1α, CD196, IL-2Rβ, SOD levels,
IL-17a, CRP, RF, clinical scoring of paw swelling, and
diameter of paw swelling had normal distribution (p >
0.050). e results of Lavene test showed expression
of HIF-1α, SOD levels, IL-17a, RF, and the clinical
scoring of paw swelling and the diameter of paw
swelling had homogeneous variance (p > 0.050), but
the expression of CD196, IL-2Rβ, and the level of CRP
did not have homogeneous variance (p < 0.050).
The independent t-test showed there was a
signicant decrease in the expression of HIF-1α in
HBO group (8.7±2.2, p < 0.001) compared to non-
HBO group (69.9±3.1, p < 0.050) [Figure 1].


Figure 2: Immunohistochemical staining of anti-cluster dierentiation 196 (CD196) in the (G1) non-
hyperbaric oxygen therapy (HBOT) and (G2) HBOT groups. Living cells that expressed the CD196 protein
(positive cells) were stained brown and blue (hematoxylin stain) cells showed no expression of the CD196
protein. Magnication (a) = 50 ×, (b) = 400 ×.
T H,  .
The Mann-Whitney test determined that the
expression of CD196 also decreased signicantly in
the HBO group (4.8±1.4, p < 0.001) compared to
non-HBO group (40.0±4.7, p < 0.050) [Figure 2].
e Mann-Whitney test showed the expression
of IL-2Rβ increased signicantly in the HBO group
(5.0±1.3, p < 0.001) compared to the non-HBO
group (48.2±17.9, p < 0.050) [Figure 3].
e dierences in the results of oxidative stress,
systemic inammation, and degree of arthritis in
experimental groups are shown in Table 1. In the
independent t-test showed there was no signicant
Table 1: Dierences of the results of systemic inammation, oxidative stress, and degree of arthritis in the
control and treatment groups.
Variables G1 G2 p-value
SOD, L/mL 0.012 ± 0.001 0.014 ± 0.001 0.093
IL-17, ng/mL 0.2 ± 0.0 0.1 ± 0.0 < 0.001
CRP, g/mL 47.3 ± 18.8 40.4 ± 10.0 0.599
RF, IU/mL 0.012 ± 0.001 41.2 ± 6.8 < 0.001
Clinical scoring of paw swelling 13.6 ± 1.9 8.3 ± 1.9 < 0.001
Diameter of paw swelling, mm 6.9 ± 0.4 6.1 ± 0.4 0.001
SOD: superoxide dismutase; IL-17: interleukin 17; C RP: C-reactive protein; RF: rheumatoid factor.
Data shown as mean±SD; p < 0.050 was considered statistically signicant.
G1: non-HBOT group; G2: HBOT group.


Figure 3: Immunohistochemical staining of anti-interleukine 2 receptor β-chain cells (IL-2Rβ) in the (G1)
non-hyperbaric oxygen therapy (HBOT) and (G2) HBOT groups. Living cells that expressed the IL-2Rβ
protein (positive cells) were stained brown and blue cells (hematoxylin stain) showed no expression of the
IL-2Rβ protein. Magnication (a) = 50 ×, (b) = 400 ×.
OMAN MED J, VOL 35, NO 1, JANUARY 2020
T H,  .
increase (p = 0.093) in SOD levels, there was a
signicant decrease (p < 0.001) in the level of IL-
17a, RF, and clinical scoring of paw swelling in the
treatment group compared to control group. e
diameter of paw swelling also decreased signicantly
in the treatment group compared to the control
group [Table 1]. ere was no signicant decrease
in CRP levels between the two groups.
DISCUSSION
Research on RA continues to develop. Research on
the use of antioxidants or antioxidant-containing
foods combined with drugs, such as methotrexate,
and the addition of natural polyphenol antioxidants,
including silibinin can function to increase the
eect of drugs and reduce oxidative stress.23,24 Our
study limited the use of HBOT alone to determine
the eect and basic mechanism of oxygen use on
the improvement of hypoxic cells and to see the
extent of the role of HBOT in polarization or
changing of phenotype from Th17 cells to Treg
cells. In the future, research on the use of HBOT
in combination with drugs, biological agents, or
other antioxidants needs to be considered and
investigated further.
Several HBOT studies on RA have been carried
out. Clinical improvement due to decreased serum
immune complexes and T lymphocyte function was
found in patients with RA aer 21 sessions of HBOT
under 1.7 ATA for 40 minutes.25 HBOT 70% at 1.5
ATA for three hours daily for two weeks reduced
neuropathic pain in eight Sprague-Dawley male
mice RA models.26 In contrast to previous studies,
this study examined the strategy of autoimmune
anti-rheumatic therapy involving polarization of
17 cells (CD196) into Treg (IL-2Rβ) through
changes in expression of HIF-1α aer HBOT. is
study used higher oxygen levels and pressure than
previous studies but was still based on safe doses. It
has been suggested that if the pressure used to deliver
hyperbaric oxygen did not exceed 3 ATA (equivalent
to 20 meters in seawater) and the duration of
treatment for elective therapy did not exceed two
hours then this HBOT was still considered safe.27
is study used HBOT with dosage according
to USN TT9 breathing 100% oxygen for 3 × 30
minutes intervals 2 × 5 minutes breathing normal
air at 2.4 ATA for 10 consecutive days. Higher doses
were expected to provide more optimal results.
Some theories stated that HBOT was considered a
safe treatment modality but carried a risk because
of hyperoxia and increased pressure. HBOT acted
as a chemical agent that could aect the oxidants
and antioxidants system. e main mechanism for
HBOT was based on the generation of intracellular
ROS. Previously, it has been stated that respiration
with high oxygen concentrations and pressure greater
than 1 ATA would increase ROS production.28,29
We thought that HBOT could lead to increased
ROS and oxidative stress if given at excessive
doses; therefore, this study was limited to 10
consecutive days.
Studies of the effects of HBOT on RA on
oxidative stress has also been carried out previously
using oxygen levels and lower pressures compared to
this study.30,31 HBOT increased the SOD activity,
decreased the value of lipoperoxide, and improved
the erythrocyte sedimentation rate and the Lansbury
articular index in patients with RA.30 HBO oxygen
36% at 1.25 ATA for three weeks reduced derivative
reactive oxygen metabolites and CRP in collagen-
induced arthritis type II mice.31
e results of the study on oxidative stress levels
could be seen in SOD levels. The level of SOD
increased but not signicantly in the HBOT group
compared to non-HBOT group. We hypothesized
that HBOT increased ROS production but, if the
level was not excessive, it could be useful because
ROS could also act as a cellular messenger in many
signal transduction pathways and induce other
cytoprotective genes.32,33 is seemingly c ontroversial
eect was strongly inuenced by therapeutic doses,
and the length and interval of exposure. ROS was
related to the amount of oxygen present, but HBOT
paradoxically induced the activity of antioxidant
enzymes such as SOD. e nuclear factor erythroid
2-related factor 2 (Nrf2)/Keap1 pathway was the
main regulator of redox homeostasis. Nrf2 had a
major contribution to the regulation of defense
systems in various antioxidants as a cytoprotective
response to endogenous and exogenous pressures
caused by ROS.34 SOD functioned to suppress or
prevent the formation of ROS in cells by rapidly
neutralizing any molecule with the potential to
develop into free radicals or any free radicals with the
ability to induce other radical production.35 is fact
was consistent with the concept of mitochondrial
hormesis, which states the production of ROS
could induce a positive response that was increased
T H,  .
resistance to stress, and actually cause oxidative stress
to decrease.36
Understanding HIF expression in RA joints
allows us to better understand the level at which
they are activated based on the severity of the disease,
and how it aects certain cell types that contribute
to perpetuating this disease. RA triggers the
accumulation of HIF-1α and HIF-2α chains, so that
the target of RA therapy was HIF-1α and HIF-2α.37
We chose the HIF-1α variable instead of HIF-2α in
this study because a previous study stated that HIF-
1α was widely expressed and was believed to play an
important role in the hypoxic response compared to
HIF-2α.38 Under normoxia or hyperoxia conditions,
HIF-1α was more easily degraded than HIF-2α,
which was more stable.39,40 Aer HBOT, HIF-1α
was hydroxylated by prolyl hydroxylase domain
proteins, recognized by the ubiquitin E3 ligase, and
directed to the proteasome for degradation.41,42
The results of this study showed significant
decreases in HIF-1α and 17 (CD196) expression,
and a signicant increase in the expression of Treg
(IL-2Rβ) in the treatment group compared to the
control group. e mechanism of HBOT hyperoxia
or normoxia aer exposure to HBOT caused HIF-
1α activity to decrease, which caused polarization or
dierentiation of phenotypes from 17 (CD196)
to Treg (IL-2Rβ). Decreasing the expression of HIF-
1α activated FOXP3 gene expression and finally
degraded RORγt in 17/Treg progenitor when
committing to polarization from 17 to Treg so
that the number of 17 (CD196) decreased.
IL-17a levels decreased signicantly and CRP
levels decreased but not signicantly in the treatment
group compared to the control group. This is in
accordance with previous studies that found a
relationship between serum IL-17a levels and CRP.
IL-17a is inducer CRP from mouse smooth muscle
cells and hepatocytes.43,44 CRP levels decreased, but
not signicantly, because many factors also inuence
CRP levels. ROS is also thought to play a role in
increasing CRP levels.45 We suspect that ROS as a
result of exposure to HBOT could also play a role in
CRP metabolism. Increased blood levels of IL-17a
from mice with RA were of limited use as biomarkers
to show disease activity.46
RFs are a family of autoantibodies directed to
the Fc portion of IgG. ey are locally produced
in RA by B cells present in lymphoid follicles and
germinal center-like structures that develop in
inamed synovium.47 ey are heterogeneous and
usually composed of IgM. Because of this, most
assays detect only IgM. RFs are used as a marker in
individuals with suspected RA or other autoimmune
conditions. Detection of IgM RFs is also helpful as a
prognostic index, and some studies have shown that
immunosuppressive treatment can decrease serum
RF levels. However, the clinical usefulness of RFs in
monitoring disease activity and treatment response is
limited. In this study, the level of IgM RF decreased
signicantly in the treatment group compared to the
control group. Decreasing the number of 17 aer
exposure to HBOT caused a signicant decrease in
IL-17a production in the treatment group compared
to the control group. is resulted in a direct decrease
in autoreactive B cell proliferation and a decrease
in dierentiation and plasma cell activity,16 which
resulted in a decrease in the production of RF.
Hypoxia had been shown to induce an
inflammatory response, in this case, ACIA. The
reduction of arthritis clinically after exposure to
HBOT could be seen from the results of clinical
scoring and diameter of paw swelling, which both
decreased significantly in the treatment group
compared to the control group. e decrease in the
amount and function of Th17 caused a decrease
in the production of pro-inammatory cytokines
IL-17a, IL-17f, IL-21, IL-22, interferon γ, and
granulocyte-macrophage-colony-stimulating factor
so the arthritis decreased.48
CONCLUSION
We recommend the use of HBOT as a supporting
therapy in RA. Our study provides new insights into
therapeutic interventions in human autoimmune
diseases.
Disclosure
The authors declared no conflict of interests. The Ethics
Committee of Naval Health Institute, Indonesian Navy stated
that this study was feasibly approved (Animal Ethical Clearance
Certificate No.009/AECC/NHI/IX/2017). This study
received support from the Department of Physiology, Faculty
of Medicine, Hang Tuah University, Surabaya, Indonesia;
Department of Hyperbaric, Drs. Med. R. Rijadi S., Phys. Naval
Health Institute, Indonesian Navy, Surabaya, Indonesia; and
Department of Biochemistry, Unit of the Experimental Animal,
Faculty of Medicine, Airlangga University, Surabaya, Indonesia.
is research was funded by the Faculty of Medicine, Hang Tuah
University, Surabaya, Indonesia.
OMAN MED J, VOL 35, NO 1, JANUARY 2020
T H,  .

1. Al Saleh J, EL Sayed M, Monsef N, Darwish E. The
prevalence and the determinants of musculoskeletal diseases
in Emiratis attending primary health care clinics in Dubai.
Oman Med J 2016;31(2):117-123.
2. Mohan SK, Priya V. Serum total sialic acid, lipid
peroxidation, and glutathione reductase levels in patients
with rheumatoid arthritis. Turk J Med Sci 2010;40(4):537-
540.
3. Gaafar T, Farid R, Raafat H, Bayoumi F, Gerges B, Rasheed
D. The TH17/Treg imbalance in rheumatoid arthritis
and relation to disease activity. J Clin Cell Immunol
2015;6(381):2.
4. Fasching P, Stradner M, Graninger W, Dejaco C, Fessler
J. erapeutic potential of targeting the 17/Treg axis in
autoimmune disorders. Molecules 2017 Jan;22(1):134.
5. Mateen S, Moin S, Khan AQ, Zafar A, Fatima N. Increased
reactive oxygen species formation and oxidative stress in
rheumatoid arthritis. PLoS One 2016 Apr;11(4):e0152925.
6. Saxena R, Suneja S, Saxena R, Sharma D, Lal AM.
Cumulative eect of systemic inammation and oxidative
stress in 40 known cases of active rheumatoid arthritis. Int J
Res Orthop. 2015 Dec;1(1):7-10.
7. Lepetsos P, Papavassiliou AG. ROS/oxidative stress
signaling in osteoarthritis. Biochim Biophys Acta 2016
Apr;1862(4):576-591.
8. Rajendiran S, Nimesh A, Ananthanarayanan PH, Dhiman
P, Ananthanarayanan PH, Dhiman P, et al; Swetha Kumari
A; Soundararaghavan S. Markers of oxidative stress in
pregnant women with sleep disturbances. Oman Med J
2015 Jul;30(4):264-269.
9. Lakhter AJ, Lahm T, Broxmeyer HE, Naidu SR. Golgi
associated HIF1a serves as a reserve in melanoma cells. J
Cell Biochem 2016 Apr;117(4):853-859.
10. Semenza GL; US National Library of Medicine National
Institutes of Health. Hypoxia-inducible factors: mediators
of cancer progression and targets for cancer therapy. Trends
Pharmacol Sci 2012 Apr;33(4):207-214.
11. Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF
transcription factors, inflammation, and immunity.
Immunity 2014 Oct;41(4):518-528.
12. Fukai T, Ushio-Fukai M. Superoxide dismutases: role in
redox signaling, vascular function, and diseases. Antioxid
Redox Signal 2011 Sep;15(6):1583-1606.
13. Pavlovic V, Dimic A, Milenkovic S, Krtinic D. Serum levels
of IL-17, IL-4, and INFγ in Serbian patients with early
rheumatoid arthritis. J Res Med Sci 2014 Jan;19(1):18-22.
14. Kim KW, Kim BM, Moon HW, Lee SH, Kim HR. Role
of C-reactive protein in osteoclastogenesis in rheumatoid
arthritis. Arthritis Res er 2015 Mar;17(1):41.
15. Shen R, Ren X, Jing R, Shen X, Chen J, Ju S, et al.
Rheumatoid factor, anti-cyclic citrullinated peptide
antibody, c-reactive protein, and erythrocyte sedimentation
rate for the clinical diagnosis of rheumatoid arthritis. Lab
Med 2015;46(3):226-229.
16. Ingegnoli F, Castelli R , Gualtierotti R. Rheumatoid factors:
clinical applications. Dis Markers 2013;35(6):727-734.
17. Hussain W, Noorwali A, Janoudi N, Baamer M, Kebbi
L, Mansafi H, et al. From symptoms to diagnosis: an
observational study of the journey of rheumatoid arthritis
patients in Saudi Arabia. Oman Med J 2016 Jan;31(1):29-
34.
18. Choy E. Understanding the dynamics: pathways involved
in the pathogenesis of rheumatoid arthritis. Rheumatology
(Oxford) 2012 Jul;51(5)(Suppl 5):v3-v11.
19. Vela P. Extra-articular manifestations of rheumatoid
arthritis. EMJ Rheumatol. 2014;1:103-112.
20. Góis M, Carvalho F, Sousa H, Ferreira AC, Sousa J, Nolasco
F. Renal involvement in rheumatoid arthritis: analysis of 53
renal biopsies. Port J Nephrol Hypert 2017;31(1):25-30.
21. Shih YT, Kao TH, Pan HC, Chen HT, Tsou HK. e
surgical treatment principles of atlantoaxial instability
focusing on rheumatoid arthritis. Biomed Res Int
2015;2015:518164.
22. Simsek K, Sadir S, Oter S. e relation of hyperbaric oxygen
with oxidative stress - reactive molecules in action. Oxid
Antioxid Med Sci 2015;4(1):17-22.
23. Dar RA, Brahman PK, Khurana N, Wagay JA, Lone ZA,
Ganaie MA, et al. Evaluation of antioxidant activity of
crocin, podophyllotoxin and kaempferol by chemical,
biochemical and electrochemical assays. Arab J Chem 2017
Feb;10:S1119-S1128.
24. Hussain SA, Mortada AH, Jasim NA, Gorial FI. Silibinin
improves the eects of methotrexate in patients with active
rheumatoid arthritis: pilot clinical study. Oman Med J 2016
Jul;31(4):263-269.
25. Lukich VL, Poliakova LV, Sotnikova TI, Belokrinitskiĭ DV.
[Hyperbaric oxygenation in the comprehensive therapy of
patients with rheumatoid arthritis (clinico-immunologic
study)]. Fiziol Zh 1991 Sep-Oct;37(5):55-60.
26. Koo ST, Shin YI, Lee DY, Lee CH. e continuance time
of pressure eect in the rat model of complete Freund’s
adjuvant induced arthritis. Pain Physician 2015 Jan-
Feb;18(1):E39-E45.
27. Eggleton P, Bishop AJ, Smerdon GR. Safety and ecacy of
hyperbaric oxygen therapy in chronic wound management:
current evidence. Chronic Wound Care Management and
Research 2015;2:81-93.
28. om SR. Hyperbaric oxygen: its mechanisms and ecacy.
Plast Reconstr Surg 2011 Jan;127(Suppl 1):131S-141S.
29. St. Nikitopoulou T, Papalimperi AH. e inspiring journey
of hyperbaric oxygen therapy, from the controversy to
the acceptance by the scientic community. Health Sci J
2015;9(4):1.
30. Kamada T. [Superoxide dismutase and hyperbaric oxygen
therapy of the patient with rheumatoid arthritis]. Nihon
Seikeigeka Gakkai Zasshi 1985 Jan;59(1):17-26.
31. Nagatomo F, Gu N, Fujino H, Okiura T, Morimatsu F,
Takeda I, et al. Eects of exposure to hyperbaric oxygen
on oxidative stress in rats with type II collagen-induced
arthritis. Clin Exp Med 2010 Mar;10(1):7-13.
32. Harch PG. Hyperbaric oxygen in chronic traumatic brain
injury: oxygen, pressure, and gene therapy. Med Gas Res
2015 Jul;5(1):9.
33. Sureda A, Batle JM, Martorell M, Capó X, Tejada S, Tur JA,
et al. Antioxidant response of chronic wounds to hyperbaric
oxygen therapy. PLoS One 2016 Sep;11(9):e0163371.
34. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev
Pharmacol Toxicol 2013;53:401-426.
35. Bouvier E, Brouillard F, Molet J, Claverie D, Cabungcal J-H,
Cresto N, et al. Nrf2-dependent persistent oxidative stress
results in stress-induced vulnerability to depression. Mol
Psychiatry 2017 Dec;22(12):1701-1713.
36. Naveed S, Aslam M, Ahmad A. Starvation based dierential
chemotherapy: a novel approach for cancer treatment.
Oman Med J 2014 Nov;29(6):391-398.
37. Hua S, Dias TH. Hypoxia-inducible factor (HIF) as a target
for novel therapies in rheumatoid arthritis. Front Pharmacol
2016 Jun;7:184.
38. Shrestha P, Davis DA, Veeranna RP, Carey RF, Viollet
C, Yarchoan R. Hypoxia-inducible factor-1 alpha as a
therapeutic target for primary eusion lymphoma. PLoS
Pathog 2017 Sep;13(9):e1006628.
39. Wilson GK, Tennant DA, McKeating JA. Hypoxia inducible
factors in liver disease and hepatocellular carcinoma: current
understanding and future directions. J Hepatol 2014
Dec;61(6):1397-1406.
40. Deynoux M, Sunter N, Hérault O, Mazurier F. Hypoxia and
hypoxia-inducible factors in leukemias. Front Oncol 2016
Feb;6:41.
41. Unwith S, Zhao H, Hennah L, Ma D. e potential role of
HIF on tumour progression and dissemination. Int J Cancer
2015 Jun;136(11):2491-2503.
T H,  .
42. Fan L, Li J, Yu Z, Dang X, Wang K. e hypoxia-inducible
factor pathway, prolyl hydroxylase domain protein
inhibitors, and their roles in bone repair and regeneration.
Biomed Res Int 2014;2014:239356.
43. Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam
K, Agrawal A, et al. Interleukin-17 stimulates C-reactive
protein expression in hepatocytes and smooth muscle cells
via p38 MAPK and ERK1/2-dependent NF-kappaB and C/
EBPbeta activation. J Biol Chem 2007 Sep;282(37):27229-
27238.
44. Siloşi I, Boldeanu MV, Cojocaru M, Biciuşcă V, Pădureanu
V, Bogdan M, et al. e relationship of cytokines IL-13
and IL-17 with autoantibodies prole in early rheumatoid
arthritis. J Immunol Res 2016;2016:3109135.
45. Xu S, Zhao J, Liu J, Gou W, Fibrinopeptide A. Fibrinopeptide
A induces expression of C-reactive protein via the ROS-
ERK1/2/ P38-NF-κB signal pathway in vascular smooth
muscle cells. Cell Physiol Biochem 2018;47(1):266-278.
46. Shao Y, Zhao FQ. Emerging evidence of the physiological
role of hypoxia in mammary development and lactation. J
Anim Sci Biotechnol 2014 Jan;5(1):9.
47. Song YW, Kang EH. Autoantibodies in rheumatoid
arthritis: rheumatoid factors and anticitrullinated protein
antibodies. QJM 2010 Mar;103(3):139-146.
48. Bystrom J, Taher TE, Muhyaddin MS, Clanchy FI, Mangat
P, Jawad AS, et al. Harnessing the therapeutic potential of
17 cells. Mediators Inamm 2015;2015:205156.
... Tregs show a strongly enhanced inhibitory function when exposed to inflammation [37] . HBO therapy boosts Treg expression while reducing HIF-1α expression in mice with antigen and collagen-induced arthritis [38] . In addition, AQP4 expression increases in TBI [39] and colonic inflammation [40] , and AQP4-knockout attenuates experimental colitis in mice [41] . ...
... 67,73 Upon reaching a threshold expression level of ROR γ T, the cell transitions to a TH17 phenotype, potentially inciting inflammation. 74 Hypoxia and B Cells B cells, integral to adaptive immunity, exhibit varying responses to hypoxic environments, which remain incompletely understood. Research on mouse models has revealed that the germinal center (GC) micro-environment is hypoxic. ...
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Immune cells are pivotal in the dynamic interplay between hypoxia and inflammation. During hypoxic conditions, HIF-1α, a crucial transcription factor, facilitates the adaptation of immune cells to the hypoxic micro-environment. This adaptation includes regulating immune cell metabolism, significantly impacting inflammation development. Strategies for anti-inflammatory and hypoxic relief have been proposed, aiming to disrupt the hypoxia-inflammation nexus. Research extensively focuses on anti-inflammatory agents and materials that target immune cells. These primarily mitigate hypoxic inflammation by encouraging M2-macrophage polarization, restraining neutrophil proliferation and infiltration, and maintaining Treg/TH17 balance. Additionally, oxygen-releasing nano-materials play a significant role. By alleviating hypoxia and clearing reactive oxygen species (ROS), these nano-materials indirectly influence immune cell functions. This paper delves into the response of immune cells under hypoxic conditions and the resultant effects on inflammation. It provides a comprehensive overview of various therapies targeting specific immune cells for anti-inflammatory purposes and explores nano-materials that either carry or generate oxygen to alleviate anoxic micro-environments.
... HBOT decreases HIF-1 α activity and Th17 differentiation to w ar d the Treg phenotype. Diminished Th17 cell population results in a decrease in the synthesis of pro-inflammatory c ytokines, thereb y mitigating the clinical manifestations of arthritis [71] . The impact of HBOT on T cells pr edominantl y manifests within the context of tumor tr eatment. ...
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Inflammatory bowel diseases, with an increasing incidence, pose a significant health burden. Although there have been significant advances in the treatment of IBD, more progress is still needed. Hyperbaric oxygen therapy (HBOT) has been shown to treat a host of conditions such as carbon monoxide poisoning, decompression sickness, and gas gangrene. In the last few years, there has been an increase in research into the use of HBOT as an adjunct to conventional treatment for IBD. Related researches have shown that HBOT may exert its therapeutic effects by decreasing oxidative stress, inhibiting mucosal inflammation, promoting ulcer healing, influencing gut microbes and reducing the incidence of IBD complications. This paper aims to provide a comprehensive review of experimental and clinical trials exploring hyperbaric oxygen therapy as a supplement to IBD treatment strategies.
... Conversely, when HBO 2 treatment is administered in hypoxic conditions with a derivational elevated HIF-1α, HBO 2 treatment decreased the disease-mediated high levels of HIF-1α [61,119,[129][130][131][132][133][134][135][136][137][138][139]. The evaluation of studies performed in conditions of relative hypoxia secondary to inflammation indicates that the effect of HBO 2 on HIF-1α protein expression is dependent on the number of HBO 2 sessions administered, with HBO 2 having an increasing effect when administered in up to five sessions [140][141][142][143], and treatment with more than six sessions having a decreasing effect under these conditions [47,120,[144][145][146][147][148][149][150][151][152][153][154][155][156]. However, six study results were not supportive of this trend [117,140,141,[157][158][159]. ...
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The perception of sepsis has shifted over time; however, it remains a leading cause of death worldwide. Sepsis is now recognized as an imbalance in host cellular functions triggered by the invading pathogens, both related to immune cells, endothelial function, glucose and oxygen metabolism, tissue repair and restoration. Many of these key mechanisms in sepsis are also targets of hyperbaric oxygen (HBO2) treatment. HBO2 treatment has been shown to improve survival in clinical studies on patients with necrotizing soft tissue infections as well as experimental sepsis models. High tissue oxygen tension during HBO2 treatment may affect oxidative phosphorylation in mitochondria. Oxygen is converted to energy, and, as a natural byproduct, reactive oxygen species are produced. Reactive oxygen species can act as mediators, and both these and the HBO2-mediated increase in oxygen supply have the potential to influence the cellular processes involved in sepsis. The pathophysiology of sepsis can be explained comprehensively through resistance and tolerance to infection. We argue that HBO2 treatment may protect the host from collateral tissue damage during resistance by reducing neutrophil extracellular traps, inhibiting neutrophil adhesion to vascular endothelium, reducing proinflammatory cytokines, and halting the Warburg effect, while also assisting the host in tolerance to infection by reducing iron-mediated injury and upregulating anti-inflammatory measures. Finally, we show how inflammation and oxygen-sensing pathways are connected on the cellular level in a self-reinforcing and detrimental manner in inflammatory conditions, and with support from a substantial body of studies from the literature, we conclude by demonstrating that HBO2 treatment can intervene to maintain homeostasis.
... Additionally, hypoxia not only induces ROS accumulation but also induces high expression of HIF-1a (64). Hyperbaric oxygen therapy reduces the levels of IL-17a, CRP, and rheumatoid factor in CIA mice by regulating the expression of HIF-1a and promotes the differentiation of Tregs, alleviating oxidative stress and inflammatory response (65). CD3 + T-cells and CD68 macrophages cultured in a hypoxic environment exhibit a stronger inflammatory response (21), confirming the critical role of hypoxia in immune inflammation in RA (27). ...
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Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, pannus formation, and bone and cartilage damage. It has a high disability rate. The hypoxic microenvironment of RA joints can cause reactive oxygen species (ROS) accumulation and mitochondrial damage, which not only affect the metabolic processes of immune cells and pathological changes in fibroblastic synovial cells but also upregulate the expression of several inflammatory pathways, ultimately promoting inflammation. Additionally, ROS and mitochondrial damage are involved in angiogenesis and bone destruction, thereby accelerating RA progression. In this review, we highlighted the effects of ROS accumulation and mitochondrial damage on inflammatory response, angiogenesis, bone and cartilage damage in RA. Additionally, we summarized therapies that target ROS or mitochondria to relieve RA symptoms and discuss the gaps in research and existing controversies, hoping to provide new ideas for research in this area and insights for targeted drug development in RA.
... [17] In addition, HBO affects the M1 to M2 phenotypic shift by decreasing the expression of HIF-1α while increasing the production of IL-10, thereby reducing arthritis in collagen-induced arthritis. [18] We expect HBO to have benefit in peripheral neuropathy as well. ...
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Acute motor axonal neuropathy (AMAN) is a rare immune-mediated disorder characterized by acute flaccid paralysis with elevated levels of GM1 antibodies. It is also known as a subtype of the Guillain-Barre syndrome (GBS) and develops since antigen s serve as antibodies in the spinal cord. We report a case diagnosed as AMAN with symptoms of ascending limb symmetrical weakness. A neurological examination revealed a flaccid paralysis with multiple cranial nerve palsies. Electromyography showed an axonal type of GBS. The patient refused bone marrow fluid aspiration. Intravenous immunoglobulin was administered at the high care unit. Unfortunately, despite the standard therapy, an optimal recovery was not obtained. Hyperbaric oxygen (HBO) therapy has been known to be common in illnesses and some clinical diseases. Although it has not been indicated for peripheral neuropathy, a remarkable recovery was soon visible in the HBO-treated AMAN case. The HBO mechanisms involved here are anti-inflammation and immunomodulation.
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T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.
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The increasing emergence of multidrug-resistant (MDR) pathogens causes difficult-to-treat infections with long-term hospitalizations and a high incidence of death, thus representing a global public health problem. To manage MDR bacteria bugs, new antimicrobial strategies are necessary, and their introduction in practice is a daily challenge for scientists in the field. An extensively studied approach to treating MDR infections consists of inducing high levels of reactive oxygen species (ROS) by several methods. Although further clinical investigations are mandatory on the possible toxic effects of ROS on mammalian cells, clinical evaluations are extremely promising, and their topical use to treat infected wounds and ulcers, also in presence of biofilm, is already clinically approved. Biochar (BC) is a carbonaceous material obtained by pyrolysis of different vegetable and animal biomass feedstocks at 200–1000 °C in the limited presence of O2. Recently, it has been demonstrated that BC’s capability of removing organic and inorganic xenobiotics is mainly due to the presence of persistent free radicals (PFRs), which can activate oxygen, H2O2, or persulfate in the presence or absence of transition metals by electron transfer, thus generating ROS, which in turn degrade pollutants by advanced oxidation processes (AOPs). In this context, the antibacterial effects of BC-containing PFRs have been demonstrated by some authors against Escherichia coli and Staphylococcus aureus, thus giving birth to our idea of the possible use of BC-derived PFRs as a novel method capable of inducing ROS generation for antimicrobial oxidative therapy. Here, the general aspects concerning ROS physiological and pathological production and regulation and the mechanism by which they could exert antimicrobial effects have been reviewed. The methods currently adopted to induce ROS production for antimicrobial oxidative therapy have been discussed. Finally, for the first time, BC-related PFRs have been proposed as a new source of ROS for antimicrobial therapy via AOPs.
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The increasing emergence of multidrug resistant (MDR) pathogens causes difficult-to-treat infections, with long-term hospitalizations and high incidence of death, thus representing a global public health problem. To manage MDR bacteria bugs, new antimicrobial strategies are necessary, and their introduction in practice is a daily challenge for scientists in the field. An extensively studied approach to treat MDR infections consists in inducing high levels of reactive oxygen species (ROS) by several methods. Although further clinical investigations are mandatory on the possible toxic effects of ROS to mammalian cells, clinical evaluations are extremely promising, and their topical use to treat infected wounds and ulcers, also in presence of biofilm, is already clinically approved. Biochar (BC) is a carbonaceous material obtained by pyrolysis of different vegetable and animal biomass feedstocks, at 200−1000 °C in limited presence of O2. Recently, it has been demonstrated that BC capability of removing organic and inorganic xenobiotics is mainly due to the presence of persistent free radicals (PFRs), which can activate oxygen, H2O2 or persulfate in the presence or not of transition metals by electron transfer thus generating ROS, which in turn degrade pollutants by advanced oxidation processes (AOPs). In this context, the antibacterial effects of BC containing PFRs have been demonstrated by some authors against Escherichia coli and Staphylococcus aureus, thus giving birth to our idea of the possible use of BC-derived PFRs as a novel method capable of inducing ROS generation for antimicrobial oxidative therapy. Here, the general aspects concerning ROS physiological and pathological production and regulation, and the mechanism by which they could exert antimicrobial effects have been reviewed. The methods currently adopted to induce ROS production for antimicrobial oxidative therapy have been discussed. Finally, for the first time, BC-related PFRs have been proposed as a new source of ROS for antimicrobial therapy via AOPs.
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Background: Rheumatoid arthritis (RA) is a systemic inflammatory disorder characterized by joint inflammation, associated with autoantibody production. Renal involvement arises as a complication of treatment or can be related to the disease itself. Methods: 53 biopsies from patients with RA from 1989 to 2015 were reviewed. Histologic diagnosis, age, gender, duration of RA, drug therapy, renal function, proteinuria and haematuria were analyzed. Results: Amyloidosis was the most common renal histologic pattern (21 patients). Membranous Nephropathy (MN) was found in 12 patients, followed by Mesangial Proliferative Glomerulonephritis (n=4) and Focal and Segmental Glomerulosclerosis (n=4), IgA Nephropathy (n=3), Necrotizing Glomerulonephritis (n=3), Chronic Interstitial Nephritis (n=3), Endocapillary Proliferative Glomerulonephritis (n=2) and Minimal Change Disease (n=1). Amyloidosis correlated with long duration RA (14.9±6.66 years vs 8.84±6.37 years; p
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A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17-cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the pro-inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases.
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