




































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: brianmarkc7@gmail.com; brian.churchill@iqvia.com; 
 
 
 

Asian Journal of Immunology 
 
3(1): 208-222, 2020; Article no.AJI.57464 
 

 
 

 

 

TNF-α, TNF Receptors and Their Complex 
Implications in Therapy 

 
Brian Mark Churchill1*, Pallavi Patri2,3, Rashna Cama4 and Jula K. Inrig5,6 

 
1
Department of Medical Science and Strategy (Asia), IQVIA, Etamin Block, Prestige Tech Park, 

Kadubeesanahalli, Bengaluru, Karnataka, 560103, India. 
2
Department of Nephrology, Columbia Asia Hospital – Sarjapur Road, Ambalipura, Bengaluru, 

Karnataka, India. 
3
Weill Cornell Medical College, New York, USA. 

4
Department of Medical Sciences and Strategy (Asia), IQVIA, Natraj by Rustomjee, 702 Western 
Express Highway, Sir Mathuradas Vasanji Road Junction, Mumbai, Maharashtra, 400069, India. 

5
Global Head Renal Center of Excellence, Therapeutic Science and Strategy Unit, IQVIA,  

10188 Telesis Ct Suite 400, San Diego, CA 92121, USA. 
6
Department of Medicine, UC Irvine and Duke University, USA. 

 
Authors’ contributions   

 
This work was carried out in collaboration among all authors. Author BMC conceptualized and 

designed the review paper, performed the literature search, wrote the paper and wrote the first draft of 
the manuscript, collected feedback, incorporated the changes, prepared subsequent drafts and then 

the final manuscript. Authors PP, RC and JKI reviewed the manuscript and helped in shaping it. 
All authors read and approved the final manuscript. 

 
Article Information 

 
Editor(s): 

(1) Dr. Cynthia Aracely Alvizo Báez, Autonomous University of Nuevo Leon, Mexico. 
Reviewers: 

(1) Joseli Lannes Vieira, Brazil. 
(2) Juei-Tang Cheng, Christian University, Taiwan. 

Complete Peer review History: http://www.sdiarticle4.com/review-history/57464 

 
 
 
 

Received 10 May 2020  
Accepted 02 June 2020 
Published 10 June 2020 

 
 

ABSTRACT 
 

Tumor necrosis factor alpha (TNF-α), also called cachectin or cachexin, is a naturally occurring 
cytokine produced by activated macrophages and monocytes, and to a smaller scale by T-
lymphocytes, B-lymphocytes, fibroblasts and astrocytes. It has both inflammatory and 
immunomodulatory roles effectuated through its action on tumor necrosis factor receptor-1 
(TNFR1) and tumor necrosis factor receptor-2 (TNFR2). TNF-α overexpression (especially of 
TNFR1 mediated actions) or under expression (especially of TNFR2 mediated actions) may 

Review Article 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
209 

 

contribute to several diseases including rheumatoid arthritis, psoriatic arthritis, ankylosing 
spondylitis, Crohn’s disease, ulcerative colitis, and juvenile inflammatory arthritis. Several anti-TNF 
therapies are proven to be beneficial in these diseases, including etanercept, infliximab, 
adalimumab, certolizumab and golimumab.  
Biological responses of TNF-α include inflammation, apoptosis, immunomodulation, tissue repair, 
antiviral and antitumor activity and mediation of endotoxin-induced septic shock, recruitment of 
inflammatory cells including neutrophils, monocytes and lymphocytes to sites of infection; and cell 
activation through action on different receptors (TNFR1 and TNFR2). 
Low grade chronic inflammation occurs in several other diseases including atherosclerosis, 
hypertension, chronic kidney disease, Alzheimer’s disease, Parkinson’s disease and multiple 
sclerosis. Researchers have explored whether anti-TNF therapies can be helpful in these diseases 
too. Both positive and negative effects of anti-TNF therapies have been observed in these 
diseases. These observations suggest that TNF-α and TNF receptors system have an incredibly 
complex pathophysiologic role, and hence blockade of this pathway results in complex effects on 
different organ systems. In this review we have explored the myriad effects on various organ 
systems due to TNF blockade, including COVID-19. 
 

 
Keywords: Tumor necrosis factor alpha (TNF-α); rheumatoid arthritis; COVID-19; TNFR1; TNFR2. 
 

1. INTRODUCTION 
 
Tumor Necrosis Factor (TNF) is a naturally 
occurring inflammatory cytokine the TNF 
superfamily that consists of 19 members 
(ligands) [1]. They are type II transmembrane 
proteins that can bind to 29 receptors of the TNF 
receptor superfamily including FAS, CD40, CD27 
and RANK [2]. 
 
TNF-α, also called cachectin or cachexin, is 
produced by activated macrophages and 
monocytes, and to a smaller scale by T-
lymphocytes, B-lymphocytes, fibroblasts, and 
astrocytes [3]. It can bind to TNFR1 (tumor 
necrosis factor receptor-1) and TNFR2 (tumor 
necrosis factor receptor-2), and has both 
inflammatory and immunomodulatory roles [4]. It 
has been implicated in pathogenesis of several 
diseases including rheumatoid arthritis, systemic 
lupus erythematosus, ulcerative colitis and 
Crohn’s disease [1,3]. 
 
TNF-α and TNF receptors system is complex 
and has complicated implications in therapy [5]. 
Anti-TNF agents including etanercept, infliximab 
and adalimumab are helpful in treatment of many 
diseases where chronic inflammation is involved- 
for example, rheumatoid arthritis, psoriatic 
arthritis, ulcerative colitis, and Crohn’s disease 
[5-8]. These therapies may predispose patients 
to increased risk of infections (including 
reactivation of tuberculosis), cardiovascular 
events, autoimmune diseases, malignancy, 
hepatitis, nephritis and tubulointerstitial diseases, 
as has been discussed later in this paper. 
 

Several other diseases including atherosclerosis, 
hypertension, chronic kidney disease, 
Alzheimer’s disease, Parkinson’s disease and 
multiple sclerosis also show evidence of low-
grade chronic inflammation. Researchers have 
explored whether anti-TNF therapies can be 
helpful in these diseases too. Both positive and 
negative effects of anti-TNF therapies have been 
observed in these diseases. These observations 
suggest that TNF-α and TNF receptors system 
have a complex pathophysiologic role, and 
hence blockade of this pathway results in 
complex effects on different organ systems. In 
this review we have explored the effects of TNF 
blockade on various organ systems. 
 

2. BIOLOGICAL PROPERTIES OF TNF-Α 
AND TNF RECEPTORS 

 

2.1 Tumor Necrosis Factor-α 
 
Tumor necrosis factor-α (TNF-α) was discovered 
by Lloyd J Old together with Elizabeth Carswell 
in 1975 [6,9]. They discovered that TNF-α is 
produced by lymphocytes and macrophages that 
cause lysis of specific type of cells like tumor 
cells [6]. This discovery led to the discovery of a 
number of other cytokines including lymphotoxin 
alpha (TNF-β), CD40L, CD27L, and FASL [6,9]. 
 
Biological responses of TNF-α include 
inflammation, apoptosis, immunomodulation, 
tissue repair, antiviral and antitumor activity and 
mediation of endotoxin-induced septic shock. It is 
involved in recruitment of inflammatory cells 
including neutrophils, monocytes and 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
210 

 

lymphocytes to sites of infection; and cell 
activation through its action on different receptors 
(TNFR1 and TNFR2) [3,4,10]. 
 

TNF-α exhibits both pro-inflammatory and 
immunoregulatory properties. In addition to its 
function as an endogenous pyrogen, TNF-α has 
been shown to initiate a powerful inflammatory 
response by stimulating the generation of other 
inflammatory cytokines such as interleukin-6 (IL-
6), interleukin-8 (IL-8), interleukin-10, 
corticosteroids, and metalloproteinases [3,10]. 
Once the triggering factor for the immune system 
activation is eliminated, TNF-α steps in again to 
control and resolve the inflammatory process [3]. 
 

The gene that codes for human TNF-α is located 
on short arm of chromosome 6, linked to human 
leucocyte antigen (HLA) B [11-13]. There are two 
forms of TNF-α: transmembrane TNF-α or 
membrane-associated TNF-α (mTNF-α) and 
soluble TNF-α (sTNF-α). Membrane-associated 
TNF-α (mTNF-α) is cleaved by 
metalloproteinases ADAM-17[TNF-α converting 
enzyme (TACE)] to soluble TNF-α [sTNF-α] that 
can subsequently be detected in blood plasma 
[4,6,11,14]. Please refer to Table 1 for an 
overview [4,6,11-14]. 
 

2.2 TNF Receptors 
 

TNF-α acts through two cell-surface receptors- 
Tumor Necrosis Factor Receptor 1 (TNFR1), 
also known as p55, TNFRSF1A, CD120a; and 
Tumor Necrosis Factor Receptor 2 (TNFR2) also 
known as p75, TNFRSF1B, CD120b [15-17]. 
Although both TNFR1 and TNFR2 can bind with 
the soluble and transmembrane forms of TNF-α, 
TNFR2 has high affinity for the transmembrane 
form of TNF-α [16]. 

 
Jonathan Holbrook et al have described TNF-α 
and TNF receptors in detail [14]. TNFR1 is 
expressed on almost all cells [14]. It has ‘death 
domain or DD’ in its intracellular region. When 
TNF-α binds with TNFR1, it leads to recruitment 

of TNFR1-associated DD (TRADD) [14]. This 
triggers an inflammatory response or cell survival 
response through activation of NF-kB (nuclear 
factor kappa-light-chain-enhancer of activated B 
cells), or cell death response depending on the 
physiological state of the cell [3,14,17]. 
 

TNFR2 is expressed in immune cells 
[predominantly in T regulatory cells (Tregs)], 
neurons and endothelial cells [3,14]. 
Besidesleading to direct actions after TNF-α 
binding occurs, TNFR2 may have a ‘ligand-
passing’ role as well: soluble TNF-α may 
dissociate from TNFR2 rapidly and then bind with 
TNFR1 [16,17]. 
 

There is no death domain (DD) in TNFR2. After 
interacting with TNF-α, TNFR2 binds with the 
proteins TNFR-associated factors 1 and 2 
(TRAF1 and TRAF2) activating NF-kB. NF-kB 
then triggers a cell survival response including 
immune modulation, inflammation and tissue 
regeneration depending on the conditions 
[3,14,17]. TNFR2 has an important role in 
pancreatic regeneration, protection of 
cardiomyocytes, remyelination, survival of some 
neuronal cells and in stem cell proliferation too 
[3]. Since TNFR2 does not bind with TRADD, it 
does not lead to cell death response. Please 
refer to Fig. 1. Please note that the figure is 
symbolic for easy understanding. It is not 
representative of true molecular structure of TNF 
or its receptors. 
 

3. TNF-α POLYMORPHISM AND 
DISEASES 

 

TNF-α polymorphisms may have an influence on 
susceptibility of diseases. A few examples are 
given below. 
 

3.1 Rheumatoid Arthritis 
 

Role of TNF-α -308G/A polymorphism and 
differential expression of TNF-α in pathogenesis 

 

Table 1. The two forms of TNF-α 
 

  Soluble TNF-α Transmembrane TNF-α 

Amino Acids 157 amino acid residues 233 amino acid residues 
Molecular 
weight 

17 kDa 26 kDa 

Receptor 
Interaction 

Attaches to Type 1 and Type 2 TNF 
receptors (TNF-R1 and TNF-R2); 
cellular actions mainly mediated through 
TNF-R1. 

Attaches to TNF-R1 and TNF-R2; 
actions mainly mediated through 
TNF-R2. 

Sites of action Acts at sites distant from TNF-α 
producing cells. 

Acts locally 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
211 

 

 
 

Fig. 1. An overview of TNF-α signaling pathway 
 

of rheumatoid arthritis was evaluated by 
Somdatta Das, et al. [18]. They conducted a 
case-control study, including 126 rheumatoid 
arthritis patients and160 community matched age 
and sex controls. The study duration was 3 
years. They found that presence of TNF-α -308A 
allele and differential TNF-α expression are 
associated with increased risk susceptibility for 
rheumatoid arthritis [18]. This study suggests that 
polymorphism of TNF-α has a role in 
pathogenesis of rheumatoid arthritis. 
 

3.2 Systemic Lupus Erythematosus 
 

Y-J Lin, et al investigated the association of TNF-
alpha genetic polymorphisms (-1031T/C, -
863C/A, -857T/C, -308A/G and +489A/G) in             

SLE patients and controls in Taiwanese 
population [19].  
 

Their observations included [19]:  
 

 The frequency of the polymorphisms at -
1031 and -857 were significantly different in 
patients with antinuclear antibodies and 
hematological disorders respectively. 

 The frequency of a allele of the 
polymorphisms at -308 was significantly 
increased in patients with malar rash, 
discoid rash, photosensitivity, oral ulcers 
and serositis. 

 The frequency of the polymorphisms at 
+489 was significantly different in patients 
with discoid rash and photosensitivity. 

 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
212 

 

Julian Ramírez-Bello, et al investigated whether 
the TNF -238G/A, -308G/A, -376G/A 
(rs1800750), and -1031T/C (rs1799964) 
polymorphisms are associated with SLE or lupus 
nephritis susceptibility in a Mexican population 
[20]. The study included 442 patients with SLE 
and 495 controls. The investigators found that 
TNF -238G/A and -1031T/C polymorphisms were 
associated with SLE susceptibility [20]. 
 

These observations of different investigators 
suggest that TNF-alpha genetic polymorphisms 
contribute to increased SLE susceptibility. 
 

3.3 Crohn’s Disease 
 

Genoile Santana, et al conducted a case-control 
and cross-sectional study to analyze whether 
TNF-α -308 polymorphism is associated with 
Crohn's disease and its clinical features [21]. 
They enrolled 91 patients with Crohn's disease 
and 91 controls (either with gastroesophageal 
reflux disease or functional dyspepsia) in 
Salvador [21]. The investigators observed that 
high TNF-α producing predicted phenotype was 
associated with the penetrating form of Crohn’s 
disease and colectomy. They found that the 
TNF-α -308 polymorphism was not associated 
with the perianal disease [21]. 
 

4. TNFR1 GENE POLYMORPHISM AND 
DISEASES 

 

4.1 Tumor Necrosis Factor Receptor-
Associated Periodic Syndrome 
(TRAPS) 

 

Missense mutations of TNFR1 gene results in 
development of Tumor Necrosis Factor receptor-
associated periodic syndrome (TRAPS), an 
autosomal dominant disease [22]. The gene 
mutation results in structural alteration of TNFR1 
receptor rendering it nonfunctional and its 
retention in endoplasmic reticulum [23]. The 
disease is associated with unprovoked prolonged 
periodic or episodic fever (fever lasting from a 
few days to months, average duration 21 days), 
severe abdominal pain, localized inflammation 
affecting multiple organs, and migrating rash on 
the limbs [23]. Since these inflammatory 
episodes are unprovoked, they are described as 
‘autoinflammation’ [14]. There is an elevation of 
cytokines IL-6 and TNF-α in this disease [23]. 
 

There is a paradox in the pathogenesis of 
TRAPS: as TNFR1 is associated with 
inflammation, nonfunctional TNFR1 should not 
lead to inflammation, contrary to the observation 

of inflammation affecting multiple organs in this 
disease [23]. This suggests that mechanism of 
action of the TNF-α and TNF receptors is 
complex, and further studies are needed to 
elucidate these mechanisms.  
 

Treatment modalities include high doses of 
prednisolone, high dose non-steroidal anti-
inflammatory drugs, colchicine, etanercept, 
anakinra (IL-1 receptor antagonist), canakinumab 
(anti-IL-1β), and tocilizumab (anti-IL-6) but each 
have variable success [14,23]. Presently, anti-
interleukin- 1β therapy is the standard to treat 
more severe cases of TRAPS [14]. 
 

4.2 Susceptibility to Develop Invasive 
Pulmonary Aspergillosis 

 

Investigators have found that polymorphism of 
both TNFR1 and TNFR2 is associated with 
increased susceptibility to invasive pulmonary 
aspergillosis. Sainz et al found that TNFR1 gene 
polymorphism results in greater susceptibility to 
invasive pulmonary aspergillosis [24]. The group 
had found in an earlier study that TNF-α gene 
polymorphism or TNF-α levels had no correlation 
with susceptibility to invasive pulmonary 
aspergillosis, while polymorphism in TNFR2 
gene was strongly associated with susceptibility 
to the infection [25]. 
 

5. TNFR2 GENE POLYMORPHISM AND 
DISEASES 

 
TNFR2 gene polymorphism may affect 
susceptibility and/or severity of some diseases. A 
few examples are given below. In all these 
examples, the sample size is small. More studies 
are needed to evaluate this area. 
 

5.1 Schizophrenia 
 
Renata Suchanek-Raif, et al conducted a case 
control study involving 401 patients and 657 
controls to study whether the three single 
nucleotide polymorphisms (rs3397, rs1061622, 
and rs1061624) in TNFR2 gene were associated 
with a predisposition to paranoid schizophrenia in 
Caucasian population [26]. They observed that 
TNFR2 gene polymorphism of rs3397, 
rs1061622, and rs1061624 are associated with a 
higher risk of developing schizophrenia and a 
more severe course of progression in males            
[26]. In this study, the rs3397 single               
nucleotide polymorphisms were found to be 
protective for women [26]. These observations 
suggest that TNFR2 gene polymorphisms              



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
213 

 

Table 2. Anti-TNF therapeutic agents 
 

TNF 
Inhibitor 

Mechanism of action Specificity Dosage 
schedule 

Approved 
Indications 

Etanercept Fully human soluble 
TNF receptor inhibitor  

sol TNF, tmTNF, Subcutaneous 
injection weekly 

RA, PA, JIA, 
AS lymphotoxin A 

Infliximab Mouse Chimeric 
monoclonal antibody to 
TNF-α 

 sol TNF, tmTNF Intravenous 
injection every 
6-8 weeks 

 RA, PA, JIA, 
AS, CD, UC 

Adalimumab Fully human 
monoclonal antibody 
against TNF-α 

 sol TNF, tmTNF Subcutaneous 
injection every 2 
weeks 

 RA, PA, JIA, 
AS, UC, CD 

Certolizumab Human Fab fragment 
against TNF attached to 
2 polyethylene glycol 
molecules 

 sol TNF, tmTNF Subcutaneous 
injection every 4 
weeks 

RA, PA, AS, 
CD 

Golimumab  Fully human 
monoclonal antibody 
against TNF-α 

 sol TNF, tmTNF Subcutaneous 
injection every 
month 

RA, AS, PA, 
UC 

RA-rheumatoid arthritis; PA-psoriatic arthritis; AS- ankylosing spondylitis; JIA-juvenile inflammatory arthritis; UC- 
ulcerative colitis; CD- Crohn’s disease; sol TNF- soluble tumor necrosis factor; tm TNF- transmembrane tumor 

necrosis factor 
 

have a role in determining severity of 
schizophrenia. 
 

5.2 Coronary Artery Disease 
 

V.H Sankar, et al conducted a study to evaluate 
whether polymorphism at position 196 in exon 6 
of tumor necrosis factor 2 (TNFR2) gene is 
associated with coronary artery disease [27]. The 
investigators found that the incidence of coronary 
artery disease in patients with MM genotype was 
65% and in those with RM genotype was 42% 
[27]. The investigators concluded that MM 
genotype of TNFR2 increases the risk of 
developing coronary artery disease, and the RM 
genotype has a protective role [27]. 
 

5.3 Chagas Disease 
 

Libeth Criado, et al included 313 Chagas disease 
patients from Colombia who were serologically 
positive for Trypanosoma cruzi [28]. Out of these 
313 patients, 159 had cardiomyopathy, and 154 
were asymptomatic [28]. The investigators found 
that distribution of the TNFA -1031C and -308A 
alleles between cardiomyopathic and 
asymptomatic subjects was significantly different 
[28]. The investigators suggested that TNFA -
1031C and -308A gene polymorphisms may 
influence susceptibility to develop 
cardiomyopathy in Chagas disease [28]. 
 

6. ANTI-TUMOR NECROSIS FACTOR 
THERAPEUTIC AGENTS 

 

TNF-α is involved in pathogenesis of several 
diseases including rheumatoid arthritis, systemic 

lupus erythematosus, ulcerative colitis and 
Crohn’s disease [1,3]. Anti-TNF therapeutic 
agents are used for several therapeutic 
indications including rheumatoid arthritis (RA), 
ankylosing spondylitis (AS), psoriatic arthritis 
(PA), juvenile inflammatory arthritis (JIA), 
Crohn’s disease (CD) and ulcerative colitis (UC) 
[5-8]. Table 2 depicts a brief overview of these 
agents [5-8,29]. 

 
7. IMPACT OF TNF BLOCKADE ON 

DIFFERENT ORGAN SYSTEMS 
 

7.1 Immune System and Infections 
 
The pro-inflammatory role of TNF-α is a vital 
component of host defense against infections 
[10]. TNF-α blockers increase the risk of 
infections (bacterial, viral, and mycotic), including 
tuberculosis, histoplasmosis, candidiasis, 
aspergillosis, listeriosis, infection with atypical 
mycobacterium, pneumocystis carinii [30,31]. 
Lymphoma, neuropathy and bowel obstruction 
have also been noted with the use of anti TNF-α 
therapeutic agents [31]. 
 
TNF-α together with other cytokines including 
interferon-delta (IFN-δ), generates a cell-
mediated immune response to intracellular 
pathogens including mycobacterium tuberculosis, 
listeria and histoplasma species leading to 
granuloma formation [10]. Granuloma formation 
is required to contain the growth of and for the 
resolution of these infections [10]. Use of ant-
TNF-α therapeutic agents inhibits this cell 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
214 

 

mediated immune response and granuloma 
formation, hence increasing the risk of 
granulomatous diseases including tuberculosis. 
 
Reactivation of infections may also occur, 
including reactivation of latent tuberculosis and 
hepatitis B virus [30,31]. Use of live vaccines 
during anti-TNF therapy is not recommended, as 
this may cause vaccine associated disease, 
including disseminated infection [32]. 
 
The risk of serious infections in highest in the first 
few months. The incidence of infection declines 
over time.  Galloway et al evaluated and 
compared data of 11,798 anti-TNF treated 
patients and 3,598 non biologic disease-
modifying antirheumatic drugs (nbDMARD) 
treated rheumatoid arthritis patients. They 
observed that the incidence rate of serious 
infections was 42 per 1000 patient-years in anti-
TNF treated patients, and 32 per 1000 patient-
years in nbDMARD treated patients indicating a 
significant increase in serious infection risk with 
the use of anti-TNF therapy [33]. The adjusted 
serious infection rate was 20% higher in anti-TNF 
treated individuals than nbDMARD treated 
subjects [33]. This risk was highest in the first six 
months of therapy, and then started to decline 
[33]. 
 

Liao et al conducted a meta-analysis and found 
that the risk of serious infections defined as 
those that were life‐threatening, requiring 
hospitalization and/or intravenous antibiotic 
therapy, or leading to significant disability/death, 
and general infections (infections regardless of 
severity and microorganisms) were lower in 
etanercept (soluble receptor) treated individuals, 
as compared with the monoclonal antibodies 
(adalimumab and infliximab) [34]. The risk of 
tuberculosis was also lower in Etanercept treated 
individuals as compared to the individuals treated 
with adalimumab or infliximab [34]. 
 
7.1.1 Leprosy 
 
TNF plays an important role in pathogenesis of 
nerve lesions in leprosy. High levels of TNF have 
been detected in reactional skin lesions in 
leprosy [35]. TNF may be involved in early 
stages of Schwann cell infection by 
mycobacterium leprae [35]. TNF induces IL-6 
and IL-8 production that contribute to 
neuroinflammation [35]. Mycobacterium leprae 
also induces IL-23 production in Schwann cells 
that contributes to demyelination [35]. More 

studies are required to evaluate the effect of anti-
TNF therapy in patients with leprosy. 
 
7.1.2 Chagas disease 
 
Chagas disease is caused by protozoan parasite 
Trypanosoma cruzi [36]. Chronic Chagas 
disease cardiomyopathy (chronic Chagasic 
cardiomyopathy), the main manifestation of 
Chagas disease, is associated with heart failure 
[36,37]. Elevated levels of TNF-α occur in 
chronic Chagas disease cardiomyopathy and are 
related to the severity of left ventricular 
dysfunction [36,37]. Low grade inflammation 
occurs in cardiac tissue in presence of elevated 
TNF and interferon-γ levels. Pereira I.R found in 
their experimental studies in mice that short term 
anti-TNF therapy together with trypanocidal 
treatment may have beneficial effect in chronic 
Chagasic cardiomyopathy [36]. However other 
investigators have observed conflicting results in 
animal studies, and have noticed that anti-TNF 
therapy may actually aggravate the 
cardiomyopathy [37]. More studies are required 
to evaluate the effect of anti-TNF therapy in 
chronic Chagasic cardiomyopathy. 
 
7.1.3 COVID-19 
 
High mortality associated with coronavirus 
disease 2019 (COVID-19) has prompted 
researchers worldwide to accelerate the research 
activities to find possible safe and effective 
treatment options and preventive measures 
including vaccines [38]. Severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) that 
causes COVID-19, enters the host cells through 
angiotensin converting enzyme-2 expressed by 
type II surfactant-secreting alveolar cells in the 
lungs [38]. The most important mediators that 
drive inflammatory response to COVID-19 are 
not completely known. Upregulation of different 
cytokines including interleukin-1 (IL-1), 
interleukin-6 (IL-6), TNF, and interferon-γ occurs 
in COVID-19 [38]. ‘Cytokine storm’, in which too 
many cytokines are suddenly released into 
circulation, can cause severe inflammatory 
response that causes more harm than good. 
Marc Feldmann, et al have discussed this topic in 
detail and have proposed that clinical trials are 
needed to evaluate safety and effectiveness of 
anti-TNF therapies, particularly infliximab and 
adalimumab [38]. They speculate that these anti-
TNF agents may be beneficial in decreasing the 
intensity of the ‘cytokine storm’, reduce 
inflammation, and help in severe COVID-19 [38]. 
 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
215 

 

7.2 Autoimmune Disorders 
 

The mechanisms leading to disease through 
TNF-α and TNF receptors pathway are complex 
showing both positive and negative effects on 
autoimmune disorders. A few cases have been 
reported of etanercept and adalimumab inducing 
systemic lupus erythematosus and lupus 
serositis [39-43]. But there are other reports 
favoring anti-TNF therapeutic agents having 
beneficial effect on these autoimmune diseases. 
Uppal, et al investigated the effect of infliximab in 
active systemic lupus erythematosus subjects 
and found that the drug significantly decreases 
the Systemic Lupus Erythematosus Disease 
Activity Index (SLEDAI). They concluded that 
anti-TNF therapeutic agents are interesting 
candidates that can be explored further for 
treatment of active SLE [44]. There are 
conflicting experiences with other anti-TNF 
therapies and autoimmune diseases too.  
 

It is known that there is deficiency of TNFR2 in 
several autoimmune diseases that could result in 
uncontrolled inflammatory activity through 
soluble TNF-α, TNFR1 pathway. Instead of using 
non-specific anti-TNF-α therapeutic agents that 
cause varying impact on both TNFR1 and 
TNFR2 pathways resulting in unpredictable 
consequences, using specific agents to target 
TNFR1 or TNFR2 pathways may yield better and 
predictable results. Yang et al have proposed 
that either using agents that specifically block 
TNF-α or TNFR1 and preserve the available 
TNFR2; or using TNFR2 agonists to increase the 
number of TNFR2 and promote tissue 
regeneration may prove to be good therapeutic 
strategies in autoimmune diseases [3]. Further 
studies are required to evaluate whether these 
strategies are indeed beneficial and could be 
safely implemented. 
 

7.3 Cardiovascular System 
 

TNF-α levels have an important relationship with 
cardiovascular diseases and events including 
congestive heart failure [30,31]. The level of 
TNF-α has been shown to be predictive of 
recurrent myocardial infarction [43]. Also, TNF-α 
level may play a role in hypertension, 
dyslipidemia, and atherosclerosis [45-48]. 
 

Investigators have proposed that TNF-α induces 
atherogenesis by promoting induction of vascular 
cell adhesion molecule-1 (VCAM-1) and 
intercellular adhesion molecule-1 (ICAM-1) 
expression by endothelial cells and vascular 
smooth muscle cells, endothelial cell apoptosis, 

and smooth muscle cell migration and 
proliferation [45]. Interestingly, the cellular 
location of TNFR1 may have effects on 
atherogenesis. As an example, TNFR1 in 
macrophages may decrease atherogenesis, 
whereas the TNFR1 in the arterial walls may 
promote atherogenesis [45,48]. 
 

TNF-α might have a role in arterial inflammation 
and intimal hyperplasia [15]. Kitagaki et al 
showed that TNF-α is an important contributor to 
arterial inflammation in mice and that blockage of 
TNFR1 inhibits intimal hyperplasia following 
experimentally induced arterial inflammation 
(post injury) [15]. TNFR2 signaling mediates 
inhibition of neointimal formation by decreasing 
adherent cells and apoptosis of endothelial cells 
as well as the activation, proliferation and 
migration of endothelial cells [15]. 
 

7.4 Malignancy 
 

TNF-α is an important cytokine that is involved in 
tumor surveillance and hence anti-TNF therapy 
theoretically poses a risk for developing 
malignancies. This has been substantiated in 
several studies indicating that anti-TNF 
therapeutic agents may be associated with an 
increased risk of malignancies including 
lymphoma, breast cancer, colorectal cancer, and 
melanoma [30,31,49]. 
 

Berghen et al observed incidence of malignancy 
in 365 rheumatoid arthritis patients receiving anti-
TNF therapy at a single center from January 
2000 until January 2012 that received anti-TNF 
therapy [49]. They observed occurrence of 34 
malignancies in 30 patients after the start of anti-
TNF treatment. Among these, 20 patients 
developed a solid malignancy, 6 a hematologic, 2 
a solid and a hematologic malignancy, and 2 
patients developed multiple (2 solid) 
malignancies. They also observed that some 
immune modulation-related lymphoproliferative 
disorders regressed spontaneously after 
stopping anti-TNF therapy. They concluded that 
the malignancy risk in rheumatoid arthritis 
patients treated with anti-TNF therapy was 
slightly higher than in the normal population [49]. 
 

However, there are other studies that have 
shown conflicting results. Mercer et al compared 
the rates of solid tumors in 11,767 anti-TNF 
treated patients with 3,249 non-biologic or 
synthetic disease modifying anti-rheumatic drugs 
(s-DMARDs- including methotrexate, 
azathioprine and cyclophosphamide) in 5-year 
data was obtained from British Society for 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
216 

 

Rheumatology Biologics Register [50]. None of 
these patients had prior history of cancer. They 
observed that solid tumors developed in 81 per 
10,000 patient-years in anti-TNF treated patients, 
and 117 per 10,000 patient-years in s-DMARDs 
treated patients. There was no statistically 
significant difference in risk of solid cancer for 
anti-TNF treated versus sDMARD treated 
patients [50]. Another study by Min Jung et al 
also showed similar results [51]. The 
investigators collected information of 45,423 
seropositive rheumatoid arthritis patients from 
Korean Nationwide Health Insurance claims 
data. They compared incidence of tumor in 
patients receiving anti-TNF therapy (2,337 
patients), and those receiving conventional 
synthetic disease-modifying anti-rheumatic drugs 
(csDMARDs- including methotrexate, 
leflunomide, hydroxychloroquine, sulfasalazine, 
cyclosporine, tacrolimus, azathioprine, 
mizoribine, and bucillamine) (43,086 patients) 
from the 5 years of data. They found that 1732 
patients in csDMARD group and 49 patients in 
anti-TNF group developed malignancy. On 
statistical analysis, the investigators found that 
incidence of cancer was similar in RA patients 
treated with anti-TNF and csDMARDs [51]. 
  

7.5 Nervous System 
 
Increased production of TNF-α has been noticed 
in several central nervous system disorders 
including multiple sclerosis, Alzheimer’s disease, 
Parkinson’s disease, HIV encephalopathy, 
meningitis, stroke, demyelinating disorders, 
neuropathy, and myelosuppression [30,31,52-
56]. High levels of TNF in nervous system 
disorders promote demyelination, axonal 
degeneration and increased permeability of 
blood brain barrier [35]. 
 
TNFR2 has a neuroprotective role and serves an 
important role in oligodendrocyte regeneration 
and remyelination [3,53]. Fischer et al 
synthesized a soluble, human TNFR2 agonist 
(TNC-scTNFR2) by genetic fusion of tenascin C 
to a TNFR2-selective single-chain TNF molecule 
and showed that TNC-scTNFR2 rescues human 
differentiated neurons from oxidative stress 
induced cell death [57]. They speculated that 
TNFR2 agonists may be good therapeutic 
options in several diseases, including 
neurodegenerative, cardiac and autoimmune and 
diseases [57]. 
 
Alzheimer’s disease: TNF-α and TNFR1 levels 
are increased, and TNFR2 levels are decreased 

in human Alzheimer’s disease brain tissues 
[30,53]. Though theoretically it appears that anti-
TNF therapy should be helpful in Alzheimer’s 
disease, investigators have observed conflicting 
results. As an example, experimental studies in 
animals have shown that infliximab that binds 
TNF-α (anti-TNF-α therapy) reduced amyloid 
plaques and tau phosphorylation in Alzheimer’s 
disease in mice as early as 3 days after the 
intracerebroventricular injection; and improves 
object recognition memory impairment                 
[58,59]. Shi et al reported that intrathecal 
injection of infliximab improved cognition 
significantly in a female suffering from 
Alzheimer’s disease [60]. Peri-spinal injection of 
etanercept has been shown to improve cognitive 
impairment within minutes of administering the 
injection [61]. 
 

It is generally accepted that total inhibition of 
TNF (especially inhibition of the neuroprotective 
TNFR2) may nullify the positive effects of anti-
TNF therapies [53]. Though there are case 
reports and experimental data supporting a 
beneficial role [58-61], more studies (large scale, 
randomized controlled trials) are needed to 
explore the safety and efficacy of anti-TNF 
therapies in Alzheimer’s disease. 
 
Multiple sclerosis: Experimental studies in 
animals with multiple sclerosis has shown 
beneficial effect of anti-TNF therapies. However, 
investigators have also reported conflicting 
evidence: several cases of development of 
multiple sclerosis after initiating anti-TNF therapy 
[54-56]. Titelbaum et al. reported new onset 
multiple sclerosis in a rheumatoid arthritis  
patient who was on etanercept therapy for two 
years. On stopping etanercept, there was 
radiological resolution of lesions. However, after 
6 months, new lesions developed [62]. These 
conflicting evidences suggest that more              
studies are required in this therapeutic                    
area to get a clearer picture regarding whether 
anti-TNF therapy is beneficial in multiple 
sclerosis. 
 

7.6 Kidneys 
 
TNF-α blockers used in rheumatoid arthritis and 
Crohn’s disease occasionally result in the 
development of autoantibodies, lupus-like 
syndrome, and glomerulonephritis [63]. This has 
raised a concern regarding the use of TNF-α 
blocking agents in patients who are at risk of 
developing renal disease or who have underlying 
renal disease [63]. 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
217 

 

TNF-α may be produced in inflamed kidneys 
from infiltrating monocytes and macrophages, 
and intrinsically by renal tissue including 
podocytes, mesangial cells, proximal tubules, 
thick ascending limb of loop of Henle, and the 
collecting ducts [16,64]. TNF-α is cytotoxic to 
renal cells and is involved in renal scarring [65-
67]. TNF-α induces the production of reactive 
oxygen species including superoxide. 
Superoxide increases glomerular permeability to 
albumin [68]. Animal studies have shown that 
nitric oxide is also produced in several 
glomerular diseases. Nitric oxide has a protective 
effect and protects the kidneys from the injurious 
effect of superoxide, and even reverses the 
damage [68]. 
 

In kidneys, TNFR1 is primarily present in 
glomeruli and peritubular endothelial cells [16]. 
TNFR2 is usually absent in the kidneys in normal 
state [16]. In several renal diseases, TNFR2 
levels increase in the kidneys especially at the 
site of injury [16]. 
 
TNF-α has been implicated in acute kidney injury 
(AKI) and chronic kidney disease (CKD) [69]. 
Studies in animal models have shown that 
inflammatory cytokines like TNF-α play a role in 
development of AKI and its inhibition may protect 
kidneys from the damage [70,71]. However, anti-
TNF therapy may also result in acute kidney 
injury. Michael B Stokes et al reported 5 cases of 
rheumatoid arthritis who developed acute kidney 
injury possibly due to anti-TNF therapy [72]. 
TNF-α and TNFR1 and TNFR2 are higher in 
chronic kidney disease [65,73]. Richard et al 
found that higher levels of TNF-α are associated 
with more rapid worsening of renal functions over 
time in patients with chronic kidney disease [65]. 
It has also been observed that high levels of 
TNFR 1 and TNFR2 in diabetes are associated 
with progression of diabetic kidney disease, and 
higher mortality [74]. 
 
TNF-α may play a role in renal ischemia-
reperfusion injury post kidney transplantation 
[69]. In the pathogenesis of renal ischemia-
reperfusion injury, TNF-α induces fibrin 
deposition, cellular infiltration, vasoconstriction 
and apoptosis [69]. 
 

Investigators have found that inhibition of TNFR2 
pathway may be helpful in decreasing incidence 
of glomerulonephritis. The possible underlying 
mechanisms that are involved in this are not 
completely understood. TNFR2 (but not TNFR1) 
is found in high concentration in renal tubular 

epithelial cells in renal tubulointerstitial nephritis 
and interacts with ‘sef’ or IL-17RD, causing 
activation of NF-kB pathway and inflammation 
[16,17]. TNF-α may enhance the interaction of 
TNFR2 and IL-17RD, but the presence of TNF-α 
is not absolutely necessary for the interaction to 
occur (upregulated TNFR2 may trigger 
interaction with IL-17RD independent of TNF-α) 
[17]. This may be one of the pathogenic 
mechanisms explaining the role of upregulated 
TNFR2 contributing to nephritis and 
tubulointerstitial renal diseases [17]. The 
evidence is helpful, but more studies are needed 
to understand the role of TNF-α and TNF 
receptors in renal diseases. 
 

Kidney transplant recipients are on 
immunosuppressive medications and are already 
at an increased risk of infections [75]. Anti-TNF 
therapy may increase this risk of infections and 
malignancy in kidney transplant recipients and 
should be used with caution [76]. 
 

8. CONCLUSION 
 

TNF-α, TNFR1 and TNFR2 systems are 
complex. Increased concentration of TNF-α is a 
prominent feature of many diseases including 
rheumatoid arthritis, ankylosing spondylitis, 
juvenile inflammatory arthritis, Crohn’s disease, 
ulcerative colitis and psoriatic arthritis. The 
beneficial effects of anti-TNF therapies in these 
diseases led to the speculation that these 
therapeutic agents may be helpful in other 
ailments that have abnormalities in concentration 
of TNF-α and TNF receptors- for example, in 
Alzheimer’s disease, Parkinson’s disease, 
systemic lupus erythematosus, tubulointerstitial 
nephritis, diabetic nephropathy, chronic kidney 
disease, and cardiovascular diseases including 
hypertension and atherosclerosis. However, 
investigators have found that this is not entirely 
true.  While some studies have shown beneficial 
effects of anti-TNF therapy, other studies have 
shown conflicting results that point towards the 
complex nature of TNF-α and TNF receptors 
pathway. More extensive research is needed to 
understand this system, so that better and more 
selective anti-TNF therapeutic agents may be 
developed to help in diseases including 
Alzheimer’s disease, multiple sclerosis, 
Parkinson’s disease, renal and cardiovascular 
diseases. 
 

DECLARATION 
 

We thank IQVIA (communications, branding, and 
legal units) for giving us permission, and ‘no 



 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
218 

 

objection’ note for publication of this paper. We 
thank IQVIA for providing us the support and 
infrastructure needed to complete this paper, 
including giving us the opportunity to form this 
great team that was instrumental in bringing this 
paper to conclusion. 
 

CONSENT 
 

It is not applicable. 
 

ETHICAL APPROVAL 
 

It is not applicable. 
 

COMPETING INTERESTS 
 

Authors have declared that no competing 
interests exist. 
 

REFERENCES 
 

1. Chen X, Li P, Yang X, Miao X, Luo H. 
Tumor necrosis factor receptor II (TNFR2) 
promotes the growth of mouse CT26 colon 
cancer. J Immunol. 2018;200(1 
Supplement):178.7. 

2. Idriss HT, Naismith JH. TNF alpha and the 
TNF receptor superfamily: structure-
function relationship(s). Microsc Res Tech. 
[Internet]. 2000;50(3):184-95.  
Available:https://www.ncbi.nlm.nih.gov/pub
med/10891884  
(Accessed on 27 May 2020) 

3. Yang S, Wang J, Brand DD, Zheng SG. 
Role of TNF-TNF Receptor 2 Signal in 
Regulatory T Cells and Its Therapeutic 
Implications. Front Immunol. 2018;9:784.  
Available:https://doi.org/10.3389/fimmu.20
18.00784 

4. Horiuchi T, Mitoma H, Harashima S, 
Tsukamoto H, Shimoda T. 
Transmembrane TNF-α: Structure, function 
and interaction with anti-TNF agents. 
Rheumatology. 2010;49(7):1215–1228. 
Available:https://doi.org/10.1093/rheumatol
ogy/keq031 

5. Kalliolias GD, Ivashkiv LB. TNF biology, 
pathogenic mechanisms and emerging 
therapeutic strategies. Nat Rev Rheumatol. 
2016;12(1):49‐62.  
DOI: 10.1038/nrrheum.2015.169 

6. Astrakhantseva IV, Efimov GA, Drutskaya 
MS, Kruglov AA, Nedospasov SA. Modern 
Anti-Cytokine Therapy of Autoimmune 
Diseases. Biochemistry (Moscow). 2014; 
79(12):1308-1321.  

Available:https://doi.org/10.1134/S0006297
914120049 

7. Porter C, Armstrong-Fisher S, Kopotsha T, 
Smith B, Baker T, Kevorkian L, et al. 
Certolizumab pegol does not bind the 
neonatal Fc receptor (FcRn): 
Consequences for FcRn-mediated in vitro 
transcytosis and ex vivohuman placental 
transfer. Journal of Reproductive 
Immunology. 2016;116:7–12.  
Available:http://dx.doi.org/10.1016/j.jri.201
6.04.284 

8. Geiler J, Buch M, McDermott M.F. Anti-
TNF Treatment in Rheumatoid Arthritis. 
Current Pharmaceutical Design. 2011;17 
(29):3141-54.  
Available:http://dx.doi.org/10.2174/138161
211798157658 

9. Smyth, M. Lloyd John Old 1933–2011. Nat 
Immunol. 2012;13:103. 
Available:https://doi.org/10.1038/ni.2209 

10. Johnston B, Conly J. Tumour necrosis 
factor inhibitors and infection: What is 
there to know for infectious diseases 
physicians? Can J Infect Dis Med 
Microbiol. 2006;17(4):209–212.  
Available:https://doi.org/10.1155/2006/385
789 

11. Vasanthi P, Nalini G, Rajasekhar G. Role 
of tumor necrosis factor-alpha in 
rheumatoid arthritis: A review. APLAR 
Journal of Rheumatology. 2007;10:270–
274.  

12. Inoko H, Trowsdale J. Linkage of TNF 
genes to the HLA-B locus. Nucleic Acids 

Res. 1987;15(21):8957‐8962.  
DOI: 10.1093/nar/15.21.8957 

13. Churchill B.M, Kossi M.E, Jin J.K, Sharma 
A,Halawa A. Understanding human 
leukocyte antigen typing and crossmatch 
techniques in renal transplantation. British 
Journal of Renal Medicine (BJRM). Winter; 
2017;22(4):115–121. 

14. Holbrook J, Lara-Reyna S, Jarosz-Griffiths 
H, McDermott M. Tumour necrosis factor 
signalling in health and 
disease. F1000Res. 2019;8:F1000. 
Available:https://doi.org/10.12688/f1000res
earch.17023.1 

15. Kitagaki M, Isoda K, Kamada H, Kobayashi 
T, Tsunoda S, Tsutsumi Y, et al. Novel 
TNF-α receptor 1 antagonist treatment 
attenuates arterial inflammation and intimal 
hyperplasia in mice. Journal of 
Atherosclerosis and Thrombosis. 2012; 
19(1):36-46.  

https://www.ncbi.nlm.nih.gov/pubmed/10891884
https://www.ncbi.nlm.nih.gov/pubmed/10891884
https://doi.org/10.3389/fimmu.2018.00784
https://doi.org/10.3389/fimmu.2018.00784
https://doi.org/10.1093/rheumatology/keq031
https://doi.org/10.1093/rheumatology/keq031
https://doi.org/10.1134/S0006297914120049
https://doi.org/10.1134/S0006297914120049
http://dx.doi.org/10.1016/j.jri.2016.04.284
http://dx.doi.org/10.1016/j.jri.2016.04.284
http://dx.doi.org/10.2174/138161211798157658
http://dx.doi.org/10.2174/138161211798157658
https://doi.org/10.1038/ni.2209
https://doi.org/10.1155/2006/385789
https://doi.org/10.1155/2006/385789
https://doi.org/10.12688/f1000research.17023.1
https://doi.org/10.12688/f1000research.17023.1


 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
219 

 

16. Al-Lamki RS, Mayadas TN. TNF receptors: 
signaling pathways and contribution to 
renal dysfunction. Kidney International. 
2015;87(2):281–296.  
Available:https://doi.org/10.1038/ki.2014.2
85 

17. Yang S, Wang Y, Mei K, Zhang S, Sun X, 
Ren F, et al. Tumor Necrosis Factor 
Receptor 2 (TNFR2)Interleukin-17 
Receptor D (IL-17RD) Heteromerization 
Reveals a Novel Mechanism for NF-B 
Activation. J Biol Chem. 2015;290(2):861-
71.  
Available:https://doi.org/10.1074/jbc.M114.
586560 

18. Das S, Baruah C, Saikia A.K, Tiwari D, 
Bose S. Genetic and expression changes 
in TNF-α as a risk factor for rheumatoid 
arthritis pathogenesis in Northeast India. J 
Genet. 2019 Mar;98:3. 

19. Lin YJ, Chen RH, Wan L, et al. Association 
of TNF-alpha Gene Polymorphisms With 
Systemic Lupus Erythematosus in 
Taiwanese Patients. Lupus. 2009;18(11): 
974-9.  
DOI: 10.1177/0961203309105361 

20. Ramírez-Bello J, Cadena-Sandoval D, 
Mendoza-Rincón JF, Barbosa-Cobos RE, 
Sánchez-Muñoz F, Amezcua-Guerra LM, 
Sierra-Martínez M, Jiménez-Morales S. 
Tumor necrosis factor gene 
polymorphisms are associated with 
systemic lupus erythematosus 
susceptibility or lupus nephritis in Mexican 
patients. Immunol Res. 2018;66(3):348-
354.  
DOI: 10.1007/s12026-018-8993-8 

21. Santana G, Bendicho MT, Santana TC, 
dos Reis LB, Lemaire D, Lyra AC. The 
TNF-α -308 polymorphism may affect the 
severity of Crohn's disease. Clinics vol.66 
no.8 São Paulo; 2011.  
Available:https://doi.org/10.1590/S1807-
59322011000800011 

22. Fischer R, Kontermann RE, Maier O. 
Targeting sTNF/TNFR1 signaling as a new 
therapeutic strategy. Antibodies. 2015;4: 
48-70.  
Available:https://doi.org/10.3390/antib4010
048 

23. Kimberley FC, Lobito AA, Siegel RM, 
Screaton GR. Falling into TRAPS--receptor 
misfolding in the TNF receptor 1-
associated periodic fever 
syndrome. Arthritis Res Ther. 2007;9(4): 
217.  
Available:https://doi.org/10.1186/ar2197 

24. Sainz J, Salas-Alvarado I, Lopez-
Fernandez E, Olmedo C, Comino A, 
Garcia F, et al. TNFRI mRNA expression 
level and TNFRI gene Polymorphisms are 
predictive markers for susceptibility to 
develop invasive pulmonary aspergillosis. 
International Journal of Immunopathology 
and Pharmacology. 2010;23(2):423-436. 

25. Sainz J, Pérez E, Hassan L, Moratalla A, 
Romero A, Collado MD, et al. VNTR  of 
TNF  receptor 2 promoter  as genetic  
biomarker  of  susceptibility  to develop  
Invasive  Pulmonary  Aspergilosis.  Human 
Immunology. 2007;68:41-50. 

26. Suchanek-Raif R, Raif P, Kowalczyk M, et 
al. Polymorphic Variants of TNFR2 Gene 
in Schizophrenia and Its Interaction with -
308G/A TNF-α Gene Polymorphism. 
Mediators Inflamm. 2018;2018:8741249. 
DOI: 10.1155/2018/8741249 

27. Sankar VH, Girisha KM, Gilmour A, Singh 
VP, Sinha N, Tewari S, Ramesh V, 
Mastana S, Agrawal S. TNFR2 gene 
polymorphism in coronary artery disease. 
Indian J Med Sci. 2005;59(3):104-8. 
DOI: 10.4103/0019-5359.15086. 

28. Criado L, Flórez O, Martín J, González C.I. 
Genetic polymorphisms in TNFA/TNFR2 
genes and Chagas disease in a Colombian 
endemic population. Cytokine. March 
2012;57(3):398-401.  
DOI:https://doi.org/10.1016/j.cyto.2011.12.
007 

29. Gerriets V, Bansal P, Khaddour K. Tumor 
Necrosis Factor (TNF) inhibitors. Bethesda 
MD: StatPearls Publishing; 2019. 
Available:https://www.ncbi.nlm.nih.gov/boo
ks/NBK482425/ 
(Accessed on 27 March 2020) 

30. Antoni C, Braun J. Side effects of anti-TNF 
therapy: Current knowledge. Clin Exp 
Rheumatol. 2002;20(Suppl. 28):S152-
S157. 

31. Hansen RA, Gartlehner G, Powell GE, 
Sandler RS. Serious adverse events with 
infliximab: Analysis of spontaneously 
reported adverse events. Clin 
Gastroenterol Hepatol. 2007;5(6):729-35. 

32. Badsha H, Daher M, Edwards CJ. Live 
polio vaccine exposure while receiving 
anti-TNF therapy for reactive arthritis.Int J 
Rheum Dis. 2010;13(2):184-6. 
Available:https://doi.org/10.1111/j.1756-
185X.2010.01466.x 

33. Galloway JB, Hyrich KL, Mercer LK, Dixon 
WG, Fu B, Ustianowski AP, et al, on behalf 
of the British Society for Rheumatology 

https://doi.org/10.1038/ki.2014.285
https://doi.org/10.1038/ki.2014.285
https://doi.org/10.1074/jbc.M114.586560
https://doi.org/10.1074/jbc.M114.586560
https://doi.org/10.1590/S1807-59322011000800011
https://doi.org/10.1590/S1807-59322011000800011
https://doi.org/10.3390/antib4010048
https://doi.org/10.3390/antib4010048
https://doi.org/10.1186/ar2197
https://www.ncbi.nlm.nih.gov/books/NBK482425/
https://www.ncbi.nlm.nih.gov/books/NBK482425/
https://doi.org/10.1111/j.1756-185X.2010.01466.x
https://doi.org/10.1111/j.1756-185X.2010.01466.x


 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
220 

 

Biologics Register. Anti-TNF therapy is 
associated with an increased risk of 
serious infections in patients with 
rheumatoid arthritis especially in the first 6 
months of treatment: Updated results from 
the British Society for Rheumatology 
Biologics Register with special emphasis 
on risks in the elderly. Rheumatology. 
2011;50(1):124–131.  
Available:https://doi.org/10.1093/rheumatol
ogy/keq242 

34. Liao H, Zhong Z, Liu Z, Zou X. Comparison 

of the risk of infections in different anti‐TNF 

agents: A meta‐analysis. International 
Journal of rheumatic diseases. 2017;20(2): 
161-168. 
Available:https://doi.org/10.1111/1756-
185X.12970 

35. Andrade PR, Jardim MR, Costa da Silva 
AC, et al. Inflammatory cytokines are 
involved in focal demyelination in leprosy 
neuritis. Journal of Neuropathology & 
Experimental Neurology. March 2016;75 
(3):272–283.  
DOI: https://doi.org/10.1093/jnen/nlv027 

36. Pereira IR, Vilar-Pereira G, Silva AA, 
Moreira OC, Britto C, Sarmento EDM, 
Lannes-Vieira J. tumor necrosis factor is a 
therapeutic target for immunological 
unbalance and cardiac abnormalities in 
chronic experimental chagas’ heart 
disease. Mediators of inflammation. 
2014;16. 
DOI: https://doi.org/10.1155/2014/798078 

37. Bilate AM, Salemi VM, Ramires FJ, de 
Brito T, Russo M, Fonseca SG, Faé KC, 
Martins DG, Silva AM, Mady C, Kalil J, 
Cunha-Neto E. TNF blockade aggravates 
experimental chronic Chagas disease 
cardiomyopathy. Microbes and Infection. 
2007;9(9):1104-1113.  
DOI: 10.1016/j.micinf.2007.05.014 

38. Feldmann M, Maini RN, Woody JN, 
Holgate ST, Winter G, Rowland M, 
Richards D, Hussell T. Trials of anti-tumour 
necrosis factor therapy for COVID-19 are 
urgently needed. The Lancet. 2020;395 
(10234):1407-1409.  
DOI:https://doi.org/10.1016/S0140-
6736(20)30858-8 

39. Swale VJ, Perrett CM, Denton CP, Black 
CM, Rustin MH. Etanercept-induced 
systemic lupus erythematosus. Clin Exp 
Dermatol. 2003;28(6):604-7. 

40. Kang MJ, Lee YH, Lee J. Etanercept-
induced systemic lupus erythematosus in a 

patient with rheumatoid arthritis. J Korean 
Med Sci. 2006;21(5):946–949.  
Available:https://doi.org/10.3346/jkms.2006
.21.5.946 

41. Cairns AP, Duncan MKJ, Hinder AE, 
Taggart AJ. New onset systemic lupus 
erythematosus in a patient receiving 
etanercept for rheumatoid arthritis. Annals 
of the Rheumatic Diseases. 2002;61:1031-
1032. 
Available:http://dx.doi.org/10.1136/ard.61.1
1.1031 

42. Vannucchi V, Grazzini M, Pieralli F, 
Giannotta M, Biagioni C, Nozzoli C. 
Adalimumab-induced lupus erythematosus 
with central nervous system involvement in 
a patient with Crohn's disease. J 
Gastrointestin Liver Dis. 201;20(2):201-3. 

43. Kelly D, O'Connell O, Henry M. 
Adalimumab-induced lupus serositis. BMJ 
Case Rep. 2015:bcr2014207323.  
Available:https://doi.org/10.1136/bcr-2014-
207323 

44. Uppal SS, Hayat SJ, Raghupathy R. 
Efficacy and safety of infliximab in active 
SLE: A pilot study. Lupus. 2009;18(8):690-
7.  
Available:https://doi.org/10.1177/09612033
09102557 

45. Zhang L, Peppel K, Sivashanmugam P, 
Orman ES, Brian L, Exum ST, et al. 
Expression of tumor necrosis factor 
receptor-1 in arterial wall cells promotes 
atherosclerosis. Arterioscler Thromb Vasc 
Biol. 2007;27(5):1087–1094.  

46. Ersozlu Bozkirli ED, Bozkirli E, Yucel AE. 
Effects of infliximab treatment in terms of 
cardiovascular risk and insulin resistance 
in ankylosing spondylitis patients. Mod 
Rheumatol. 2014;24(2):335-9.  
Available:https://doi.org/10.3109/14397595
.2013.843752 

47. Wong M, Oakley SP, Young L, Jiang BY, 
Wierzbicki A, Panayi G, et al. Infliximab 
improves vascular stiffness in patients with 
rheumatoid arthritis. Ann Rheum Dis. 
2009;68(8):1277-84.  
Available:https://doi.org/10.1136/ard.2007.
086157 

48. Zhang L, Connelly JJ, Peppel K, Brian L, 
Shah SH, Nelson S, et al. Aging-related 
atherosclerosis is exacerbated by arterial 
expression of tumor necrosis factor 
receptor-1: Evidence from mouse models 
and human association studies. Hum Mol 
Genet. 2010;19(14):2754–2766.  

https://doi.org/10.1093/rheumatology/keq242
https://doi.org/10.1093/rheumatology/keq242
https://doi.org/10.1111/1756-185X.12970
https://doi.org/10.1111/1756-185X.12970
https://doi.org/10.1093/jnen/nlv027
https://doi.org/10.1155/2014/798078
https://doi.org/10.3346/jkms.2006.21.5.946
https://doi.org/10.3346/jkms.2006.21.5.946
http://dx.doi.org/10.1136/ard.61.11.1031
http://dx.doi.org/10.1136/ard.61.11.1031
https://doi.org/10.1136/bcr-2014-207323
https://doi.org/10.1136/bcr-2014-207323
https://doi.org/10.1177/0961203309102557
https://doi.org/10.1177/0961203309102557
https://doi.org/10.3109/14397595.2013.843752
https://doi.org/10.3109/14397595.2013.843752
https://doi.org/10.1136/ard.2007.086157
https://doi.org/10.1136/ard.2007.086157


 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
221 

 

Available:https://doi.org/10.1093/hmg/ddq1
72 

49. Berghen N, Teuwen LA, Westhovens                 
R, Verschueren P. Malignancies and anti-
TNF therapy in rheumatoid arthritis:                  
A single-center observational cohort  
study. Clin Rheumatol. 2015;34(10):1687-
95.  

Available:https://doi.org/10.1007/s10067-
015-3026-7 

50. Mercer LK, Lunt M, Low ALS, Dixon WG, 
Watson KD, Symmons DPM, et al, BSRBR 
Control Centre Consortium. Risk of solid 
cancer in patients exposed to anti-tumour 
necrosis factor therapy: Results from the 
British Society for Rheumatology Biologics 
Register for Rheumatoid Arthritis. Annals 
of the rheumatic diseases. 2015;74:1087-
1093. 

51. Jung SM, Kwok SK, Ju JH, Park YB, Park 
SH. Risk of malignancy in patients with 
rheumatoid arthritis after anti-tumor 
necrosis factor therapy: Results from 
Korean National Health Insurance claims 
data. Korean J Intern Med. 2019;34(3): 
669-677.  

Available:https://doi.org/10.3904/kjim.2016
.374 

52. Probert L. TNF and its receptors in the 
CNS: The essential, the desirable and the 
deleterious effects. Neuroscience. 2015; 
302:2-22.  

Available:https://doi.org/10.1016/j.neurosci
ence.2015.06.038 

53. Ortí-Casañ N, Wu Y, Naudé PJW, De 
Deyn PP, Zuhorn IS, Eisel ULM. Targeting 
TNFR2 as a Novel Therapeutic Strategy 
for Alzheimer's Disease. Front Neurosci. 
2019;13:49.  

Available:https://doi.org/10.3389/fnins.201
9.00049 

54. Kemanetzoglou E, Andreadou E. CNS 
Demyelination with TNF-α Blockers. Curr 
Neurol Neurosci Rep. 2017;17(4):36.  

Available:https://doi.org/10.1007/s11910-
017-0742-1 

55. No authors listed. TNF neutralization in 
MS: results of a randomized, placebo-
controlled multicenter study. The 
Lenercept Multiple Sclerosis Study Group 
and The University of British Columbia 
MS/MRI Analysis Group. Neurology. 1999; 
53(3):457-65.  

Available:https://www.ncbi.nlm.nih.gov/pub
med/10449104 

(Accessed on: 9 Dec 2019) 

56. Sicotte NL, Voskuhl RR. Onset of multiple 
sclerosis associated with anti-TNF therapy. 
Neurology. 2001;57(10):1885-1888.  
Available:https://doi.org/10.1212/wnl.57.10.
1885 

57. Fischer R, Maier O, Siegemund M, Wajant 
H, Scheurich P, Pfizenmaier K. A TNF 
Receptor 2 selective agonist rescues 
human neurons from oxidative stress-
induced cell death. PLoS ONE. 
2011;6(11):e27621.  
Available:https://doi.org/10.1371/journal.po
ne.0027621 

58. Shi JQ, Shen W, Chen J, Wang BR, Zhong 
LL, Zhu YW, et al. Anti-TNF-α reduces 
amyloid plaques and tau phosphorylation 
and induces CD11c-positive dendritic-like 
cell in the APP/PS1 transgenic mouse 
brains. Brain Res. 2011;1368:239-47. 
Available:https://doi.org/10.1016/j.brainres.
2010.10.053 

59. Kim DH, Choi SM, Jho J, Park MS, Kang J, 
Park SJ, et al. Infliximab ameliorates AD-
associated object recognition memory 
impairment. Behav Brain Res. 2016; 
311:384-391.  
Available:https://doi.org/10.1016/j.bbr.2016
.06.001 

60. Shi JQ, Wang BR, Jiang WW, Chen J, Zhu 
YW, Zhong LL, et al. Cognitive 
improvement with intrathecal 
administration of infliximab in a woman 
with Alzheimer's disease. J Am Geriatr 
Soc. 2011;59(6):1142-4. 
Available:https://doi.org/10.1111/j.1532-
5415.2011.03445.x 

61. Tobinick EL, Chen K, Chen X. Rapid 
intracerebroventricular delivery of Cu-
DOTA-etanercept after peripheral 
administration demonstrated by PET 
imaging. BMC Res Notes. 2009;2:28.  
Available:https://doi.org/10.1186/1756-
0500-2-28 

62. Titelbaum DS, Degenhardt A, Kinkel RP. 
Anti-tumor necrosis factor alpha-
associated multiple sclerosis. American 
Journal of Neuroradiology. 2005;26(6): 
1548-1550.  

63. Vielhauer V, Mayadas TN. Functions of 
TNF and its receptors in renal disease: 
distinct roles in inflammatory tissue injury 
and immune regulation. SeminNephrol. 
2007;27(3):286-308. 
Available:https://doi.org/10.1016/j.semnep
hrol.2007.02.004 

64. Ernandez T, Mayadas T. 
Immunoregulatory role of TNFα in 

https://doi.org/10.1093/hmg/ddq172
https://doi.org/10.1093/hmg/ddq172
https://doi.org/10.1007/s10067-015-3026-7
https://doi.org/10.1007/s10067-015-3026-7
https://doi.org/10.3904/kjim.2016.374
https://doi.org/10.3904/kjim.2016.374
https://doi.org/10.1016/j.neuroscience.2015.06.038
https://doi.org/10.1016/j.neuroscience.2015.06.038
https://doi.org/10.3389/fnins.2019.00049
https://doi.org/10.3389/fnins.2019.00049
https://doi.org/10.1007/s11910-017-0742-1
https://doi.org/10.1007/s11910-017-0742-1
https://www.ncbi.nlm.nih.gov/pubmed/10449104
https://www.ncbi.nlm.nih.gov/pubmed/10449104
https://doi.org/10.1212/wnl.57.10.1885
https://doi.org/10.1212/wnl.57.10.1885
https://doi.org/10.1371/journal.pone.0027621
https://doi.org/10.1371/journal.pone.0027621
https://doi.org/10.1016/j.brainres.2010.10.053
https://doi.org/10.1016/j.brainres.2010.10.053
https://doi.org/10.1016/j.bbr.2016.06.001
https://doi.org/10.1016/j.bbr.2016.06.001
https://doi.org/10.1111/j.1532-5415.2011.03445.x
https://doi.org/10.1111/j.1532-5415.2011.03445.x
https://doi.org/10.1186/1756-0500-2-28
https://doi.org/10.1186/1756-0500-2-28
https://doi.org/10.1016/j.semnephrol.2007.02.004
https://doi.org/10.1016/j.semnephrol.2007.02.004


 
 
 
 

Churchill et al.; AJI, 3(1): 208-222, 2020; Article no.AJI.57464 
 

 

 
222 

 

inflammatory kidney diseases. Kidney 
International. August 2009;76(3):262-276.  
Available:https://doi.org/10.1038/ki.2009.1
42 

65. Amdur RL, Feldman HI, Gupta J, Yang W, 
Kanetsky P, Shlipak M, et al. Inflammation 
and Progression of CKD: The CRIC Study. 
CJASN. September 2016;11(9):1546-
1556.  
Available:https://doi.org/10.2215/CJN.1312
1215 

66. Donate-Correa J, Martín-Núñez E, Muros-
de-Fuentes M, Mora-Fernández C, 
Navarro-González JF. Inflammatory 
cytokines in diabetic nephropathy. J 
Diabetes Res. 2015:948417.  
Available:https://doi.org/10.1155/2015/948
417 

67. Navarro-González JF, Mora-Fernández C. 
The role of inflammatory cytokines in 
diabetic nephropathy. JASN. March 2008; 
19(3):433-442.  
Available:https://doi.org/10.1681/ASN.2007
091048 

68. Sharma M, McCarthy ET, Savin VJ, Lianos 
EA. Nitric oxide preserves the glomerular 
protein permeability barrier by 
antagonizing superoxide. Kidney Int. 2005; 
68(6):2735-2744. 
https://doi.org/10.1111/j.1523-
1755.2005.00744.x 

69. Donnahoo KK, Shames BD, Harken AH, 
Meldrum DR. Review article: The role of 
tumor necrosis factor in renal ischemia-
reperfusion injury. Journal of Urology. 
1999;162(1):196-203.  
Available:https://doi.org/10.1097/00005392
-199907000-00068 

70. Akcay A, Nguyen Q, Edelstein CL. 
Mediators of inflammation in acute kidney 
injury. Mediators of Inflammation. 2009:12.   
Available:https://doi.org/10.1155/2009/137
072. 

71. Gao G, Zhang B, Ramesh G, Betterly D, 
Tadagavadi RK, Wang W, et al. TNF-α 
mediates increased susceptibility to 
ischemic AKI in diabetes. Am J Physiol 
Renal Physiol. 2013;304(5):F515–      
F521.  
Available:https://doi.org/10.1152/ajprenal.0
0533.2012 

72. Stokes MB, Foster K, Markowitz GS. 
Development of glomerulonephritis during 
anti-TNF-α therapy for rheumatoid arthritis. 
Nephrology Dialysis Transplantation. July 
2005;20(7):1400–1406.  
Available:https://doi.org/10.1093/ndt/gfh83
2 

73. Gupta J, Mitra N, Kanetsky PA, Devaney J, 
Wing MR, Reilly M, et al. Association 
between Albuminuria, Kidney Function, 
and Inflammatory Biomarker Profile in  
CKD in CRIC. CJASN. 2012;7(12):1938-
1946. 
Available:https://doi.org/10.2215/CJN.0350
0412 

74. Gohda T, Maruyama S, Kamei N, 
Yamaguchi S, Shibata T, Murakoshi M, et 
al. Circulating TNF receptors 1 and 2 
predict mortality in patients with end-stage 
renal disease undergoing dialysis. Sci Rep. 
2017;7:43520.  
Available:https://doi.org/10.1038/srep4352
0 

75. Patri P, Churchill B.M, Ghosh R.P. 
Vaccines for kidney transplant recipients: 
efficacy considerations and 
recommendations. British Journal of Renal 
Medicine. 2019;24(1):21-27. 

76. Garrouste C, Anglicheau D, Kamar N, et 
al. Anti-TNFα therapy for chronic 
inflammatory disease in kidney transplant 
recipients: Clinical outcomes. Medicine 
(Baltimore). 2016;95(41):e5108. 
Available:https://doi.org/10.1097/MD.0000
000000005108 

_________________________________________________________________________________ 
© 2020 Churchill et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License 
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, 
provided the original work is properly cited. 
 
 

 

 
 

Peer-review history: 
The peer review history for this paper can be accessed here: 

http://www.sdiarticle4.com/review-history/57464 

https://doi.org/10.1038/ki.2009.142
https://doi.org/10.1038/ki.2009.142
https://doi.org/10.2215/CJN.13121215
https://doi.org/10.2215/CJN.13121215
https://doi.org/10.1155/2015/948417
https://doi.org/10.1155/2015/948417
https://doi.org/10.1681/ASN.2007091048
https://doi.org/10.1681/ASN.2007091048
https://doi.org/10.1111/j.1523-1755.2005.00744.x
https://doi.org/10.1111/j.1523-1755.2005.00744.x
https://doi.org/10.1097/00005392-199907000-00068
https://doi.org/10.1097/00005392-199907000-00068
https://doi.org/10.1155/2009/137072
https://doi.org/10.1155/2009/137072
https://doi.org/10.1152/ajprenal.00533.2012
https://doi.org/10.1152/ajprenal.00533.2012
https://doi.org/10.1093/ndt/gfh832
https://doi.org/10.1093/ndt/gfh832
https://doi.org/10.2215/CJN.03500412
https://doi.org/10.2215/CJN.03500412
https://doi.org/10.1038/srep43520
https://doi.org/10.1038/srep43520
https://doi.org/10.1097/MD.0000000000005108
https://doi.org/10.1097/MD.0000000000005108
http://creativecommons.org/licenses/by/4.0

