Unpublished Review article talking about Macrophage fusion, which I researched and wrote in my supervised study course at the University of Toronto.

1. Targets inducing Macrophage-derived Multinucleated Giant Cells
and the Mechanisms of Giant Cell Formation
Mohammad Mohib Abbasi
1002267744
BIOD95
Supervisor: Dr. Rene Harrison
April 5th, 2020

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Table of Contents
• Abstract------------------------------------------------------------------------------------------- 3
• Introduction-------------------------------------------------------------------------------------- 3-4
• Background on Immune system and Macrophages----------------------------------------- 4-5
• The roles of Macrophages---------------------------------------------------------------------- 5
• Types of Multinucleated Giant cells---------------------------------------------------------- 6-8
• Targets inducing Multinucleated Giant cells------------------------------------------------ 8-24
• Mechanism for Multinucleated Giant Cell Formation-------------------------------------- 24-27
• Discussion and Perspectives------------------------------------------------------------------- 27-28
• Summary------------------------------------------------------------------------------------------ 28
• References---------------------------------------------------------------------------------------- 29-35

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Abstract
The fusion of macrophages to form multinucleated giant cells is a mechanism used by the
immune system to help form the first line of defense against foreign threats in the body. These
foreign bodies can be a range of various things, such as bacterial infections, implanted biomaterials
or any such material that the body may not recognize. Currently there has been research done into
deriving the mechanism of the formation of these giant cells, the different types of giant cells that
can be formed and the types of foreign bodies that can induce this response. This paper will provide
a review of the literature that has been published attempting to derive the mechanism of this
process as well as the types of foreign bodies that may cause the formation of giant cells. There
has been extensive research performed on the different types of biomaterial implants that may
cause the formation of foreign body giant cells. This will also help researchers predict what type
of response the immune system will have against novel foreign bodies that people may not have
even considered to be harmful.
Introduction
One of the body’s most important defense is the immune system. The immune system
contains various mechanisms to combat infections and provide self-healing properties after the
fact. It can be divided into either the innate or adaptive immune system. Innate is for when the
infection is first detected, and if it is unable to stop the spread of the infection, the adaptive
immune system will come into play, employing cells for chronic inflammation and trying to
adapt to the infectious particle (Janeway & Medzhitov, 2002). One of the most important type of
cells involved in the immune system are the macrophage cells. Macrophages are among the first
cells sent to the site of infection, with the main purpose to contain the infection. This can be done
either by phagocytosing the infectious particle or deploying cytokines that recruit inflammation

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inducing cell (Rayahin & Gemeinhart, 2017). Often times, macrophages are not able to
phagocytose the infectious particle, usually in the case of chronic inflammation, resulting in
frustrated phagocytosis. This is one of the factors that can cause the macrophages to fuse
together through various different mechanisms to form different types of cells known as
Multinucleated Giant Cells (MGC) (McNally & Anderson, 2003). These MGCs can exist in
various different forms, depending on the cause of their formation, the mechanism of their
formation and what type of response may be needed from the body against the infection. These
different types are the Langhans Type Giant Cell (LGC), whose main purpose is to promote
inflammation of the infection site (Gupta, Athanikar, Pai, & Naveen, 2014) and Foreign Body
Type Giant Cells (FBGC), which are formed most commonly in the presence of an implanted
biomaterial, such as a medical suture (McNally & Anderson, 2011). The last type of giant cell
derived from macrophages is the Touton Giant cell, which are not much different from LGCs
except for the fact that they contains lipids inside the cytoplasm and can only be formed when
accompanied by a lipid uptake factor (Aterman, Remmele, & Smith, 1988). This review will
look at the known factors that may cause the formation of any of these cells as well as the
different molecular mechanisms that have been determined to understand how these huge cells
are formed.
Background on the Immune system and Macrophages
The immune system is the human body’s way of defending itself against the many threats that it
may encounter in daily life. The immune system can further be divided into the innate immune
system and the adaptive immune system. The innate immune system is the first system that
activates in case of an infection. Acting quickly and non-specifically, it creates a state of
inflammation at the site of infection using effector cells that release cytokines to enhance the

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inflammation. The innate immune system is usually enough to deal with any minor infections,
due to its ability to recognize pathogen-associated molecular patterns, however, if the innate
immune system is unable to deal with the infection, the adaptive immune system will get
activated (Janeway & Medzhitov, 2002). The adaptive immune system acts slowly but is able to
provide specific recognition of foreign antigens as well as providing an immunological memory
of the infection in case of the same infection occurring again, this creates the basis of
vaccinations (Janeway & Medzhitov, 2002). The adaptive immune system involves T-cells and
B-cells, while the innate immune system can utilize a variety of cells, such as natural killer cells,
dendritic cells, macrophages and several more.
The Roles of Macrophages
Macrophages are one of the first cells sent on the site of infection within the innate immune
system. They play a key role in homeostasis, wound healing, immune responses, phagocytosis
and killing of microorganisms. Macrophages are able to go through molecular reprogramming
based on different signals they may receive, either microbial, environmental or immune-derived
(Edholm, Rhoo, & Robert, 2017). Macrophages exist in one of two phenotypes, classically
activated, also known as inflammatory (M1) Type, or alternatively activated phenotypes, also
known as regenerative (M2) Type (Rayahin & Gemeinhart, 2017) (see Figure 1). M1 cells
promote inflammation and activate Type 1 T-helper cells of the adaptive immune system, while
M2 cells promote anti-inflammation and activate Type 2 T-helper cells (Rayahin & Gemeinhart,
2017).
Figure 1: Macrophages exist in a wide array of
polarization stats, ranging from being inflammatory
(M1) to anti- inflammatory/ wound healing (M2).
Source: Rayahin, J. E., & Gemeinhart, R. A.
(2017). Activation of Macrophages in Response to
Biomaterials. Macrophages Origin, Functions and
Biointervention, 62, 317–351.
https://doi.org/10.1007/978-3-319-54090-0

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Type of Multinucleated Giant Cells
Macrophages have the ability to fuse together in various ways to form multinucleated
macrophages, also known as multinucleated giant cells (MGCs), during chronic inflammation
(McNally & Anderson, 2011). Many of the studies that investigated the formation of MGCs, had
a non-phagocytosable foreign body foreign body present, which suggests that frustrated
phagocytosis might be one of the driving forces for multinucleation (McNally & Anderson,
2011). The foreign body could be present as an implanted biomedical device or biomaterial or a
pathological agent (McNally & Anderson, 2011). Macrophages fuse together based on the fusion
factors that may be activating them, which can produce the different kinds of MGCs; it is
important to note that there are cases where a single response can trigger the formation of
multiple types of MGCs as was seen in the study of Cryptococcus neoformans, discussed ahead
(Shibuya et al., 2005).
One of the types of MGCs is the Langhans-Type Giant cell
(LGC) (see Figure 2). LGCs are commonly seen associated
with granulomas during chronic microbial infections (McNally
& Anderson, 2011) and these granulomas control the spread of
bacteria and inhibit its growth (Quinn & Schepetkin, 2009).
These cells are typically circular or ovoid in shape, with ten to
twenty nuclei present in them (McNally & Anderson, 2011).
The nuclei can be seen arranged in a horseshoe-shape in the cell
(see Figure 2) (Gupta et al., 2014). LGCs main purpose is to
assist with inflammation by secreting interleukins (Gupta et al., 2014). LGCs don’t have usually
have a phagocytic role since they are derived from epithelioid cells (Gupta et al., 2014).
Figure 2: Langhans Giant Cell. The
nuclei can be seen to be arranged in a
horseshoe shape. Source: Gupta, G.,
Athanikar, S. B., Pai, V. V, &
Naveen, K. N. (2014). Giant cells in
dermatology. Indian Journal of
Dermatology, 59(5), 481–484.

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However, LGCs have been seen to respond to agents that are of a phagocytosable size in vivo,
indicating that they do have phagocytic receptors still present (Anderson, 2000).
The second type of MGC is the Foreign Body-Type Giant Cell (FBGC) (see Figure 3). FBGCs
are usually formed and found around implanted biomedical devices or foreign materials such as
surgical sutures (McNally & Anderson, 2011). These cells have no defined shape and the number
of nuclei present in them can range from ten to hundreds, which is considerably more than LGCs
(McNally & Anderson, 2011). The nuclei in FBGCs are have no set pattern or shape (see Figure
3), as is the case in LGCs and the Touton Giant cell (Gupta et al., 2014). FBGCs only arise under
chronic inflammation and work to “degrade” implanted biomaterials (McNally & Anderson,
2011). The FBGC remain on the implanted biomaterial as long as they are present, which can be
several years or even decades of a person’s life (Anderson, 2000). FBGC also seem have
different interactions based on the surface area of the implant;
for example vascular grafts have shown to have several layers of
FBGC while a more flat surface, such as breast implants only
has one or two layers (Anderson, 2000).
Figure 3: Foreign Body Giant Cell. These cells have a range of nuclei in the
cell and their cellular distribution has no pattern. Source: Gupta, G.,
Athanikar, S. B., Pai, V. V, & Naveen, K. N. (2014). Giant cells in
dermatology. Indian Journal of Dermatology, 59(5), 481–484.
The third type of MGC is the Touton Giant Cell, also known as Xanthelasmatic giant cell (see
Figure 4). These are derived from Xanthoma cells, which are also known as the foamy
macrophages (Aterman et al., 1988). These cells are not much different from LGCs, the only
major discernable difference being the fact that there are lipids present in the cytoplasm of these
cells (Aterman et al., 1988). It was also noted that the stimulus for the fusion of macrophages has
to be accompanied with a lipid uptake factor, only then will the Touton giant cell form (Aterman

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et al., 1988). Since these MGCs are derived from foamy macrophages, a cell type present heavily
in granulomas (Peyron et al., 2008), it can be assumed that Touton giant cells also form in
granulomas, just like LGCs. The lipid uptake factor would be missing in the other two types of
macrophage derived giant cells (Gupta et al., 2014). The other noticeable difference is the fact
that the nuclei were arranged in a ring structure in these cells (see Figure 4). Other than these
differences there are no other significant difference between Touton Giant cells and LGCs
(Aterman et al., 1988).
Figure 4: Touton Giant Cell. The nuclei can be seen with a ring pattern.
The picture is after the extraction of the lipids from the cell. Source:
Aterman, K., Remmele, W., & Smith, M. (1988). Karl Touton and His
“Xanthelasmatic Giant Cell” A selective Review of Multinucleated
Giant Cells. The American Journal of Dermatopathology, 10(3), 257–
269.
Targets inducing Multinucleated Giant cells
Multinucleated giant cells form via the fusion of macrophages. This fusion event takes
place at the site of inflammation, following an infection of sorts or a granulomatous condition
(Helming & Gordon, 2008). The formation of MGCs can be due to several reasons. The most
prominent one being when there is an implant in the body and the host immune system
recognizes it as a foreign body (Goswami, Arya, Biswas, Zhu, & Rahaman, 2019). Even though
the implants may be made of biomaterials, with the ultimate purpose to assist in regenerative
processes, the host immune system may recognize it as a foreign body which will induce a
cellular and humoral inflammatory response (Lucke et al., 2018). Macrophages are one of the
most important cells on the inflammation site, trying to phagocytose or eliminate the foreign
body through digestive enzymes, as well as secreting pro- or anti-inflammatory cytokines, which
will either help recruit other cells of the immune system, such as T-lymphocytes, or work to end
the immune response to that particular site (Lucke et al., 2018).

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There are several conditions that can cause the formation of MGCs and these have been
recorded by Trout, Jessop & Migliaccio (Trout, Jessop, & Migliaccio, 2016) in their paper titled
“Macrophage and Multinucleated Giant Cell Classification”. They classified the conditions
under several subheadings, these included Autoimmune/idiopathic, endogenous materials,
exogenous materials, infection-bacteria, infection-fungus and infection-parasite.
Autoimmune/Idiopathic
Annular elastolytic giant cell granuloma and the granuloma annulare
Two types of conditions inducing the formation of MGCs that have been observed are the
annular elastolytic giant cell granuloma (AEGCG) and the granuloma annulare (GA) (Limas,
2004). Both of these granulomas form smooth-surfaced, discolored plaques with an annular
shape. The MGCs are believed to be induced to insults including solar radiation exposure,
trauma or some types of infection (Limas, 2004).
Crohn’s disease and ulcerative colitis
Crohn’s disease and ulcerative colitis have both been shown to cause the formation of
MGCs (Mahadeva, Martin, Patel, & Price, 2002). In this study, the authors determined the
location of MGCs and/or granulomas and how they differed between Crohn’s disease and
ulcerative colitis. They observed that isolated MGCs and well-defined epithelioid granulomas
were not present in ulcerative colitis, giving strong suggestion that the bowel disease could be
diagnosed as Crohn’s disease ((Mahadeva et al., 2002). However, the same cells could also be
associated with intestinal crypts, and when this was the case, the presence of these cells was an
unreliable way to diagnose either Crohn’s disease or ulcerative colitis (Mahadeva et al., 2002).

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Langerhans cell histiocytosis
Another condition shown to produce MGCs is the Langerhans cell histiocytosis, which is
a form of cancer containing Langerhans cells (LCH cells) (Favara & Jaffe, 1994). LCH cells are
abnormal cells that are derived from bone marrow and have the ability to migrate from the skin
to the lymph nodes. Lesions due to the pathological LCH cells contain macrophages,
lymphocytes, eosinophils, neutrophils, plasma cells and MGCs (Favara & Jaffe, 1994). Some of
the MGCs contain complex folded nuclei, a key characteristic of LCH cells, which suggests that
these MGCs formed due to the fusion of Langerhans cells (Favara & Jaffe, 1994).
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a condition that causes inflammation at the lining of joints,
most commonly in hands and fingers. In particular RA causes the synovial tissue to get
inflammed, called RA synovitis (Koizumi et al., 1999). One of the key distinguishing factors for
RA synovitis, is the appearance of MGCs (synovial giant cells) (Koizumi et al., 1999). Synovial
MGCs can be differentiated into two different kinds, either non-foreign body type or the foreign
body type (Koizumi et al., 1999). The non-foreign body type are accompanied by LGC and
contain three to four nuclei, while the foreign body type are distinguishable by their ability to
phagocytose bone chips (Koizumi et al., 1999). One of the patients that Koizumi et al. looked at,
displayed calcium pyrophosphate dihydrate (CPPD) crystal synovitis; they found FBGCs with
CPPD crystals in them and non-foreign body type MGCs around the site.
Sarcoidosis
Sarcoidosis is a granulomatous disease which causes the inflammation of tissues in
certain organs in the body, most predominantly in the lungs and lymph nodes (Van Maarsseveen,
Vos, & Van Diest, 2009). The purpose of the paper by Van Maarsseveen, Vos & Van Diest was

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to determine the formation mechanism and function of the MGCs seen in lymph nodes with
sarcoidosis. It was found that both LGCs and FBGCs were seen in sarcoidosis, where an increase
of LGCs in the granulomatous lymph nodes was accompanied by an increase in FBGCs as well
(Van Maarsseveen et al., 2009). By using [3H]-thymidine and [3H]-uridine labelling, the
researchers were able to determine that the MGCs were forming due to the fusion of epithelioid
cells rather than defective cytokinesis (Van Maarsseveen et al., 2009). They also found that the
MGCs in sarcoidosis were causing the apoptosis of nearby CD4+ lymphocytes or histiocytes,
since apoptotic bodies of these cells were found around the MGCs (Van Maarsseveen et al.,
2009).
Endogenous Materials
Keratin
There have been cases where Foreign Body type MGCs have been seen in response to
keratin granulomas on the peritoneal surface due to a ruptured dermoid cysts (Kim & Scully,
1990). These keratin granulomas are associated with the formation of endometrioid
adenocarcinoma on the ovaries. However, keratin granulomas associated with malignant tumors
are rare and have not been reported often (Kim & Scully, 1990).
Lipids
As was mentioned previously, lipids can also cause the formation of a specific type of
MGC known as the Touton Giant cell (Aterman et al., 1988). These MGCs, also known as
Xanthelasmatic giant cells are generally not very different from LGCs. The major difference is
that if there is a generalized disturbance of lipid metabolism, macrophage cells may uptake the
lipids and fuse together to form the Touton giant cells (Aterman et al., 1988).

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Cholesterol Crystals
Cholesterol crystals have been implicated in inducing giant cells as MGCs were seen to
form depending on the size of the crystal (Bayliss, 1976). In this study, the authors examined
macrophage cultures that contained cholesterol crystals of various sizes. They found that smaller
crystals were phagocytosed by single nuclear cells, while cells with two or three nuclei contained
lipids, whereas FBGCs were associated with uptake of larger crystals (Bayliss, 1976).
Monosodium urate
Monosodium urate (MSU) is a substance present in the synovial fluid of the joints.
Crystallization of monosodium urate can cause an inflammatory response which can result in a
form of chronic arthritis known as gout (Lai & Zhou, 2013). This condition is most prominent in
males and is characterized by its increase in uric acid levels in the synovial fluid, which can
cause the formation of synovial fluid crystals resulting in the mediation of chronic inflammation
(Lai & Zhou, 2013). MSU crystals can then form when the plasma concentration in the fluid
exceeds its solubility. The cells involved in the inflammatory response are most commonly T-
lymphocytes, neutrophils, plasma cells, B-Lymphocytes (not as much as T-lymphocytes) and
some macrophages with the presence of FBGCs as well (Lai & Zhou, 2013).
Exogenous Materials
Polytetrafluoroethylene
One of the most common materials used in making cardiovascular implants is
polytetrafluoroethylene (PTFE) (Lamichhane et al., 2017). While constructing cardiovascular
devices, PTFE can be used in three different forms, either flat PTFE, with a smooth planar
surface, expanded PTFE (ePTFE), with a node-fibril morphology and electro spun PTFE, which
has randomly oriented microfibers. These forms vary based on their physical and topographical

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features, promoting different responses from the various vascular and blood cells (Lamichhane et
al., 2017). Surface topography is therefore concluded to be a key feature in determining the type
of response against PTFE, affecting the quantity and the kind of cytokines that the macrophages
release (Lamichhane et al., 2017). The release of these cytokines may also affect the morphology
of the macrophages, as Lamichhane et al. showed electro spun PTFE caused the release of TNF-
alpha, which resulted in the surrounding macrophages to be more rounded and have a
smaller cell area. Lamichhane et al. showed that planar surfaces induce the fusion of
macrophages versus rough surfaces with distinct topographical features. Electro spun PTFE had
the least percentage of macrophage forming around it while flat PTFE had the highest
percentage, this could be due to the large gaps between the fibers, which could have caused the
cell spreading and movement to be obstructed, resulting in the cells not fusing (Lamichhane et
al., 2017).
Asbestos
Asbestos is implicated in lung cancer and asbestosis, a disease similar to pulmonary
fibrosis (Murray, 1990). Although its effects on the lungs have been studied extensively, its
ability to cause the formation of MGCs has not. A study done in 1996 by Prieditis and Adamson
examined alveolar macrophages and the formation of MGCs after injection of various different
elements into the lungs of mice. These elements were carbon, silica, crocidolite asbestos,
bleomycin and as a control, saline solution. The mice were sacrificed up to sixteen weeks later
and thymidine was injected into them one hour before death as a marker (Prieditis & Adamson,
1996). Each of the injected materials caused a significant inflammatory response, which was due
to the fact that alveolar macrophage (AM) numbers increased three to four times as much
compared to the control (Prieditis & Adamson, 1996). In the case of carbon, this increase was

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only for two weeks, before the AM numbers returned to normal. There was still evidence of the
carbon substance present in the AM in the later weeks, however, the inflammatory response was
significantly lessened (Prieditis & Adamson, 1996). Bleomycin caused elevated levels of AM
through the sixteen weeks and even caused interstitial fibrosis, though no MGCs were seen
(Prieditis & Adamson, 1996). The last two elements, silica and asbestos, had a similar
inflammatory response where the AM numbers remained twice that of the control throughout the
sixteen weeks (Prieditis & Adamson, 1996). Both materials showed increased fibrosis and
granulomas, however, granulomas due to asbestos far more prominent. Both materials also
showed the formation of MGCs in the alveoli, however again, asbestos showed more MGCs
which were also larger in size (Prieditis & Adamson, 1996). The researchers suggested that
MGCs cannot form due to the phagocytic process alone and also do not form due to acute
inflammation since none were seen for carbon and bleomycin, as well as in the two week period
after the first injection of the substances. Large quantities of MGCs were only seen after the four
week period post-injection of silica and asbestos (Prieditis & Adamson, 1996). Another study
relating to asbestos found that when macrophages were able to phagocytose the asbestos fiber, of
a relatively longer length (>10 μm), the cells could fuse together to form a binucleated cell
(Ishida et al., 2019).
Talc crystals
Talc is a very common mineral used in a variety of products, such as baby powder, chalk
and even candies. A study done by Kobayashi in 2019 investigated a seventy-three year-old man
who had a nodular lesion in his lung and was diagnosed with primary lung cancer. Numerous
amounts of LGCs and FBGCs were located in the fibrous scars, with transparent crystals that
were phagocytosed by these MGCs (Kobayashi et al., 2019). The researchers used powder x-ray

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diffraction to show that the crystals were talc. However, this case is uncommon and few studies
have been performed comparing the link between talc and cancer (Kobayashi et al., 2019).
Cellulose nanocrystals
Cellulose-based materials such as wood, hemp and cotton are of high demand in the
market due to their various uses; from cellulose, a compound known as nanocellulose can be
derived via hydrolysis or oxidation (Shvedova et al., 2016). Nanocellulose can then be formed
into cellulose nanocrystals (CNC) via acid hydrolysis (Shvedova et al., 2016). CNC has been
also proven to cause lung toxicity, similar to that of asbestos (Shvedova et al., 2016). CNC
exposure can lead to pulmonary inflammation and damage as well as induced oxidative stress
(Shvedova et al., 2016). The research done by Shvedova et al. in 2016 studied the effects of
inhaled CNC on male and female mice. When the mice were exposed to CNC, the number of
macrophages increased significantly in the bronchoalveolar lavage (BAL); This increase was
even more significant in the female mice (Shvedova et al., 2016). After three months of
exposure, MGCs were found in the BAL of both the male and female mice, however, many more
were present in the females (Shvedova et al., 2016). Interleukin-4 and interleukin-13 have been
shown to be important macrophage fusion factors that support the formation of MGCs (McNally
& Anderson, 2011). Due to the prolonged CNC exposure, certain inflammatory cytokines and
chemokines became overexpressed, these included the IL-4 and IL-13 for females, but only IL-4
in males. This meant that females contained a greater density of MGCs as opposed to the males
(Shvedova et al., 2016).
Alpha-tocopherol
Another factor shown to induce the fusion of macrophages is the antioxidant vitamin E
(90% alpha-tocopherol) (McNally & Anderson, 2003). A study done by McNally & Anderson

16. 16
found that alpha-tocopherol caused an increase in the MGCs that formed due to the fusion factor
IL-4. They tested the effects of purified alpha-tocopherol as well, and that lead to cultures of
FBGCs being formed that were far more confluent than when vitamin E was used or even when
the beta-, gamma- or delta- variants of tocopherol were used (McNally & Anderson, 2003). One
more factor is interferon-gamma, which caused the fusion of macrophages, however, in this case
only LGCs were seen to be formed (McNally & Anderson, 2011). The fusion via IFN-γ also
seemed to require a cofactor, unlike the fusion of FBGCs. This cofactor needed to be a
macrophage maturation factor such as granulocyte-macrophage colony-stimulating factor (GM-
CSF) or interleukin-3 (IL-3) (McNally & Anderson, 2011).
tarSys xenograft
Another relatively recent cause for FBGC formation is the tarSys xenograft, which is a
bioengineered eyelid spacer graft, with the purpose to reinforce and aid in the reconstruction of
an eyelid (Munday, Klett, McNiff, & Ko, 2014). The tarSys is made to mimic the extracellular
environment of a tarsus, which contains type 1 collagen, extracellular matrix proteins and
glycoproteins (Munday et al., 2014). The composition of the actual tarSys includes
decellularized porcine small intestinal submucosa and its main purpose to allow a platform for
host cells to infiltrate, integrate and remodel for tissue regeneration (Munday et al., 2014). The
study done by Munday et al. examined two patients, both of which had undergone a surgical
procedure to retract their lower eyelid, with the resultant implantation of tarSys. Both patients
developed chronic swelling, which required the removal of the xenograft which resulted in the
swelling stopping. However, for the second patient, the right eye did not produce the same
symptoms. After the removal of the grafts for both patients and for both eyes for the second
patient, the researchers examined them to find that there were FBGC present on the periphery of

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the implant, indicating that a FBGC formation reaction may be induced by this implant (Munday
et al., 2014). The results from these two patients is uncommon and further research is required.
Bacterial Infections
Brucella
Brucellosis is a disease caused by an infection of the bacteria Brucella. It can infect both
animals and humans, however, in humans only 1%-2% of recorded cases are fatal (Hunt &
Bothwell, 1967). Hunt and Bothwell looked at fourteen different patient cases involving
brucellosis in different organs of the body. The infections were seen in the liver, the gall bladder,
the testicle, the heart and the spleen (Hunt & Bothwell, 1967). In the cases examined, focal
granulomas were seen on site of the active infection in the liver, these granulomas contained
several immunological cells, including MGCs in most of the of the granulomas; these MGCs
varied from a few nuclei to forty or fifty nuclei in a cell (Hunt & Bothwell, 1967). Similarly, it
was reported that the gall bladder contained granulomatous inflammation during brucellosis,
within which a few MGCs were found (Hunt & Bothwell, 1967). The singular case looked at
regarding the testicles involvement in brucellosis, showed that the right testicle of the man was
infiltrated with chronic inflammatory cells, however, the collection of cells could not be
categorized as true granulomata and no MGCs were present here either (Hunt & Bothwell,
1967). Similarly, the heart had no granulomas present, and hence no MGCs were present either;
the spleen however did show focal granulomas but no MGCs were seen in these granulomas
(Hunt & Bothwell, 1967).
Nontuberculous mycobacteria and Bartonella henselae
Lymphadenopathy is a disease that can occur in the lymph nodes. It can cause the lymph
nodes to become an abnormal size or lose the consistency in its size. One of the most common

18. 18
causes for lymphadenopathy, in children specifically, is infection from various bacteria (Nunes
Rosado, Stratton, & Mosse, 2011). Nunes Rosado, Stratton and Mosse did a study that involved
looking at different cases of lymphadenopathy and the various bacteria that caused it. Two of the
bacteria that they looked at were nontuberculous mycobacteria and Bartonella henselae, the
bacteria responsible for cat scratch disease (Nunes Rosado et al., 2011). Nontuberculous
mycobacteria displayed caseating granulomas and central acellular necrosis, which would be
surrounded by granulomatous inflammation with MGCs (Nunes Rosado et al., 2011). Bartonella
henselae caused stellate necrotizing granulomas, containing MGCs as well, but these were not
present in all the cases and were rare (Nunes Rosado et al., 2011).
Mycobacterium Leprae
Leprosy is an infectious disease that can cause nerve damage in the limbs and skin areas
around the body. It is caused by the Mycobacterium Leprae and can cause type 1 reactions (T1R)
within infected patients (Lockwood et al., 2008). T1R is defined as new erythema forming in
skin lesions and the loss of nerve function in peripheral nerves (Lockwood et al., 2008). One of
the most common histological features of T1R were the presence of LGCs, the other features
being giant cell maturity and oedema (Lockwood et al., 2008).
Mycobacterium tuberculosis
Mycobacterium tuberculosis (M. tb) is the causative agent for the disease Tuberculosis,
which usually affects the lungs, but can affect other parts of the body as well. The bacteria can
retain itself in the host for several years in a dormant form; this is due to the fact that M. tb has a
tight interplay within the granulomas of the host cells (Lay et al., 2007). The cellular aggregates
can restrict the spread of M. tb but cannot kill it entirely (Lay et al., 2007). The formation of the
granuloma post infection involves the initial on-site macrophage releasing cytokines and

19. 19
chemokines to recruit more macrophages, lymphocytes and dendritic cells (Lay et al., 2007). Lay
et al. showed that this event is shared amongst other Mycobacterium as well, such as M. avium
and M. smegmatis, however, M. tb was the only one shown to induce the formation of MGCs
similar in size to LGCs (>15 nuclei). M. avium and M. smegmatis were only able to induce the
formation much small multinucleated cells, with the number of nuclei being less than or equal to
seven (Lay et al., 2007). Another feature specific to the MGCs formed due to the induction of M.
tb, is that these MGCs have lost the ability for bacterial uptake (Lay et al., 2007). This is not due
to the cells being in a quiescent state, as it was seen that their NADPH oxidase activity was
similar to that of other macrophages; But rather due to the reduction in phagocytic receptors,
such as mannose receptor and CD11b (Lay et al., 2007). The antigen presentation ability of these
MGCs was however, enhanced due to an increase in the MHC class II antigen presenting cells on
the surface (Lay et al., 2007).
Treponema pallidum
Treponema pallidum is the bacteria responsible for the infectious disease syphilis (Barrett
et al., 2004). The main mode of transmission for this bacteria is sexual contact with someone
who is infected by it (Barrett et al., 2004). Syphilis can be broken down into three stages,
primary, secondary or tertiary, all of which can produce an oral manifestation of the infection
(Barrett et al., 2004). Primary syphilis can form lesions with a hard base on the lips, tongue or
palate; secondary syphilis can create white plaques or mucous patches which can fuse to form
ulcers on the lips, tongue or palate as well; tertiary syphilis can also form mucosal lesions
typically on the palates (Barrett et al., 2004). Barrett et al. looked at fivecases of syphilis, two of
which were tertiary, two were primary and one was secondary. Out of these cases, the tertiary
cases were the most granulomatous and therefore were dense with LGCs while the one primary

20. 20
case contained less amounts of LGCs while the other primary case did not contain any; the
secondary case also did not contain any LGCs (Barrett et al., 2004).
Fungal Infections
Aspergillus
Aspergillus is a spore-producing fungus that can easily transport its spore through the air,
into someone’s airways. However, it usually does not cause any disease unless the person has a
weakened or undeveloped immune system (Das, Dey, Chakrabarti, & Ray, 1997). The paper by
Das et al. utilized fine needle aspiration biopsy (FNAB) when diagnosing fungal infections.
FNAB was performed at various sites of infections, which included lymph nodes, the skin and
the prostate (Das et al., 1997). The cases Das et al. looked at in their study had people ranging
from fifteen months to sixty-five years, while the split between male and female was 2:1
respectively. They encountered the fungal infections most commonly in head and neck area with
majority of infections being from the Aspergillus species. In the majority of the infection cases,
the inflammation contained a mix of lymphocytes, polymorphs, eosinophils, histocytes, MGCs
and epithelioid cell granulomas (Das et al., 1997). The MGCs were of the foreign body type and
were mixed with foamy macrophages and lymphocytes, with signs of necrosis in the surrounding
area (Das et al., 1997).
Cryptococcus neoformans
Cryptococcus neoformans is a fungus that if it enters the body can cause inflammation
and a granulomatous response (Shibuya et al., 2005). Much like Aspergillus, Cryptococcus
neoformans affects immunocompromised individuals most severely than those who have a
healthy immune system. Even then, the mechanism of its infection is different from that of
Aspergillus and therefore, a different defense mechanism is applied by the human body (Shibuya

21. 21
et al., 2005). Shibuya et al. examined this fungus specifically in individuals with acquired
immunodeficiency syndrome (AIDS) and those patients on highly active antiretroviral therapy
(HAART), which essentially prevents the virus from making copies of itself. They found that
AIDS patients who were not being treated with HAART could not stop the dissemination of
cryptococci in the bloodstream (Shibuya et al., 2005). On the other hand, patients that were
treated with HAART displayed greater quantities of the T helper cell CD4+, a greater response
of histocytes as well as MGC formation (Shibuya et al., 2005). The granulomatous aggregates of
cells on the site of infection contained macrophages with epithelioid features, as well both
foreign body type MGCs and Langhans type MGCs; yeast cells could also be seen present inside
the cytoplasm of these cells (Shibuya et al., 2005).
Parasitic Infections
Dirofilaria immitis
Dirofilaria immitis is a heartworm, commonly seen in dogs; it can however be
transmitted to humans by insects such as mosquitos and can cause a rare zoonotic diseases called
human pulmonary dirofilariasis (Araya et al., 2007). The worm usually places itself inside the
pulmonary artery and necrotic nodules can be seen in the surrounding area, usually in a spherical
shape, proposed to be due to the embolization taking place (Araya et al., 2007). Arya et al.
examined thirteen cases of individuals with pulmonary dirofilariasis. All of the patients
displayed eosinophils, lymphocytes and plasma cells in the peripheral encapsulating wall of the
pulmonary artery, while eight out of the thirteen cases also showed the presence of MGCs
(Araya et al., 2007).

22. 22
Onchocerca volvulus
Onchocerca volvulus is a parasite that is commonly found in Africa and Latin America.
When it infects humans it can cause a disease known as onchocerciasis, which causes dermal and
ocular pathology, resulting in blindness (Gatrill, Mackenzie, McMahon, Williams, & Guderian,
1987). The adult parasites reside in areas known as nodules which are located in subcutaneous
tissue, surrounded by the host inflammatory cells (Gatrill et al., 1987). The offspring, also known
as microfilariae, exit from the mature female worms and migrate towards the eyes, which results
in an inflammatory response in that region, causing the disease (Gatrill et al., 1987). Upon
inspection of the infected sites, the nodules were observed to be surrounded by macrophages,
some of which were multinucleated, while some were just mononucleated; these cells were also
often accompanied by eosinophils and lymphocytes (Gatrill et al., 1987). Gatrill et al. also
mentioned in their paper that the multinuclear cells in some nodules even tested positive for
lipids; though not mentioned specifically in the paper, this could be an indication of the presence
of the Touton giant cell, as the formation of that requires a lipid uptake factor.
Leishmania
The species of intracellular protozoan parasites under the genus Leishmania can cause the
disease leishmaniasis (Mehregan, Mehregan, & Mehregan, 1999). The parasite can usually get
transmitted via a bite from the sand-fly family, causing a cutaneous infection. This leads to an
immune response which can involve the migration of several immunological cell types to the site
of infection, including macrophages which might contain the amastigotes of the Leishmania
species or even highly organized epithelioid cell granulomas (Mehregan et al., 1999). The cell
infiltrate often contains MGCs, more specifically LGCs, as the lesion starts to grow (Mehregan
et al., 1999). The organisms can be found inside the macrophages, however, if the parasite

23. 23
continues to grow and multiply, they are seen in the surrounding area as well, warranting the
need for the macrophages to expand, as well as increasing the immunological response
(Mehregan et al., 1999).
Schistosoma mansoni and Schistosoma haematobium
Schistosomiasis is a helminth disease caused by the parasites Schistosoma mansoni or
Schistosoma haematobium (Geboes, El-Dosoky, El-Wahab, & Almagd, 1990). The main
differentiating characteristic for these parasites is the fact that they can have living eggs present,
which is what induces the formation of lesions and there can be different types of lesions present
simultaneously in different areas (Geboes et al., 1990). The lesions that form early on contain T
lymphocytes and as the lesion grows, other different immunological cells arrive and the lesion
eventually gets granulomatous filled eosinophils, T lymphocytes, B lymphocytes and MHC class
II antigens (Geboes et al., 1990). Geboes et al. looked at biopsies of fourteen different cases of
people with schistosomiasis. They found that most of the granulomas contained free ova in the
center, while being surrounded by the various immunological cells, as listed above. In four cases
MGCs were observed, which the researchers believed to be of the foreign body type, due to some
of cells engulfing the egg (Geboes et al., 1990).
Miscellaneous
Irradiation
Another factor that may result in the formation of these MGCs is irradiation, as seen in
the study done by Trosic in 2001 showed. Trosic sought to determine the effects of irradiation on
the fusion of alveolar macrophages. The study was done on rats divided into four subgroups,
each receiving a set amount of irradiation treatments, either two, eight, thirteen or twenty-two,
spaced out in two-hour sessions. The animals were then killed on experimental days one, eight,

24. 24
sixteen and thirty. After examination, rats that were treated with irradiation twice or eight times
had macrophages with two nuclei present quite commonly, while the rats that were treated with
irradiation thirteen or twenty two times had macrophages with three or more nuclei present
frequently (Trosic, 2001).
Mechanism for Multinucleated Giant cell Formation
Multinucleated cells are formed by cells fusing together in a granuloma, and are called
syncytia. Multinucleated cells can also form via repeated rounds of mitosis without cytokinesis,
these cells are called coenocytes (Trout et al., 2016). Macrophage syncytia is another common
name for MGCs (Trout et al., 2016). The purpose for macrophages fusing together is to combat
pathological conditions or foreign bodies that a singular macrophage may not be able to deal
with alone (Quinn & Schepetkin, 2009). This fusion requires the involvement of multiple factors
that can then result in the formation of either one of the three types of MGCs that were
discussed, or depending on the condition, two or even all three of those MGCs may form. The
different conditions that can cause the fusion of these macrophages were discussed in the
previous section, this section will discuss the factors that need to be released for the fusion to
actually commence and how that fusion takes place.
One of the major conditions under which MGCs may form, is the implantation of
biomaterial into human tissue. Before even the host cells are able to get to the biomaterial, the
foreign object acquires layer of host proteins, this process occurs spontaneously, as the
implantation occurs (Anderson, Rodriguez, & Chang, 2008). It is then highly possible that the
response from the host cells may be determined by the types of proteins that attached themselves
as well as the surface conformation (Anderson et al., 2008). As the blood interacts with the

25. 25
foreign object, the platelets release chemokines and chemoattractant, that direct macrophages to
the infection site; these chemoattractant include transforming growth factor (TGF-ß), platelet-
derived growth factor (PDGF), CXCL4, platelet factor (PF4), leukotriene (LTB4) and interleukin
(IL-1) (Anderson et al., 2008). Mast cell degranulation as well as the release of histamines, can
also direct more macrophages to the infection site. As the macrophages start to gather, more
chemoattractants are released, causing the propagation of even more macrophages; these
chemoattractants include PDGF, tumor necrosis factor (TNF-∂), IL-6, granulocyte-colony
stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF)
(Anderson et al., 2008). These prolonged series of reactions, that continue to bring macrophages
to the site, is known as the foreign body response (FBR) (MacLauchlan et al., 2009).
For the formation of FBGCs, the factors that induce the actual fusion have been found to
include IL-4 and IL-13 (Helming & Gordon, 2008). IL-4 was shown to induce the MGC
formation in vitro and in vivo (Helming & Gordon, 2008). Formation of FBGCs also requires
matrix metalloproteinase 9 (MMP-9), as reducing its levels significantly reduced macrophage
fusion (MacLauchlan et al., 2009). McNally and Anderson also showed that another factor
involved in the formation of FBGCs is the primary compound in Vitamin E, ∂-tocopherol, which
allows the of IL-4 induced fusion to take place (McNally & Anderson, 2003). For the formation
of LGCs, the main fusion factor is interferon gamma (Trout et al., 2016). Both of these fusion
processes require the presence of macrophage maturation factors GM-CSF, M-CSF, or IL-3,
however, the maturation factors alone cannot induce fusion (Trout et al., 2016). Some other
factors that have been proposed to be necessary for efficient fusion to take place are calcitriol
(1,25-dihydroxyvitamin D3), phorbol 12-myristate 13-acetate, and T-cell mitogenic plant lectins
concanavalin A and phytohemagglutinin (Trout et al., 2016).

26. 26
The fusion takes place in three steps termed competence, commitment and fusion (Trout
et al., 2016). Competence involves expression of fusion proteins within the macrophage to give it
the capacity to fuse. The foreign material sends poorly understood signals to increase the
transcription of key proteins, such as MMP-9, E-cadherin, dendritic cell-specific transmembrane
protein (DC-STAMP) (Trout et al., 2016). The second step is commitment, this involves having
the fusion competent macrophage migrating near another fusion competent macrophage. This
migration is mediated by the chemokine CCL2, also known as monocyte chemoattractant protein
1 (MCP-1) (Jay, Skokos, Laiwalla, Krady, & Kyriakides, 2007). Adhesion factors ß1 and ß2
integrins are then expressed on the cell surface of the macrophages, allowing cytoskeleton
remodeling, and podosome formation (Anderson et al., 2008). The final factor involved is Rac1,
which has been shown to be involved in actin polymerization and reorganization, resulting in the
formation of podosomes (Trout et al., 2016). The podosomes then connect with the opposing
Figure 5: The formation mechanism scheme for the three different giant cells. Foreign Body giant cell
(Left); Langhans giant cell (Middle); Touton giant cell (Right).

27. 27
macrophages’ podosomes (Anderson et al., 2008), this is similar to how macrophages use these
podosomes to perform mechano-sensing to interact with adsorbed proteins on the foreign body
structure (Sheikh, Brooks, Barzilay, Fine, & Glogauer, 2015). The final step is the actual fusion
occurring, which involved cytoskeletal rearrangements during and after the fusion (Trout et al.,
2016) (see Figure 5).
Discussion and Perspective
Even after all the factors that were discussed in this review, I am sure there are several
more that have yet to be discovered to cause the formation of MGCs. The mechanism, although
has started to be more and more clear, still has gaps present. For example, the fusion factors that
were listed above and in Figure 5, are only the confirmed mediators that are required for the
formation of MGCs. There may be more factors than the ones listed required for each of the
different MGCs to form, further research in this area is required. Another area requiring further
research is the classification of the MGCs, as to date, the strategy to classify a MGC is
determined by the number of nuclei and whether the cell contains lipids, in the case of Touton
giant cell. Specifically, for the Touton giant cell, the research is scant. The only major discerning
factor from the LGCs is the presence of the lipid uptake factor, and the role of the giant cell is
not clear. Therefore, more research is required to really put the Touton giant cell in its own
category.
As has been seen, based on the numerous conditions under which MGCs can form as well
as the length of time they persist, these giant cells are clearly an important aspect of the immune
system when combating foreign objects. A common trend observed is that MGCs form in the
presence of a foreign object. Therefore, it is reasonable to think that they perform a role in
frustrated phagocytosis, as was suggested in a couple of the older research studies. There are

28. 28
many more factors at play that warrant the formation of MGCs. Of course, frustrated
phagocytosis may be one of the factors, but it is definitely not the only one, as mentioned before,
further research is required to fully map out all the different functions that they perform in
disease.
The mechanism that was also discussed here is a very streamlined version of what may
be actually happening. There are many different factors that have already been shown to be of
importance by the several studies that were looked at in this review. This is not a simple process,
rather a quite complex one and it should not be overlooked in the research studies to come.
Summary
There are several types of conditions and infections that have resulted in the formation of
MGCs. Although some of these conditions may not necessarily be anything severe, some such as
the infection from Cryptococcus neoformans can prove life threatening for people with
preexisting conditions. Therefore, further research into the different types of MGCs that are
present in the human body can prove to be a very useful endeavor seeing as to how important the
foreign body response actually is. Even though the importance of the foreign body response is
clear, the main role of MGCs remains unclear. From what has been seen, MGCs can either be
helping with the containment of the infection, trying to phagocytose the infectious particle or
simply a by-product of the inflammation due to the numerous amounts of macrophages that are
present. The detailed derivation of the mechanism of formation as well as the role each MGC
may play in the event of an infection can help researchers come up with different techniques and
processes to help build up our knowledge of defense mechanisms. For example, there has not
been many studies performed that link MGCs with viral infections, this is particularly relevant
during the COVID-19 pandemic.

29. 29
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