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Tingible body macrophages

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Suhasini Palakshappa Gotur
Suhasini Palakshappa Gotur
Suhasini Palakshappa Gotur
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Vijay Wadhwan at Swami Vivekanand Subharti University
Vijay Wadhwan
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418 © 2021 Journal of Oral and Maxillofacial Pathology | Published by Wolters Kluwer - Medknow
Described in 1885 by Flemming, tingible body
macrophages (TBMs) represent unique, large phagocytic
cells that reside in germinal centers (GCs) of secondary
lymphoid tissues and are a subset of mononuclear
phagocytes. TBMs contain many phagocytized, apoptotic
cells in various states of degradation. They owe their
name to their ability to actively phagocytose apoptotic
lymphoid cells, and the “tingible bodies” (TBs) observed
in their cytoplasm are apoptotic bodies.[1,2] They are seen
scattered among proliferating centroblasts, giving the
typical starry-sky appearance to developing GCs.[1,3]
The closely apposed medium sized tumor cells or the
normal lymphocytes in the reactive lymphnodes which
have minimal cytoplasm, and a dark nuclei impart a dark
blue background (the “sky”) to the histological sections.
These cells have a very high turnover rate, so that the
nearby macrophages get lled with cellular debris. Upon
xation, the cytoplasm of the macrophages disintegrates,
leaving round white spaces lled with debris (the “stars”),
imparting a “starry-sky pattern” at low magnication.
Nobody knows who created the histological comparison
with the “starry-sky” pattern. Perhaps, the unknown author
was inspired by the Dutch postimpressionist, Vincent
Willem van Gogh’s beautiful night paintings.[3]
“Starry-sky pattern” is distinctive for Burkitt lymphoma
but can be a nonspecific feature of pronounced
follicular hyperplasia seen in bone marrow, lymph node,
extranodal mass sections, some thymomas and rheumatoid
lymphadenopathy.[3] They may also be observed in other
malignant lymphomas with rapid cell turnover, such as
precursor B- or T-cell lymphomas and lymphoblastic
lymphomas. These high-grade lymphomas, however,
often accompany a monomorphic population of atypical
lymphoid cells as compared to the polymorphic pattern
of small “normal” lymphocytes in reactive conditions.[1]
Polarization, normal encompassing mantle zone, absence of
bcl-2 positivity, absence of capsular invasion and perinodal
fat invasion differentiate the reactive process in lymph
nodes from malignancy.[2,4] The appearance of TBMs and
a starry-sky appearance in the paracortex are indicative of
increased apoptosis and are suggestive of T-cell production
but may also occur with lymphocytolysis.[5] TBMs are also
noted in ne-needle aspiration of angiosarcoma of an
intraparotid lymph node.[6]
Lymphoid hyperplasia involving both the B-cell-rich
follicles and the T-cell-rich paracortex is generally a
reactive or immune response and is not considered to
be a preneoplastic lesion. Stimulated (reactive) follicles/
secondary follicles are usually larger than the unstimulated
primary follicles and will have a paler staining GC with
large lymphoblasts and increased number of apoptotic
lymphocytes and TBMs,[4] as seen in Figure 1.
TBMs range in size from 20 to 30 u or larger and contain
a variable number of inclusions [Figures 2 and 3]. Electron
microscopically TBMs show the nucleus, 12–15 p in
diameter, containing two dense, nucleolar-like areas and
peripheral dispersed chromatin. Mitochondria, smooth
and rough endoplasmic reticulum and a well-developed
Golgi region are present in the macrophage cytoplasm.[7]
The inclusions or the phagolysosomes (TBs) represent not
only nuclear but also cytoplasmic debris in varying stages
of lysis (apoptotic cell debris).[5,7] Following antigenic
stimulation, granulocytes are also seen in TBMs.[7]
It is generally accepted that the TBMs represent
phagocytized debris of small lymphocytes or both
lymphocyte and erythrocyte debris. This “graveyard
theory” emphasizes the phagocytosis of pyknotic small
lymphocytes. This theory was extended by Hamilton,
Trowell and Sundberg who postulated reutilization of
Figure 1: Photomicrograph from the reactive submandibular lymph
node of an elderly female patient with a large mandibular tumor,
histologically diagnosed as follicular ameloblastoma. (a) Capsule,
(b) Paracortical germinal center. Tingible body macrophages impart
the paracortical germinal center “starry-sky” appearance (H&E, ×10)
Tingible body macrophages
Enigmatic Morphoinsight
Gotur and Wadhwan: Tingible body macrophages
Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 3 | September-December 2020 419
small lymphocytes in lymphocytopoiesis. Andrew stressed
the role of degeneration and phagocytosis of small
lymphocytes in GCs as indicating that these centers are
not germinal but reactive, contradicting Hellman. Ortega
and Mellors suggested that intrinsic GC cells degenerated
after secreting gamma globulin and were phagocytized by
TBMs. Electron microscopically plasma cell inclusion by
TBs is also seen in hyperplastic GCs of lymphatic tissue in
the mouse following antigenic stimulation. The plasma cell
phagocytosis by TBMs may reect plasma cell proliferation
rather than lymphocyte production from the population
of cells comprising GCs after antigenic stimulation. This
proposal is in agreement with the suggestion by Ringertz
and Adamson and Congdon and Goodman that the
centers form either antibody-producing plasma cells or
lymphocytes, depending on an antigenic stimulus. This
idea is also consistent with the functional proposal by
Ortega and Mellors that depleted GC cells are phagocytized
following protein synthetic activity.[7]
Unique to TBMs is the GC microenvironment,
characterized functionally by long-term antigen retention
on follicular dendritic cells, antigen presentation by
B-cells to T-helper cells, a high rate of somatic mutations,
affinity maturation, induction of antibody-forming
cells and memory B-cell development. Apart from the
scavenging function, TBMs also may be important in
initiating the GC reaction. This suggestion was based on
the observations that TBM initially appeared at the onset
of GC development and that a peak number of TBMs
were seen at peak GC development. However, it has been
shown that GCs can develop in old mice in the absence of
TBM. This advocates a regulatory role of TBM and that
TBMs are more likely to downregulate than to stimulate
the GC reaction.[8] Further, TBMs were found to be rich
in prostaglandins via which they downregulate the GC
reaction.[2,9]
It has been suggested that the scavenging activity of TBM
may play a signicant role in preventing autoimmunity.[2]
Fat globule-epidermal growth factor 8 (Mfge8) promotes
TBMs to engulf apoptotic bodies in GCs and helps
minimize autoimmunity.[9] Furthermore, this is illustrated
by a confocal microscopic study of TBMs, to evaluate the
in vivo capacity to remove apoptotic cell material, conducted
on patients with systemic lupus erythematosus (SLE). In
lymph nodes GCs from the patients with SLE, the apoptotic
cells were more and the TBMs were reduced in number, in
contrast to the control group. This nding suggested that
in SLE patients, apoptotic cells are not properly cleared
by TBMs. Consequently, retained nuclear autoantigens can
be presented to and bind to follicular dendritic cells and
may thus provide survival signals for autoreactive B-cells,
thereby initiating or propagating autoimmune disease.[2,10]
To conclude, TBMs in GCs of reactive lymph nodes
represent a benign process which should be differentiated
from the lymphomas and other malignancies. Further
studies are required to understand the role of TBMs in the
pathogenesis of various autoimmune diseases.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conicts of interest.
Suhasini Palakshappa Gotur, Vijay Wadhwan
Department of Oral Pathology and Microbiology, Subhar Dental College
Figure 2: Higher magnication of Figure 1, showing (a) tingible body
macrophages with intracytoplasmic apoptotic bodies, which represent
nuclear debris, surrounded by (b) lymphocytes (H&E, ×40)
Figure 3: Hand-drawn illustration showing (a) tingible body
macrophages with intracytoplasmic apoptotic bodies, surrounded by
(b) lymphocytes
Gotur and Wadhwan: Tingible body macrophages
420 Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 3 | September-December 2020
and Hospital, Swami Vivekanand Subhar University, Meerut, Uar
Pradesh, India
E-mail: suhasrajukk@gmail.com
Submied: 27-Jul-2020,
Accepted: 06-Oct-2020, Published: 09-Jan-2021
REFERENCES
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... ; https://doi.org/10.1101/2022.08.18.504434 doi: bioRxiv preprint TBMs contain apoptotic cellular debris at different degradation stages and are named after apoptotic nuclear debris ('tingible bodies') that can be observed in their cytoplasm. A presence of TBMs rich in tingible bodies is a hallmark of follicular hyperplasia and Burkitt's lymphoma, both characterized by fast cell turnover (Gotur and Wadhwan 2020). We examined hyperplastic LN from two different patients and two Burkitt's lymphoma cases, and found that TBMs in both conditions contain many tingible bodies and display high IL4I1 expression (Fig 4C-D). ...
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