Germinal centers
or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in
secondary lymphoid organs
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...
–
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s, ileal
Peyer's patch
Peyer's patches or aggregated lymphoid nodules are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer.
* Reprinted as:
* Peyer referred to Peyer's patches as ''plexus'' or ''agmina glandularum'' (cl ...
es, and the
spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
– where mature
B cell
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s are activated, proliferate, differentiate, and mutate their
antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
genes (through
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...
aimed at achieving higher affinity) during a normal immune response; most of the germinal center B cells (B
GC) are removed by
tingible body macrophage
A tingible body macrophage (TBM) is a type of macrophage predominantly found in germinal centers of lymph nodes. They contain many phagocytized, apoptotic cells in various states of degradation, referred to as tingible bodies (''tingible'' meani ...
s.
There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production.
The B cells develop dynamically after the activation of
follicular B cell
Within the immune system, follicular B cells (FO B cells) are a type of B cell that reside in primary and secondary lymphoid follicles (containing germinal centers) of secondary and tertiary lymphoid organs, including spleen and lymph nodes. Antibo ...
s by T-dependent
antigen
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
...
. The initiation of germinal center formation involves the interaction between B and T cells in the interfollicular area of the lymph node, CD40-CD40L ligation,
NF-kB signaling and expression of
IRF4
Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the ''IRF4'' gene. IRF4 functions as a key regulatory transcription factor in the development of human immune cells.Nam S, Lim J-S (2016). "Essentia ...
and
BCL6
Bcl-6 (B-cell lymphoma 6) is a protein that in humans is encoded by the ''BCL6'' gene. BCL6 is a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. BCL6 has three evolutionary conserved structural d ...
.
GC B cells cycle through the two distinct zones of the germinal center: the light zone and the dark zone.
As they undergo rapid and mutative cellular division, B cells of the germinal center's dark zone are known as
centroblasts. Once these B cells have stopped proliferating in the dark zone and moved to the light zone, they are known as
centrocytes, and are subjected to selection by
follicular helper T (TFH) cells in the presence of
follicular dendritic cells
Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles (lymph nodes) of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hema ...
(FDCs).
There are three possible fates for GC B cells that have been positively selected in the light zone: plasma cell, memory B cell or B cell licensed to return to the dark zone for proliferation and mutation.
These three fates are achieved via the distinct mechanisms described below. Germinal centers are an important part of the B cell
humoral immune response
Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because ...
, acting as central factories for the generation of
affinity matured B cells specialized in producing improved antibodies that effectively recognize antigen (e.g. infectious agents), and for the production of
long-lived plasma cells and durable
memory B cells.
Naive B cells vs. germinal center B cells
There are several key differences between naive B cells and GC B cells. Naive B cells do not undergo lots of cell division. On the other hand, B cells in GC tend to divide rapidly and frequently, and they can have cell cycles as short as only five hours. As a result of their highly proliferative quality, GC B cells are larger in size and are more metabolically active, as compared to naive B cells. Although GC B cells have a greater energy demand than naive B cells, they mainly produce energy by the process of
fatty acid oxidation, while naive B cells depend on
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
.
Germinal center initiation
Germinal centers are initiated in the B cell follicle of the
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
. Following activation of naive B cells in the lymph node follicles, the B cells migrate to the interfollicular areas so that they can interact with T cells. When the B and T cells interact, the antigen-specific T cell receptors bind the antigen + MHC presented by the B cells. Additionally, the T cells are able to help the B cells by the interaction of the T cell
CD40 ligand with the
B cell CD40 molecule, which causes a
signaling cascade
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
that is beneficial for the survival and proliferation of B cells. B cell receptor activation results in the activation of the
NF-kB signaling pathway, which is essential for the initiation of the germinal center reaction. Specifically, the expression of IRF4 and BCL6 transcription factors are both required for germinal center development and regulated by NF-kB signaling. For example, BCL6 controls the location of B cells in the lymph node and allows them to have a higher tolerance to DNA damage, thus promoting the proliferation of GC B cells. All B cells begin by co-expressing antibodies that have
IgM
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
and
IgD constant regions, but they are later able to exchange these constant regions for
IgA IGA or IgA may refer to:
Businesses and organizations
* IGA (supermarkets) (initially Independent Grocers Alliance), a name used by many independent supermarkets throughout the world
** IGA (Australian supermarket group), the local Australian v ...
,
IgG or
IgE
Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...
constant regions and express antibodies of a different class type via class switch recombination.
Class switch recombination
Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the ...
occurs during the germinal center initiation phase. The precursors of germinal center B cells start to expand four days following immunization and polarize into dark zones and light zones a week after immunization.
Two distinct germinal center zones: dark zone and light zone
There are two distinct regions of the germinal center: the light zone (LZ) and the dark zone (DZ).
These two zones are formed from pre-GC B cells that proliferate and polarize seven days following immunization.
GC B cells alternate between the dark zone and the light zone and undergo several rounds of mutation and selection, respectively.
Dark zone
The dark zone of the germinal center is proximal to the T cell zone in the lymph node, and it consists of GC B cells and
reticular cells that resemble
follicular dendritic cells
Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles (lymph nodes) of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hema ...
.
The B cells within the dark zone of the germinal center are called
centroblasts.
They are larger than the cells in the light zone of the germinal center and are more proliferative (i.e. undergo more cell division).
Somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...
, a process in which the
activation-induced cytidine deaminase
Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the ''AICDA'' gene. It creates mutations in DNA by deamination of cytosine base, which ...
(AID) enzyme randomly mutates the variable regions of the antibody and alters their affinity for the antigen, occurs in the dark zone.
Additionally, B cells that were positively selected in the light zone because they express B cell receptors with high affinity for the antigen proliferate extensively in the dark zone, which is a process called clonal expansion.
After
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...
and before entering the light zone, the old B cell receptors on the surfaces of the B cells are replaced with the new, mutated B cell receptors.
B cells expressing B cell receptors that have decreased affinity for the antigen following somatic hypermutation undergo
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, while B cells expressing B cell receptors that have increased affinity for the antigen after somatic hypermutation migrate to the light zone for further selection.
Light zone
The light zone consists of GC B cells and
T follicular helper cells.
It is proximal to the lymph node and near the network of
follicular dendritic cells
Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles (lymph nodes) of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hema ...
.
The GC B cells in the light zone, known as
centrocytes, are smaller, less abundant and divide less as compared to the GC B cells in the dark zone.
The nearby follicular dendritic cells present the antigen to the light zone GC B cells that were mutated in the dark zone previously, and those with the highest affinity for the antigen are able to bind and receive help from T follicular helper cells that have T cell receptors specific for the same antigen.
Therefore, the GC B cells in the light zone compete for antigen and stimulation by T follicular helper cells.
The mechanism by which this occurs is that, when the B cell receptor binds the antigen presented by the follicular dendritic cells, the antigen is internalized. Then the antigen is bound by
class II MHC and presented on the surface of the T cell, which allows the B cell to be helped by the T follicular helper cell.
GC B cells that are best able to present antigen to T follicular helper cells and produce the strongest B cell receptor signal are positively selected in the light zone of the germinal center.
Therefore, positive selection of GC B cells in the light zone results in B cells that express antibodies with high affinity for the antigen.
The B cells that are positively selected in the light zone begin to express
cMyc, which regulates the germinal center and the proliferation of the B cells in the germinal center.
Finally, the positively-selected GC B cells (cMyc
+) are "licensed," which means they are ready to be sent back to the dark zone of the germinal center where they will further proliferate and be mutated by
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...
.
Process
# Within lymph nodes, mature peripheral B cells known as
follicular (Fo) B cells acquire antigen from
FDCs and in turn present it to cognate
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...
+
TFH cells at the border that demarcates the interfollicular T cell area and B cell zone (also known as lymphoid follicles).
# After several rounds of cellular division, the B cells go through
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...
, a process by which they mutate their
antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
-
encoding
In communications and Data processing, information processing, code is a system of rules to convert information—such as a letter (alphabet), letter, word, sound, image, or gesture—into another form, sometimes data compression, shortened or ...
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
and thus generate a diversity of
clones in the germinal center. This involves pseudo-random substitutions biased towards regions encoding the antigen recognition surface of the antibodies the B cells produce. This phenomenon underscores the process of
affinity maturation
In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...
, whereby greater affinity antibodies are produced and selected for after antigen recognition.
# Upon receiving an unidentified stimulus, the maturing B cells (centroblasts) migrate from the dark zone to the light zone and start to express their edited BCRs on the cell surface and at this stage are referred to as
centrocytes. The centrocytes are in a state of
activated apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
and compete for survival signals derived from FDCs and
TFH cells. This rescue process, known as germinal center selection, is believed to be dependent on the
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Pa ...
of their surface antibody to the antigen. Such that, a B cell that has successfully gained mutations that confer a higher affinity surface antibody towards antigen gains a survival advantage over lower affinity B cell clones and those that have gained deleterious mutations. Cyclic re-entry into the dark zone once again as
centroblasts allows a chance for otherwise non-selected B cell mutants to gain more mutations in order to improve affinity towards antigen. Interactions with T cells are also believed to prevent the generation of autoreactive germinal center B cells.
# At some unclear stage of their centroblast-centrocyte cycling, maturing B cells receive a final differentiation signal to exit the germinal center as an antibody producing
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
which are cells that secrete large quantities of antibody or a
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quie ...
that can be reactivated in subsequent contacts with the same antigen. Selected B cells may also restart the whole cycle of mutative centroblast division and centrocyte selection. In this way the adaptive immune system, in part through these germinal center reactions, can gradually better recognize antigens over time.
The role of T follicular helper cells in the germinal center
There are
T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s in the follicles of the lymph nodes called T follicular helper cells that promote germinal center formation and the differentiation of GC B cells into plasma cells and memory B cells.
T follicular helper cells mediate the germinal center reaction in two key ways. First, T follicular helper cells express
CD40L
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 (protein), CD40 on antigen-presenting cells (APC), which leads to many e ...
, which is a
tumor necrosis factor
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
(TNF) cytokine that binds the
CD40
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T helper cell, TH cells to CD40 activates antigen presenting cells and i ...
molecule expressed on GC B cells. This interaction upregulates the NF-kB signaling pathway, which stimulates the division of GC B cells. Second, T follicular helper cells secrete the
IL-21 cytokine which serves as a signal for GC B cells to proliferate and for the creation of plasma cells with long life spans.
The fates of positively-selected germinal center B cells
Following positive selection, there are three possible fates for B cells undergoing the germinal center reaction: become a
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
, become a
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quie ...
or enter into the dark zone of the germinal center.
The processes initiating each of these three fates are described below:
Plasma cell differentiation
The GC B cells that differentiate into
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
s are B cells that show high affinity for the antigen.
When GC B cells receive help from T follicular helper cells, there is an interaction between CD40 (expressed on the B cell) and CD40L (expressed on the T follicular helper cell), which increases the activation of NF-kB in the B cell. The upregulation of the NF-kB signaling pathway results in greater expression of IRF4, a transcription factor that is essential for plasma cell differentiation.
The progression of the germinal center response results in plasma cells that secrete higher affinity antibodies having an increased lifespan and being sent to the
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
.
Memory B cell differentiation
The GC B cells that differentiate into
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quie ...
s are distinct from plasma cell precursors, as they show lower affinity for the antigen
and do not need much help from T follicular helper cells. Because of this, many scientists believe that memory B cell precursors are B cells from the light zone that were "non-positively selected." Memory B cell precursors express a transcription factor called
hematopoietically-expressed homeobox protein (Hhex) that drives differentiation of memory B cells from GC B cells.
Entering the dark zone of the germinal center
Any B cells that were positively selected in the light zone of the germinal center, but that did not differentiate into
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
s or
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quie ...
s are sent to the dark zone of the germinal center for further proliferation. These are the B cells that had intermediate affinity for the antigen.
The dark zone proliferation program is regulated by
FoxO1
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
and
cyclin D3. These two genes are down-regulated by strong BCR signals. Therefore, when there are weak BCR signals and the GC B cell does not have high affinity for the antigen, it will be sent to the dark zone of the germinal center so that it can continue to divide rather than being secreted as a plasma cell or a memory B cell.
Morphology at different stages
The
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
*Morphology (archaeology), study of the shapes or forms of artifacts
*Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
of GCs is very specific and shows properties which are characteristic for different stages of the reaction.
* In an early state of the reaction a network of FDCs is fully filled with proliferating B cells.
* Later at day 4 of the reaction, GCs show a separation of two zones, the dark and the light zone. The former still contains dominantly proliferating and mutating B cells while the latter one is the area of B cell selection.
* These zones dissolve after 10 days of GC development which ends after about 3 weeks.
Medical relevance
As germinal centers are important structures of the
adaptive immune system
The adaptive immune system (AIS), also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The ac ...
, their deregulation is implied in many immune diseases, for example
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
,
immunodeficiency
Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that aff ...
and many
lymphomas
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
like
DLBCL and
Burkitt's lymphoma
Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...
.
Germinal centers in evolution
Despite that
V(D)J recombination
V(D)J recombination (variable–diversity–joining rearrangement) is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire ...
is observed in all
vertebrates
Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain.
The vertebrates make up the subphylum Vertebra ...
, GC appeared in
homeothermic animals. Under evolutionary new conditions, when elevated body temperature contributed to the increased rates of microorganism proliferation, dissemination in tissues, and their antigenic diversification
, these temporary but constantly observed histological structures turned to be beneficial as their unique microenvironment could provide the conditions favourable for the shift from the initial broad to subsequent specific immune response resulting in B lineage cells differentiated to those producing high-affinity
Ab and maintaining long-lasting humoral immune memory.
Among cold-blooded vertebrates, fish seem have functionally analogous structures represented by "clusters of
Aicda+ cells encircled by pigmented 'melano-macrophages'".
See also
*
Lymphatic system
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...
*
Tingible body
*
Mantle zone
The mantle zone (or just mantle) of a lymphatic nodule (or lymphatic follicle) is an outer ring of small lymphocytes surrounding a germinal center.
It is also known as the "corona".
It contains transient lymphocytes.
It is the location of th ...
References
External links
*
* - "Lymphoid Tissues and Organs: lymph node, germinal centre"
Hyperlinked Human Histology*
{{Lymphatic system
Lymphatic system
Lymphatic tissue