Germinal center
Encyclopedia
Germinal centers are sites within lymph nodes (also within lymph nodules in peripheral lymph tissues) where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies (through somatic hypermutation
), and class switch their antibodies
during a normal immune response to an infection. During this process of rapid division and selection, B cells are known as centroblasts, and once they have stopped proliferating they are known as centrocytes
. Germinal centres are an important part of the B-cell humoral immune response
. They develop dynamically after the activation of B-cells by T-dependent antigen
.
Histologically
, the GCs describe microscopically distinguishable parts in lymphoid
tissues.
expansion in the environment of follicular dendritic cells (FDC). During this time they are referred to as centroblasts.
2. After several days of expansion the B cells undergo somatic hypermutation
, a process by which they mutate their
antibody
-encoding
DNA
and thus generate a diversity of clones in the
germinal centre. This involves pseudo-random substitutions biased towards regions encoding the antigen recognition surface of they antibodies the B cells produce. During this time they also undergo isotype switching, or class switching.
3. Upon some unidentified stimulus from the FDC, the maturing B cells (centroblasts) migrate from the dark zone to the light zone and start to express their antibody on the cell surface and in this stage are referred to as centrocyte
s. The centrocytes are in a state of activated
apoptosis
and compete for survival signals from FDCs that present the antigen, meaning the cells will die unless "rescued" by these survival signals. This rescue process is believed to be dependent on the affinity of the antibody to the antigen. That is, if a B cell has mutated to have an antibody with more affinity to an antigen, it will be more likely to survive. In this way the immune system can better recognize antigens.
4. The functional B-cells then have to interact with helper T cells
to get final differentiation signals. This also involves isotype switching, for example from the antibody type IgM
to another antibody type such as IgG.
The interaction with T cells is believed to prevent the generation of autoreactive antibodies.
5. The B cells become either a plasma cell
which are cells which secrete large quantities of antibody or a memory B cell
that can be reactivated in subsequent contacts with the same antigen. B cells may also restart the whole process of proliferation
, mutation
and selection
according to the recycling hypothesis.
The above process involves TNF-alpha.
of GCs is very specific and shows properties which are characteristic for different stages of the reaction.
, their deregulation is implied in many immune diseases, for example rheumatoid arthritis
and many lymphomas.
Somatic hypermutation
Somatic hypermutation is a mechanism inside cells that is part of the way the immune system adapts to the new foreign elements that confront it . SHM diversifies the receptors used by the immune system to recognize foreign elements and allows the immune system to adapt its response to new threats...
), and class switch their antibodies
Immunoglobulin class switching
Immunoglobulin class switching is a biological mechanism that changes a B cell's production of antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG...
during a normal immune response to an infection. During this process of rapid division and selection, B cells are known as centroblasts, and once they have stopped proliferating they are known as centrocytes
Centrocyte
A centrocyte generally refers to a B cell with a cleaved nucleus, as may appear in e.g. follicular lymphoma.It can also refer to a cell with a protoplasm that contains single and double granules of varying size stainable with hematoxylin, as seen in lesions of lichen planus, or a nondividing,...
. Germinal centres are an important part of the B-cell humoral immune response
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
. They develop dynamically after the activation of B-cells by T-dependent antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
.
Histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
, the GCs describe microscopically distinguishable parts in lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
tissues.
Process
1. Activated B-cells migrate from the primary focus of infection into the primary follicles and begin monoclonalMonoclonal
Monoclonal cells are defined as a group of cells produced from a single ancestral cell by repeated cellular replication. Thus they can be said to form a single "clone". The process of replication can occur in vivo, or may be stimulated in vitro for laboratory manipulations...
expansion in the environment of follicular dendritic cells (FDC). During this time they are referred to as centroblasts.
2. After several days of expansion the B cells undergo somatic hypermutation
Somatic hypermutation
Somatic hypermutation is a mechanism inside cells that is part of the way the immune system adapts to the new foreign elements that confront it . SHM diversifies the receptors used by the immune system to recognize foreign elements and allows the immune system to adapt its response to new threats...
, a process by which they mutate their
antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-encoding
Encode
Encode may refer to:* Can be related to "Code"* Encode ApS, a Danish software company* Encode SA, a Greek information security company* ENCODE, the ENCyclopedia Of DNA Elements...
DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and thus generate a diversity of clones in the
germinal centre. This involves pseudo-random substitutions biased towards regions encoding the antigen recognition surface of they antibodies the B cells produce. During this time they also undergo isotype switching, or class switching.
3. Upon some unidentified stimulus from the FDC, the maturing B cells (centroblasts) migrate from the dark zone to the light zone and start to express their antibody on the cell surface and in this stage are referred to as centrocyte
Centrocyte
A centrocyte generally refers to a B cell with a cleaved nucleus, as may appear in e.g. follicular lymphoma.It can also refer to a cell with a protoplasm that contains single and double granules of varying size stainable with hematoxylin, as seen in lesions of lichen planus, or a nondividing,...
s. The centrocytes are in a state of activated
Activation
Activation in chemical sciences generally refers to the process whereby something is prepared or excited for a subsequent reaction.- Chemistry :...
apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and compete for survival signals from FDCs that present the antigen, meaning the cells will die unless "rescued" by these survival signals. This rescue process is believed to be dependent on the affinity of the antibody to the antigen. That is, if a B cell has mutated to have an antibody with more affinity to an antigen, it will be more likely to survive. In this way the immune system can better recognize antigens.
4. The functional B-cells then have to interact with helper T cells
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
to get final differentiation signals. This also involves isotype switching, for example from the antibody type IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
to another antibody type such as IgG.
The interaction with T cells is believed to prevent the generation of autoreactive antibodies.
5. The B cells become either a plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
which are cells which secrete large quantities of antibody or a memory B cell
Memory B cell
Memory B cells are a B cell sub-type that are formed following primary infection.-Primary response, paratopes, and epitopes:In wake of first infection involving a particular antigen, the responding naïve cells proliferate to produce a colony of cells, most of which differentiate into the plasma...
that can be reactivated in subsequent contacts with the same antigen. B cells may also restart the whole process of proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
and selection
Selection
In the context of evolution, certain traits or alleles of genes segregating within a population may be subject to selection. Under selection, individuals with advantageous or "adaptive" traits tend to be more successful than their peers reproductively—meaning they contribute more offspring to the...
according to the recycling hypothesis.
The above process involves TNF-alpha.
Morphology at different stages
The morphologyMorphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
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 cells while the latter one is the area of B cells selection.
- These zones dissolve after 10 days of GC development which ends after about 3 weeks.
Medical relevance
As germinal centres are important structures of the adaptive immune systemAdaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
, their deregulation is implied in many immune diseases, for example rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
and many lymphomas.