関: germinal center

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containing seeds of later development; "seminal ideas of one discipline can influence the growth of another" (同)originative, seminal
a fractional monetary unit of several countries
seventh month of the Revolutionary calendar (March and April); the month of buds
a low-lying region in central France

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/15 18:11:14」(JST)

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Germinal centers or germinal centres (GC) are sites within secondary lymphoid organs where mature B lymphocytes proliferate, differentiate, and mutate their antibody genes (through somatic hypermutation), and switch the class of their antibodies (for example from IgM to IgG) during a normal immune response to an infection. They develop dynamically after the activation of follicular (Fo) B cells by T-dependent antigen.

As they undergo rapid and mutative cellular division in the dark zone, B cells of the germinal center are known as centroblasts. Once these B cells have stopped proliferating, they migrate to the light zone where they are known as centrocytes, and are subjected to selection by follicular helper T (T_FH) cells in the presence of follicular dendritic cells (FDCs). Germinal centers are an important part of the B cell humoral immune response, acting as central factories for the generation of affinity matured B cells specialized in producing improved antibodies that effectively recognize infectious agents, and for the production of durable memory B cells. Histologically, the GCs describe microscopically distinguishable parts in lymphoid tissues.

Process

Within secondary lymphoid organs, mature peripheral B cells known as follicular (Fo) B cells acquire antigen from follicular dendritic cells (FDCs) and in turn presents it to cognate CD4+ T_FH cells at the border that demarcates the T cell zone and B cell follicles (also known as lymphoid follicles). During T_FH-B cell conjugation, the B cell receives critical signals to undergo isotype switching (also called immunoglobulin class switching) and to commence monoclonal expansion. During this time they are referred to as centroblasts and make up the dark zone.
After several rounds of cellular division, the B cells go through somatic hypermutation, a process by which they mutate their antibody-encoding DNA 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, 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 antibody on the cell surface and at this stage are referred to as centrocytes. The centrocytes are in a state of activated apoptosis and compete for survival signals derived from follicular dendritic cell and T_FH cells. This rescue process, known as germinal center selection, is believed to be dependent on the affinity 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.^[1]
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 which are cells that secrete large quantities of antibody or a memory B cell 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.

Morphology at different stages

The morphology 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.^[2] 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, their deregulation is implied in many immune diseases, for example rheumatoid arthritis, immunodeficiency and many lymphomas like DLBCL and Burkitt's lymphoma.

References

^ Thorbecke GJ, Amin AR, Tsiagbe VK (1994). "Biology of germinal centres in lymphoid tissue". FASEB 8 (11): 832–840. PMID 8070632.
^ Meyer-Hermann ME (2002). "A Mathematical Model for the Germinal Centre Morphology and Affinity Maturation". J. Theor. Biol. 216 (3): 273–300. doi:10.1006/jtbi.2002.2550. PMID 12183119.

External links

UIUC Histology Subject 563
Histology image: 07103loa – Histology Learning System at Boston University - "Lymphoid Tissues and Organs: lymph node, germinal centre"
Hyperlinked Human Histology
MedEd at Loyola Histo/practical/lymph/hp12-42.html

UpToDate Contents

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1. 成人における末梢リンパ節腫大の評価 evaluation of peripheral lymphadenopathy in adults
2. 体液性免疫応答 the humoral immune response
3. 非ホジキンリンパ腫の病理の概要 overview of the pathobiology of the non hodgkin lymphomas
4. びまん性大細胞型B細胞性リンパ腫および原発性縦隔大細胞型B細胞リンパ腫の病理学 pathobiology of diffuse large b cell lymphoma and primary mediastinal large b cell lymphoma
5. 濾胞性リンパ腫の病理生物学 pathobiology of follicular lymphoma

English Journal

Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome.

Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, Brokstad K, Jonsson R, Jonsson MV.SourceCorrespondence to Professor Roland Jonsson, Broegelmann Research Laboratory, The Gade Institute, University of Bergen, N-5021 Bergen, Norway; roland.jonsson@gades.uib.no.
Annals of the rheumatic diseases.Ann Rheum Dis.2011 Aug;70(8):1363-8.
OBJECTIVE: The development of non-Hodgkin's lymphoma (NHL) confers a high risk of mortality in primary Sjogren's syndrome (pSS) patients, but the sensitivity and specificity of proposed lymphoma predictors are insufficient for practical use. The performance of lymphoid organisation in the form of g
PMID 21715359

Nucleotide excision repair and B lymphoma: somatic hypermutation is not the only culprit.

Hyka-Nouspikel N, Nouspikel T.SourceUniversity of Sheffield; Sheffield, UK.
Cell cycle (Georgetown, Tex.).Cell Cycle.2011 Jul 15;10(14). [Epub ahead of print]
Different mechanisms account for the development of B lymphoma. Malignant transformation of B lymphocytes arises from progressive loss of genome integrity, combined with uncontrolled cell proliferation often triggered by foreign or self antigens. It is well established that somatic hypermutation, th
PMID 21701262

Japanese Journal

Low prevalence of ectopic germinal centre formation in patients with HTLV-I-associated Sjogren's syndrome.

Nakamura Hideki,Kawakami Atsushi,Hayashi Tomayoshi,Nakamura Tatsufumi,Iwamoto Naoki,Yamasaki Satoshi,Ida Hiroaki,Eguchi Katsumi
Rheumatology (Oxford, England) 48(7), 854-855, 2009-07
NAID 120002219589

The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells

PHAN R. T.
Nature 432, 635-639, 2004
NAID 30013950640

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