Immune System Development
|Embryology - 26 Jun 2017 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Spleen Development
- 4 Thymus Development
- 5 Lymph Node Development
- 6 T Lymphocyte Development
- 7 Gastrointestinal Tract
- 8 Other Organs
- 9 Maternal Antibodies
- 10 Additional Images
- 11 Histology
- 12 Immune Cells
- 13 Movies
- 14 References
- 15 Terms
- 16 Glossary Links
Development of the immune system will also link to cardiovascular development notes (blood and vessel) and bone marrow development. Two organs which also relate to this system are the thymus and spleen, which have in the past been included in endocrine and gastrointestinal tract development respectively. There are now also movies showing lymphocyte (B and T cells) traffic within adult lymph nodes.
- During prenatal development, maternal IgG antibodies are transferred from about GA week 13 from maternal blood across the placenta. Placenta syncytiotrophoblast cell endosomes bind IgG, in maternal blood lacunae, through neonatal Fc receptors.
- During early postnatal development, maternal IgA, IgM, IgG antibodies are transferred from breast milk into the infant gastrointestinal tract.
- During postnatal development, the immune system matures..
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Wei Peng Neuroprotective effects of G-CSF administration in microglia-mediated reactive T cell activation in vitro. Immunol. Res.: 2017; PubMed 28646409
Tobechukwu K Ukah, Alexis N Cattin-Roy, Weirong Chen, Mindy M Miller, Subhasis Barik, Habib Zaghouani On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes. J. Immunol.: 2017; PubMed 28646042
Dong Eon Kim, Mi-Jin Jang, Young Ran Kim, Joo-Young Lee, Eun Byul Cho, Eunha Kim, Yeji Kim, Mi Young Kim, Won-Il Jeong, Seyun Kim, Yong-Mahn Han, Seung-Hyo Lee Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells. Toxicology: 2017; PubMed 28645575
Harm Westdorp, Sigrid Kolders, Nicoline Hoogerbrugge, I Jolanda M de Vries, Marjolijn C J Jongmans, Gerty Schreibelt Immunotherapy holds the key to cancer treatment and prevention in Constitutional Mismatch Repair Deficiency (CMMRD) syndrome. Cancer Lett.: 2017; PubMed 28645564
Nicolás Sarute, Susan R Ross New World Arenavirus Biology. Annu Rev Virol: 2017; PubMed 28645238
| The human spleen arises in week 5 within the dorsal mesogastrium as proliferating mesenchyme overlying the dorsal pancreatic endoderm. Cells required for its hemopoietic function arise from the yolk sac wall and near dorsal aorta.
The spleen generates both red and white cells in the 2nd trimester. Note that many embryonic RBCs remain nucleated.
|D4 Dorsal Mesogastrium (stage 13)|
- Links: Spleen Development
| The thymus has a key role in the development of an effective immune system as well as an endocrine function.
The thymus has two origins for the lymphoid thymocytes and the thymic epithelial cells. The thymic epithelium begins as two flask-shape endodermal diverticula that form from the third pharyngeal pouch and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta.
|D4 Developing Thymus (stage 22)|
- Links: Thymus Development
Lymph Node Development
- Links: Lymph Node Development
T Lymphocyte Development
A study of cord blood from 19 early second and third trimester fetuses (GA 18-36 weeks) and 16 term newborns (GA 37-42 weeks).
- Percentage of lymphocytes in fetal white blood cells was 79.3%, reducing to 40% by term birth
- higher than that of adults.
- Mononuclear cells (cord blood mononuclear cells (CBMC)
- fetal mononuclear cells were unable to produce IL-2, IL-4 or IFN-gamma.
- spontaneously secreted IL-10, IL-6 and TNF-alpha in vitro.
- fail to respond to mitogen (PHA) or allogeneic stimulation in vitro.
- Stimulation with PHA up-regulated the production of IL-10, IL-6 and TNF-alpha substantially.
- CD3+ T cells in fetal (40.1%) and neonatal (42.4%)
- lower than that of men (59.6%) and pregnant women (53.6%).
- CD8+ T cells (9.5%)
- gamma delta - T cells (0.5%)
- NK cells (4.8%)
Thymic and peripheral differentiation of natural and induced intraepithelial lymphocyte.
Peyer's patches appear and are continuously formed from 13.5 weeks (GA 15.5 wk) through to about 36 weeks in the gastrointestinal tract. Then between 15.5 and 20 weeks (GA17.5 wk to 22 wk) they develop the surface markers of lymphocytes in the mucosal immune system of the gut. This developmental change is also occurring within the appendix lymphocyte markers: HLA - DR, CD19 (B cell population), CD9 (pre-B cells), CD3 T lymphocytes, CD4 helper / inducer lymphocytes, the CD8 suppressor / cytotoxic cells and lastly, the CD57 Natural Killer cells.
- Liver - The adult liver is a lymphoid organ with a predominantly innate immune system. NK cells are abundant in the normal liver (about one-third of intrahepatic lymphocytes), differs from other lymphoid organs and peripheral blood.
During prenatal development, maternal antibodies are transferred across the placenta to the fetus. Immunoglobulin G (IgG) is transferred across the syncytiotrophoblast cell layer is mediated by the Neonatal Fc receptor (FcRn). Once inside placental villi, immunoglobulins then need to enter fetal circulation by crossing the second cellular endothelial cell layer by an as yet unknown mechanism.
During postnatal development, maternal antibodies are transferred by maternal milk across the neonatal gastrointestinal tract epithelium by the Neonatal Fc receptor (FcRn). (See Neonatal Fc receptor review)
Developing Human Thymus (stage 22)
F1 Developing Human Spleen (stage 22)
F2 Developing Human Spleen (stage 22)
F3 Developing Human Spleen (stage 22)
The images below are from adult immune Lymph Nodes.
- Human natural killer cells (NK) - originate from CD34(+) hematopoietic progenitor cells.
Adult Lymphocyte Histology
- Lymphocyte EM Images: T and B Lymphocytes 1 TEM | T and B Lymphocytes 2 TEM | T Lymphocyte SEM | B lymphocyte 1 TEM | B lymphocyte 2 TEM | B lymphocyte 3 TEM | Plasma Cell TEM | T2 Lymphocyte 1 TEM | T2 Lymphocyte 2 TEM | lymphocyte rosettes | T lymphocyte 1 | T lymphocyte 2 | T lymphocyte 3 | T lymphocyte 4 | T lymphocyte 5 | T lymphocyte 6 | B lymphocyte | B lymphocytes TEM | Immune System Development | Blood
Adult Lymphocyte Motility
|Adult Mouse Lymphocyte Motility|
|T cell zone||Medullary sinus|| Sinus endothelial|
|Bi-directional traffic|| Cross the sinus
|T and B cell motility||T and B cell coupling|
|Mouse Immune Movies: Transendothelial migration | T cell zone | Medullary sinus | Sinus endothelial barrier | Bi-directional traffic | cross the sinus endothelial barrier | T and B cell motility | T and B cell coupling | T cell Elimination | Immune System Development | Mouse Development|
|Page | Play|
- Friedemann Kiefer, Ralf H Adams Lymphatic endothelial differentiation: start out with Sox--carry on with Prox. Genome Biol.: 2008, 9(12);243 PubMed 19138383 | PMC2646268 | Genome Biology
- Xianghu Qu, Bin Zhou, H Scott Baldwin Tie1 is required for lymphatic valve and collecting vessel development. Dev. Biol.: 2015; PubMed 25576926
- Gabriela D'Amico, Dylan T Jones, Emma Nye, Karen Sapienza, Antoine R Ramjuan, Louise E Reynolds, Stephen D Robinson, Vassiliki Kostourou, Dolores Martinez, Deborah Aubyn, Richard Grose, Gareth J Thomas, Bradley Spencer-Dene, Daniel Zicha, Derek Davies, Victor Tybulewicz, Kairbaan M Hodivala-Dilke Regulation of lymphatic-blood vessel separation by endothelial Rac1. Development: 2009, 136(23);4043-53 PubMed 19906871
- G Eberl, M Lochner The development of intestinal lymphoid tissues at the interface of self and microbiota. Mucosal Immunol: 2009, 2(6);478-85 PubMed 19741595
- Eva Sanz, Norman Muñoz-A, Jorge Monserrat, Ana Van-Den-Rym, Pedro Escoll, Ismael Ranz, Melchor Alvarez-Mon, Antonio de-la-Hera Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways. Proc. Natl. Acad. Sci. U.S.A.: 2010, 107(13);5925-30 PubMed 20231472
- Akhil Maheshwari, Ashish R Kurundkar, Sadiq S Shaik, David R Kelly, Yolanda Hartman, Wei Zhang, Reed Dimmitt, Shehzad Saeed, David A Randolph, Charles Aprahamian, Geeta Datta, Robin K Ohls Epithelial cells in fetal intestine produce chemerin to recruit macrophages. Am. J. Physiol. Gastrointest. Liver Physiol.: 2009, 297(1);G1-G10 PubMed 19443732
- Takashi Satoh, Eiichi Sakurai, Hiroshi Tada, Tomoyuki Masuda Ontogeny of reticular framework of white pulp and marginal zone in human spleen: immunohistochemical studies of fetal spleens from the 17th to 40th week of gestation. Cell Tissue Res.: 2009, 336(2);287-97 PubMed 19255788
- Y Zhao, Z-P Dai, P Lv, X-M Gao Phenotypic and functional analysis of human T lymphocytes in early second- and third-trimester fetuses. Clin. Exp. Immunol.: 2002, 129(2);302-8 PubMed 12165087
- Hilde Cheroutre, Florence Lambolez, Daniel Mucida The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol.: 2011, 11(7);445-56 PubMed 21681197 | Nat Rev Immunol.
- S A Bhide, K V Wadekar, S A Koushik Peyer's patches are precocious to the appendix in human development. Dev. Immunol.: 2001, 8(2);159-66 PubMed 11589311
- <pubmed25601863 </pubmed>| Front Immunol.
Cara C Bertozzi, Paul R Hess, Mark L Kahn Platelets: covert regulators of lymphatic development. Arterioscler. Thromb. Vasc. Biol.: 2010, 30(12);2368-71 PubMed 21071706
Hélène Maby-El Hajjami, Tatiana V Petrova Developmental and pathological lymphangiogenesis: from models to human disease. Histochem. Cell Biol.: 2008, 130(6);1063-78 PubMed 18946678
David Zawieja Lymphatic biology and the microcirculation: past, present and future. Microcirculation: 2005, 12(1);141-50 PubMed 15804980
Young-Kwon Hong, Jay W Shin, Michael Detmar Development of the lymphatic vascular system: a mystery unravels. Dev. Dyn.: 2004, 231(3);462-73 PubMed 15376314
Reina E Mebius Organogenesis of lymphoid tissues. Nat. Rev. Immunol.: 2003, 3(4);292-303 PubMed 12669020
- adenoid - (Greek " +-oeides = in form of) in the form of a gland, glandular; the pharyngeal tonsil.
- afferent lymph - vessel carrying lymph towards a node.
- acquired immune deficiency syndrome - (AIDS) note this is now better described as "advanced HIV disease", decrease in the number of CD4 T cells. (More? Immunobiology - AIDS)
- anastomose - joining of two tubes or structures together.
- Antibody mediated immunity - the immune function of plasma cells (active B lymphocytes) secreting antibody which binds antigen.
- antibodies - mammals have five classes (IgA, IgD, IgE, IgG, and IgM)
- antigen - any substance that is recognised by the immune system and stimulates antibody production.
- appendix - is a gut-associated lymphoid tissue (GALT) located at the beginning of the colon. The anatomy is as a finger-like structure that arises from the cecum. The length (2.5-13 cm) is longer in both infants and children and also has more abundant lymphatic tissue in early life. The wall structure is similar to the small intestine (though with no villi), nor plicae circularis. Lymph nodules surround the lumen of the gastrointestinal tract and extend from the mucosa into the submucosa.
- B cell - (B-cell, B lymphocyte) historically named after a structure called the bursa of Fabricius in birds, a source of antibody-producing lymphocytes. These immune cells develop in the bone marrow. (More? Electron micrographs of nonactivate and activated lymphocytes)
- B lymphocyte - (B cell, B-cell)
- BALT - (Bronchus Associated Lymphoid Tissue) immune tissue associated with the respiratory tract.
- band cell - (band neutrophil or stab cell) seen in bone marrow smear, a cell undergoing granulopoiesis, derived from a metamyelocyte, and leading to a mature granulocyte. Also occasionally seen in circulating blood.
- cecum - (caecum, Latin, caecus = "blind") within the gastrointestinal tract a pouch that connects the ileum with the ascending colon of the large intestine.
- cell - has a specific cell biology definition, but is often used instead of "lymphocyte" when describing B and T cells.
- cell-mediated immunity - the immune function of T lymphocytes. (More? Immunobiology - T Cell-Mediated Immunity)
- central tolerance - in thymus mediated by cortical epithelial cells, medullary epithelial cells and thymic DCs, involves deletion of self reactive thymocytes (T cell).
- "clockface" - a term used to describe the appearance of plasma cell nuclei due to the clumping of the chromatin at the nucleus periphery. More clearly seen in tissue plasma cells that the bone marrow smear, where they are sometimes confused with the basophilic erythroblasts. Image - plasma cell
- CD - (cluster of differentiation) identifies immunological surface markers on cells.
- CD4+ - (T helper cells) refers to T lymphocytes that express CD4 (glycoprotein of the immunoglobulin superfamily) on their surface. These cells can be infected by human immunodeficiency virus (HIV).
- CD8+ - (cytotoxic T cells) refers to T lymphocytes that express CD8 (glycoprotein of the immunoglobulin superfamily) on their surface.
- "clockface" - a term used to describe the appearance of plasma cell nuclei due to the clumping of the chromatin at the nucleus periphery. More clearly seen in tissue plasma cells that the bone marrow smear, where they are sometimes confused with the basophilic erythroblasts.
- cords of Billroth - spleen cellular columns located in red pulp. surrounded by splenic sinusoids. Cords contain reticular cells, macrophages, lymphocytes, plasma cells and erythrocytes.
- cortex - outer layer, used in association with medulla (innner layer or core) a general description that can be applied to describing an organ with a layered structure.
- dendritic cell - (DC, antigen-presenting cell, APC) cells that present antigens and induce a primary immune response in resting naïve T lymphocytes. Originate from the same common progenitor as monocytes (PMID 20193011). In 2011 Ralph M. Steinman received half the Nobel Prize half of the award to to Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity.
- Effector cells - the immune functioning (active) B and T lymphocytes.
- Efferent lymph - vessel carrying lymph away from a node.
- fibroblastic reticular cell - (FRC) specialized myofibroblasts that form the structural mesenchymal network "sponge" within lymphoid tissue, through which T cells, B cells, dendritic cells (DCs), plasma cells and macrophages move and interact.
- GALT - Gut Associated Lymphatic Tissue consisting of Peyer’s patches, isolated lymphoid follicles and mesenteric lymph nodes.
- haemopoiesis (hemopoiesis) formation of blood cells.
- Hassall's corpuscle - thymic corpuscle.
- high endothelial venule - (HEV) the specialised post-capillary venous region that enables blood lymphocytes to enter a lymph node. These specialised post-capillary venules enables blood lymphocytes to enter a lymph node. Their endothelial cells express ligands that bind lymphocytes, aiding their adhesion and subsequent transmigration into the lymph node.
- humoral immune response - production of antibody by plasma cells derived from B lymphocytes (B cells).
- IEL - Intraepithelial Lymphocyte are T lymphocytes located in the gastrointestinal tract epithelium. Natural IELs (previously ‘type b’ IELs) acquire activated phenotype during development in the thymus in the presence of self antigens. Induced IELs (previously ‘type a’ IELs) progeny of conventional T cells activated post-thymically in response to peripheral antigens.
- IgA - the main class of antibody in secretions (saliva, tears, milk, and respiratory and intestinal secretions).
- IgD - the immunoglobulin B cell starts to produce as a cell-surface molecule after leaving the bone marrow.
- IgE - bind Fc receptors (surface of mast cells in tissues and basophils in the blood) release of potent pro inflammatory molecules mediators of allergic reactions.
- IgG - the major class of immunoglobulin in the blood.
- IgM - the first class of antibody made by a developing B cell, which may switch to making other classes of antibody.
- immunodeficiency - when one or more components of the immune system is defective. (More? Immunobiology - immunodeficiency)
- immunoglobulin - (antibody, Ab) protein produced by plasma cells.
- intraepithelial lymphocyte (IEL) immune cells residing in the gastrointestinal tract epithelium. image - Intraepithelial lymphocyte differentiation
- involution - in the thymus refers to the replacement, mainly in the cortex, of cells by adipose tissue. (More? PubMed- thymus involution) | Cancer Medicine - Thymomas and Thymic Tumors)
- Kupffer cells - stellate macrophage cells located in the liver sinusoids, named after Karl Wilhelm von Kupffer (1829 - 1902) a German anatomist who originally identified these cells. (More? Liver Development)
- lacteal - term used to describe the lymphatic vessels of the small intestine.
- lamina propria - a layer of loose connective tissue found underneath an epithelium, together with the epithelium described as mucosa.
- Langerhans cell - (LC, dendritic cell) Antigen-presenting immune cell found mainly in the basal/suprabasal layers of adult skin and mucosa. Cells lie in the basal/suprabasal layers of stratified epidermal and mucosal tissues. First in the innate antiviral immune defines and can migrate to lymph nodes and induce a T cell–mediated adaptive immune response. (More? Integumentary | Immune System Development)
- Leukocyte - (Greek, lukos = clear, white) white blood cell.
- lingual - related to the tongue.
- lymph node - connective tissue encapsulated lymphoid organ (1mm - 2cm in size), positioned in the pathway of lymph vessels. (More? Lymph Node Development)
- lymphangion - the functional unit of a lymph vessel that lies between two semilunar (half moon-shaped) valves.
- M cell - (microfold cell) found in the follicle-associated epithelium of the Peyer's patch. Function to transport gut lumen organisms and particles to immune cells across the epithelial barrier.
- macrophage - a large highly motile white blood cell which engulfs foreign material (bacteria etc) and both degenerating cells and cell fragments. Differentiates from a monocyte and found in many different tissues and locations. Current theory suggests tissue macrophage is also derived from resident stem cell population in many tissues. More? Immunobiology - Defects in phagocytic cells are associated with persistence of bacterial infection)
- MALT - Mucosa Associated Lymphoid Tissue
- medulla - inner layer or core, used in association with cortex (outer layer) a general description that can be applied to describing an organ with a layered structure.
- Memory Cell - effector T cell (lymphocyte)
- mesenteric lymph nodes - Part of GALT as well as being involved in gut-draining. image - mesenteric lymph nodes
- Mononuclear Phagocytic System - (MPS, Lymphoreticular System, Reticuloendothelial System, RES) Consists of circulating monocytes in the peripheral blood and non-circulating (fixed) tissue macrophages (MΦ) located in tissues and organs.
- negative selection - T cells bearing autoreactive T cell antigen receptors (TCRs) are eliminated during their development in the thymus, protects against autoimmunity.
- normoblast - seen in bone marrow smear, a developing erythroblast (red blood cell) that still retains a nucleus.
- nude mice - (nu/nu) mice which are congenitally hairless and athymic, therefore they do not reject tissue and tumor grafts.
- parenchyma - (Greek = enkeim "to pour in") cells forming the functional cells of an organ or tissue. These cells carry out the function of the organ at a cellular level, and are not the structural cells, connective tissue, extracellular matrix (stromal).
- periarterial lymphoid sheath - (PALS) in the spleen the white pulp that surrounds the central arteries. (T-lymphocytes,macrophages and plasma cells)
- Plasma Cell - active B cell (lymphocyte) which is secreting antibody. Located in either bone marrow or peripheral lymphoid tissues, these cells have and increased cytoplasmic volume (due to increase rough endoplasmic reticulum) in comparison to the inactive (non-secreting) lymphocyte.
- red pulp - spleen region, organized as cell cords (splenic cords, cords of Billroth) and vascular sinuses.
- regulatory T cells - (Tregs) maintain self tolerance and suppress pathological immune responses by control of immune response to non-self antigens.
- sentinel lymph node - the hypothetical first lymph node or group of nodes reached by metastasizing cancer cells from a primary tumour.
- splenic sinusoids - enlarged spleen capillary spaces located in red pulp and surrounding cords of Billroth.
- stroma - (Greek = "a cover, table-cloth, bedding") tissue forming the framework/support of an organ or tissue. That is the structural cells which form connective tissue and secrete extracellular matrix, rather than the functional cells (parenchymal). All organs can therefore be functionally divided into these 2 components, stromal/parenchymal.
- Subcapsular sinus (=marginal sinus) space lying under the connective tissue capsule which receives lymph from afferent lymphatic vessels.
- T cell - (T-cell, T lymphocyte) named after thymus, where they develop, the active cell is responsible for cell-mediated immunity (killer T cells and helper T cells). Cells express T-cell receptor on surface and directly kill virally or bacterially infected cells. These cells can themselves be infected by HIV. (More? Electron micrographs of nonactivate and activated lymphocytes)
- T cell activation - (T lymphocyte activation)The activation process begins with T-cells searching for and encountering antigen-bearing dendritic cells within lymph nodes.
- Thymic corpuscle (=Hassall's corpuscle) a mass of concentric epithelioreticular cells found in the thymus. The number present and size tend to increase with thymus age. (see classical description of Hammar, J. A. 1903 Zur Histogenese und Involution der Thymusdriise. Anat. Anz., 27: 1909 Fiinfzig Jahre Thymusforschung. Ergebn. Anat. Entwickl-gesch. 19: 1-274.)
- thymic epitheliocytes - reticular cells located in the thymus cortex that ensheathe the cortical capillaries, creating and maintain the microenvironment necessary for the development of T-lymphocytes in the cortex.
- T helper cells - (helper T-cells) (Th cells, CD4+) refers to T lymphocytes that when mature express CD4 (glycoprotein of the immunoglobulin superfamily) on their surface.
- T lymphocyte - (T cell, T-cell).
- thymus - an immune/endocrine (thymic hormone) organ involved in the maturation of T lymphocytes (T-cells). Thymus Development
- tonsils - lymph nodules embedded in the mucus membranes located at the back of the mouth and top of the throat. The overlying epithelium helps identify the location.
- vermiform appendix - see appendix, anatomical region containing gut-associated lymphoid tissue located within the gastrointestinal tract at the beginning of the colon. The anatomy is as a finger-like structure that arises from the cecum. The length (2.5-13 cm) is longer in both infants and children and also has more abundant lymphatic tissue in early life. The wall structure is similar to the small intestine (though with no villi), nor plicae circularis. Lymph nodules surround the lumen of the gastrointestinal tract and extend from the mucosa into the submucosa.
- VDJ recombination - (variable, diversity and joining gene segments) genetic recombination event that occurs in immune cell maturation in primary lymphoid organs, B cells ((bone marrow) and T cells (thymus).
- white pulp - (Malpighian bodies of the spleen, splenic lymphoid nodules) spleen lymphoid region, organized as lymphoid sheaths with both T-cell and B-cell compartments, around the branching arterial vessels (resembles lymph node structure).
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Cite this page: Hill, M.A. 2017 Embryology Immune System Development. Retrieved June 26, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Immune_System_Development
- © Dr Mark Hill 2017, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G