In addition to surface Ig, B lymphocytes possess other characteristic surface proteins:
Class II MHC proteins (MHC stands for Major Histocompatability Complex)
The presence of Class II MHC proteins permits B lymphocytes to act as antigen presenting cells (APCs) to T helper lymphocytes.
CR1 & CR2
receptors for complement components
FcgRII
receptor for the Fc portion of IgG
B7 [present on B lymphocytes which have been activated by specific antigen] costimulatory molecule which interacts with CD28 on T helper cells
When a mature, but naive (or virgin) B lymphocyte encounters antigen and receives the proper signals from an antigen-specific T helper lymphocyte, the B lymphocyte will be activated to proliferate and to differentiate into immunoglobulin-secreting plasma cells. A certain sub-population of cells will differentiate into memory B lymphocytes. These cells are long-lived and are responsible for the memory component of the acquired immune response.
Mature T lymphocytes
The T lymphocytes (so-called because they complete their maturation in the thymus), bear T cell receptors (TcRs) on their surface. As with Ig on B lymphocytes, the TcRs on a single T lymphocyte have identical binding sites .
TcRs only function as cell surface receptors for antigen + MHC and the TcRs are not secreted.
In addition to surface TcRs, T lymphocytes possess other characteristic surface proteins:
Thy-1
This protein is the earliest marker of the T cell lineage and is expressed on the surface of all T lymphocytes.
CD3
The term CD3 refers to a protein complex which is always associated with the TcR.
CD28
The receptor for B7 [which is found on the surface of APCs]
CD45
A signal transduction protein which binds to CD54L (CD45 ligand) on the surface of antigen presenting cells.
In addition, T helper lymphocytes express CD4 on their surface, while T cytotoxic lymphocytes express CD8.
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The term hematopoiesis refers to the formation and development of the cells of the blood. In humans this process begins in the yolk sac in the first weeks of embryonic development. By the third month of gestation, stem cells migrate to the fetal liver and then to the spleen (between 3-7 mths these two organs play a major hempatopoietic role). Next, the bone marrow becomes the major hematopoietic organ and hematopoiesis ceases in the liver and spleen.
Every functional specialized mature blood cell is derived from a common stem cell. These stem cells are therefore, PLURIPOTENT.
It has been estimated that there is approximately 1 stem cell per 10^4 bone marrow cells. These stem cells represent a Self-renewing population of cells.
Due to the low frequency of these cells and the inability to culture these cells in vitro, stem cells have been very difficult to study.
In vivo studies have shown:
Mouse with lethal irradiation (950rads). Death in 10 days.
Normally a mouse has ~3X10^8 marrow cells.
If mouse is infused with 10^4-10^5 bone marrow cells from a syngeneic donor, the hematopoietic system can be completely restored.
Initial differentiation of pluripotent stem cells:
Along one of two major pathways
------------------> lymphoid
-------------------> myeloid
Multipotent Stem Cell
gives rise to:
Myeloid Stem Cell---> progenitor cells--->
---->neutrophil
-------->macrophage / monocyte
---------> eosinophil
---------> erythrocyte
----------> megakaryocytes
---------> mast cells
---------> basophils
Lymphoid Stem Cell --->
progenitor B---->
plasma cell
-------------->memory B cell
------------------->progenitor T ---------------Th
----------------Tc
Stem cells then become progenitor cells for each type of mature blood cell. These cells have lost the capacity for self-renewal and are committed to a given cell lineage. T&B progenitors, and progenitor cells for erythrocytes, neutrophils, eosinophils, basophils, monocytes, mast cells, and platelets. This progenitor committment depends upon the acquisition of responsiveness to certain growth factors. The particular microenvironment within which the progenitor cell resides controls differentiation. The hematopoietic cells grow and mature on a meshwork of stromal cells, which are nonhematopoietic cells that support the growth and differentiation of the hematopoietic cells. Include: fat cells, endothelial cells, fibroblasts, and macrophages.
These cells provide a HEMATOPOIETIC -INDUCING MICROENVIRONMENT
This microenvironment consists of cellular matrix and either membrane-bound or diffusable growth factors.
Hematopoietic Growth Factors
Colony Stimulating Factors
multilineage colony-stimulating factor (multi-CSF or IL-3)
granulocyte-macrophage colony stimulating factor (GM-CSF)
macrophage colony stimulating factor (M-CSF)
granulocyte colony-stimulating factor (G-CSF)
Erythropoietin - Induces terminal erythrocyte development and regulates RBC production.
IL-4
IL-5
IL-6
IL-7
IL-8
IL-9
Extremely low concentrations and biological activity at concentrations as low as 10^-12 M. Now all of the genes have been cloned and recombinant products have definable activity in culture.
CSFs- act in a stepwise manner inducing proper maturation. IL-3 [multi-CSF] acts early, possibly even at the level of the pluripotent stem cell, to induce formation of the nonlymphoid cells (erythrocytes, monocytes, granulocytes[neutrophils, eosinophils, basophils], and megakaryocytes).
GM-CSF acts at a slightly later stage, but it also induces formation of all the nonlymphoid blood cells. M-CSF and G-CSF act still later to promote the formation of monocytes and granulocytic cells, respectively.
IL-4 - stimulates B progenitors, mast progenitors, and basophil progenitors
IL-5 - stimulates eosinophil progenitor
IL-6 - stimulates the myeloid stem cell
IL-7 - induces the differentiation of lymphoid progenitor into B progenitor and T progenitor
IL-8 - stimulates the neutrophil progenitor
IL-9 - stimulates mast cell growth
Committment of a progenitor cell is associated with the expression on the cell membrane of membrane receptors that are specific for particular cytokines.
Hematopoiesis is a continuous process throughout adulthood. Production of mature blood cells equals their loss. Estimated that the average human must produce 3.7X10^11 blood cells per day.
This process is regulated by complex mechanisms. Controlled cytokine production by the stromal cells which produce (GM-CSF, M-CSF, G-CSF, IL-4, IL-6, IL-7). The process is also regulated in response to inflammation.
In particular, this inducible hematopoietic activity is regulated by activated TH cells and activated macrophages.
Production of different lineages can be regulated by changes in local concentrations of cytokines or by altered expression of receptors.
Also binding of CSFs may also cause internalization of the receptors
Programmed Cell Death
apoptosis- one form of PCD
Cell division and differentiation during hematopoiesis are balanced by apoptosis - there must by maintenance of a steady state.
During apoptosis you see:
a decrease in cell volume
modification of the cytoskeleton with pronounced membrane blebbing
condensation of chromatin
degradation of DNA into oligonulceosomal fragments
shedding of apoptotic bodies
quick phagocytosis to prevent inflammation
If apoptosis fails, a leukemic state can occur.
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