The Birth of an Army

Everything has a start right? This is indeed true for the cell types of the immune system. From the unholy trinity of the granulocytes (i.e. the neutrophils, eosinophils and basophils) to the cytotoxix  CD8+ T cells which specializes in the art of cell destruction, all these forces of death and might must have a beginning. And this beginning is of course from the haematopoietic stem cells (HSC). HSCs reside in the bone marrow and these cells can give unleash shiteload of cell types, in other words, these beasts will give birth to every single foot soldier of the immunological army under the sun. The process itself is rather complicated I have to say but the diagram below shows the birth of what is probably one of the greatest army that has graced our universe:

Colony stimulating factors

- subclass of cytokine superfamily

- protein factors able to stimulate the production of one or more colony type in semi-solid cultures of bone marrow or other haematopoietic tissue

- IL-3, IL-5, GM-CSF, Epo, Tpo, G-CSF, IL-6, LIF, OSM, M-CSF, SCF, FLT-3L

- produced by activated macrophages/T-cells and other cell types

- bind specific receptors

  -> some have receptor subunits in common

  -> stimulate signal transduction leading to transcription factor activation enhancing proliferation, viability, differentiation

Ikaros and leukaemia.

Ikaros and leukaemia.

Br J Haematol. 2015 May;169(4):479-91

Authors: Olsson L, Johansson B

The IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukaemia in both mice and men. During recent years, constitutional as well as acquired genetic changes of IKZF1 have been associated with human disease. For example, certain germline single nucleotide polymorphisms in IKZF1 have been shown to increase the risk of some disorders and abnormal expression and somatic rearrangements, mutations and deletions of IKZF1 (ΔIKZF1) have been detected in a wide variety of human malignancies. Of immediate clinical importance is the fact that ΔIKZF1 occurs in 15% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and that the presence of ΔIKZF1 is associated with an increased risk of relapse and a poor outcome; in some studies such deletions have been shown to be an independent risk factor also when minimal residual disease data are taken into account. However, cooperative genetic changes, such as ERG deletions and CRLF2 rearrangements, may modify the prognostic impact of ΔIKZF1, for better or worse. This review summarizes our current knowledge of IKZF1 abnormalities in human disease, with an emphasis on BCP ALL.

PMID: 25753742 [PubMed - indexed for MEDLINE]

via pubmed: lymphoma daily http://ift.tt/1T0qtIb
Thrombopoietin (Tpo)

- produced by the liver and kidney, as well as striated muscle and stromal cells in the bone marrow

- production in the liver augmented by IL-6

- regulates differentiation of megakaryocytes and platelets

  -> Tpo receptor KO studies show its effects on haemopoiesis are more widespread

- negative feedback different from most hormones

  -> the effector regulates the hormone directly

  -> Tpo binds to surface of platelets, thereby reducing megakaryocyte exposure to Tpo

Erythropoietin (Epo)

- stimulates the proliferation, viability and differentiation of erythroid progenitors

- produced mainly by kidneys

- acts on bone marrow to producing more mature RBCs

- Epo used clinically to treat anaemia and in renal failure

- also used by athletes, can cause death (high haematocrits)

   -> can be detected in urine up to 3 days after doping

   -> changes in transferrin:ferritin ratios can be detected up to 3 weeks after         doping

Haematopoiesis - important diagram to understand/know

HSC = haematopoietic stem cell

CMP = common myeloid progenitor

CLP = common lymphoid progenitor

MEP = megakaryocyte-erythroid progenitor

GM = granulocyte-macrophage progenitor

TNK = T-cell - natural killer cell progenitor

BCP = B-cell precursor

MkP = megakaryocyte progenitor

EP = erythroid progenitor

MP = macrophage precursor

GP = granulocyte precursor

TP = T-cell precursor

NKP = natural killer precursor

EPO = erythropoietin

TPO = thrombopoietin

SCF = stem cell factor

GM-CSF = granulocyte-macrophage colony-stimulating factor

M-CSF = macrophage colony-stimulating factor

G-CSF = granulocyte colony-stimulating factor