Immunology: hematopoiesis

Hematopoiesis is the production of blood cells, a developmental process located in the (red) bone marrow, though some cells mature elsewhere. For example, T lymphocytes are so named because they mature in the thymus, and antigenic stimulation of B lymphocytes to become plasma cells typically takes place in the periphery.

▼ B lymphocyte development : common lymphoid progenitor : common myeloid progenitor : E2A : EBF : early B lineage : erythropoiesis : granulopoiesis : hematopoietic growth factors : lymphopoiesis : monocytopoiesis : Pax-5 : pluripotential stem cell : precursors : progenitors : regulatory transcription factors : stages : stem cells : thrombopoiesis : transcriptional regulatory proteins▼

The process of haematopoiesis occurs in several stages, and is controlled by at least 11 hematopoietic growth factors (including the colony-stimulating factors, IL-2 through IL-7, G-CSF, GM-CSF, and M-CSF). The first stage involves the differentiation of a pluripotential stem cell into a committed progenitor, which is followed by maturation of committed progenitors in distinct pathways, in which precursors are partially developed, 'adolescent' cells en route to maturity.

stem → progenitor → precursor → adult → mature

[] labeled photomicrograph of bone marrow, diagram of adult stem cell plasticity, diagram of stem cell versus progenitor cell

Stem cell stage:

pluripotential hematopoietic stem cell

↓ --------------------↓

common myeloid progenitor----or----common lymphoid progenitor

The common myeloid progenitor can generate:

● proerythroblasts (pronormoblasts) → erythropoiesis

● myeloblasts → granulopoiesis

● monoblasts → monocytopoiesis

● megakaryoblasts → thrombopoiesis

The common lympoid progenitor can generate:

● lymphoblasts → lymphopoiesis

Committed progenitor stage to mature cell : granulopoiesis

common myeloid progenitor

↓

myeloblast

↓

B/E/N promyelocyte

↓---↓---↓

B/E/N myelocyte

↓---↓---↓

B/E/N metamyelocyte

↓---↓---↓

B/E/N band

↓---↓---↓

basophil, eosinophil, neutrophil

↓ -----------------------

mast cell -----------------------

Committed progenitor stage to mature cell : lymphopoiesis

common lymphoid progenitor

↓

lymphoblast

----------------------------------------↓ rearrangements H: D-J → H: V-DJ

prolymphocyte

-----------------↓ rearrangements L: V-J --------------------------↓

small lymphocyte------or----- natural killer cell (large granular lymphocyte)

------------↓ IgM→IgD ---------↓------------------------------------ ↓

------B lymphocyte--or-- T lymphocyte

------------↓----------------------------------------------------------- ↓

--------plasma cell------------------------------------------lymphoid dendritic cell

Development of mature B lymphocytes from multipotent progenitors requires the coordinated activities of a number of transcriptional regulatory proteins, including EBF, Pax-5, and E2A.

During B cell-development from the precursor stage, differentiation involves rearrangement of the heavy chain gene segments. The functional integrity of the rearranged gene is tested: Precursor-B cells express two single domain Ig-like proteins of invariant sequence that substitute for the light chain. Formation of a complex comprising the μ (mu) heavy chain with the surrogate light chains instructs the cell to discontinue rearrangement of the heavy chain locus and to commence rearrangement of the k (kappa) locus. If successful light chain rearrangement is achieved such that the light and heavy chains form a complete antibody, then this complex instructs the cell to discontinue rearrangement of light chains, ensuring that only a single specificity is produced (allelic exclusion). Џ B cell maturation - animation Џ

Those developing B cell clones that fail to generate a productive rearrangement at both one of their heavy chain alleles and a light chain locus will undergo apoptosis. Immune tolerance mechanisms also exist to ensure the death of any newly produced B cells that express an antibody that reacts strongly with self proteins on the surface of host cells.

E2A proteins function in early B lineage development to regulate B lineage-specific gene expression as well as B cell survival. E2A-encoded proteins are involved in the differentiation of a number of cell types, and they are especially important in lymphocyte development.

The E2A gene encodes E47 and E12, which are basic-helix-loop-helix (bHLH) transcription factors that bind DNA either as homodimers or as heterodimers with other bHLH proteins. Such bHLH DNA binding activity in the B-lineage comprises E47 homodimers. Development of thymocytes mainly involves heterodimers of E47 and a related bHLH protein, HEB. Thymocytic E2A protein expression is required to initiate T-cell differentiation. During the development of thymoctyes, E-proteins and their antagonists, Id2 and Id3, regulate T-lineage specific gene expression and TCR rearrangement. E2A and Id proteins block thymocytic maturation in the absence of pre-TCR expression, and pre-TCR signaling acts to promote development in part by inhibiting E2A activity. [l]

Committed progenitor stage to mature cell : monocytopoiesis

common myeloid progenitor

↓

monoblast

↓

promonocyte

↓

monocyte

↓ ----↓

macrophage or myeloid dendritic cell

Committed progenitor stage to mature cell : erythropoiesis

common myeloid progenitor