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Bone marrow - nonneoplastic

Normal

Lymphocyte maturation


Reviewers: Dragos Luca, M.D. (see Reviewers page)
Revised: 16 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
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● Lymphocyte precursors originate in bone marrow
● Mature lymphocytes are present in variable proportions in the bone marrow: children < 24 months of age may have up to 60%; adults usually have < 20%, but some develop lymphoid aggregates (non-paratrabecular), especially with age
● Unlike other hematopoietic cells, terminal differentiation of mature lymphocytes takes place in secondary lymphoid organs after they leave the bone marrow
● Mature to B cells (humoral immune response) or T/NK cells (cell-mediated immune response)
● B cells complete most of their development within the bone marrow, but T cells are generated in the thymus from precursor cells that migrate from the bone marrow
● Recombination-assembly of Ig and TCR genes represents the main process in the development of B and T cells (regulated by RAG-1, RAG-2 and TdT)
● Initially (children) have B:T cell ratio ~ 2:1; after 4-5 years of age, proportion of B cells decreases and T cells increases, reaching adult levels during adolescence (1:4-5)

B cell maturation
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● B cell development in marrow is dependent on CD10+ stromal cells (J Pathol 2005;205:311), which form specific, adhesive contacts with developing B lineage cells and also provide growth factors (stem cell factor, IL-7, stromal cell derived factor 1)
● Earliest stem cells are in subendosteum, adjacent to inner bone surface; with maturation, B lineage cells move towards central axis of marrow; final stages of development of immature B cells occur in peripheral lymphoid organs (spleen, lymph nodes)
● Germline B cells undergo a series of Ig gene rearrangements to produce a heavy chain (μ) followed by light chains (κ or λ)
● Commitment to B lineage was initially thought to be indicated by CD79; subsequent studies showed that cytoplasmic CD22 appears to be the most specific B cell marker
● A minor subset of B cells also express CD5 (T cell marker)
● Plasma cells are last stage of B cell maturation, express CD38 but lose CD19

T/NK cell maturation
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● T cells migrate from bone marrow to thymus and mature via TCR gene rearrangements
● Most specific T cell marker appears to be cytoplasmic CD3
● During thymic maturation sequence, T cells are initially double negative for CD4 and CD8 (pro- and pre-thymocytes), then double positive (cortical thymocytes), then express either CD4 or CD8 (medullary thymocytes)
● In NK cells, rearrangements of T cell receptor genes do not occur; proportion of NK cells in bone marrow does not change with age
● Most NK cells (both true and cytotoxic) are morphologically large granular lymphocytes

Micro description
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● Lymphocytes diffusely scattered throughout interstitium; represent 10-15% of marrow cells in adults; aggregates often present
● Different subsets (B, T, NK) appear morphologically similar: small to large size, variable amount of cytoplasm, round nuclei, dense chromatin, variable inconspicuous nucleoli

Micro images
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Left: normal lymphocytes; right-movement of B lineage cells with maturation

Immunophenotype
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Earliest immunologically recognizable B cells: TdT, CD34, CD79a, HLA-DR, +/-CD10 and +/-CD45; they subsequently acquire CD19, cCD22, CD22 and CD20
Pre-B cells: +/-TdT, HLA-DR, CD19, CD10, CD20, CD22, CD79a, CD45 and cμ
Mature B cells: HLA-DR, CD19, CD20, CD22, CD79a, CD79b, CD45 and sIg

Precursor T cells: TdT, CD34, cCD3, CD2, CD5, CD7, CD38, +/-CD1a and +/-CD45; they are initially double negative for CD4 and CD8 (pro- and pre-thymocytes), then double positive (cortical thymocytes) and then they only express either CD4 or CD8 (medullary thymocytes)
Mature T cells: CD2, CD3, CD5, CD7. CD45, either CD4 or CD8

NK cells: CD16, CD56, CD57, +/-sCD3, +/-CD8, +/-CD2, +/-CD7 and +/- cytotoxic proteins (perforin, granzyme, etc.)

Electron microscopy images
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Left-Small lymphocyte; middle/right-with cytoplasmic projections

Additional references
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Janeway's Immunobiology (8th ed, 2011), Wikipedia, Clin Chem Lab Med 2006;44:775

End of Bone Marrow - nonneoplastic > Normal > Lymphocyte maturation


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