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Lymphoma - B cell neoplasms

Molecular analysis - theory


Reviewer: Nikhil Sangle, M.D., University of Utah and ARUP Laboratories (see Reviewers page)
Revised: 26 March 2011, last major update February 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Lymphocyte physiology
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● B cells express surface immunoglobulin (Ig), composed of 2 heavy (H) and 2 light (L) chains (either kappa or lambda)
● T cell receptors (TCR) are either alpha/beta (95%) or gamma/delta (5%) heterodimers
● An estimated 100 million different Ig and TCR exist, due to various physiologic mechanisms that create diversity
● Ig and TCR germline configuration contains Variable, Diversity, Joining and Constant region segments
● Early in normal lymphocyte differentiation within the bone marrow, the antigen receptor genes undergo recombination to create a variable region, containing an antigen combining site and a constant region
● Diversity occurs through recombination of segments plus imprecise V-D-J joining
● Terminal deoxytransferase (TdT) adds or removes nucleotides, causing even more diversity
● Point mutations in V and J regions occurs commonly within Ig genes, adding to diversity
● Reference: Arch Pathol Lab Med 1999;123:1189

Diagrams
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Germline configuration of immunoglobulin heavy and light-chain genes



Immunoglobulin gene rearrangement: The germline configuration of the kappa light chain (upper line) consists of variable gene segments (Vk), joining segments (Jk) and a single constant gene segment (Ck). To assemble a functional light chain gene (lower line), a V and J segment is juxtaposed by deleting intervening DNA. The deletion reconfigures restriction enzyme cutting sites upstream of JK, changing the size of the BamH1 fragment detected with a Ck hybridization probe from 12 kb germline to 10 kb rearranged (AFIP 3rd Series Vol 14)


Germline configuration of T-cell receptor (TCR) genes



Immunoglobulin heavy-chain gene rearrangement


Clonality
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● Rearrangement forms a distinct band if multiple cells have the same rearrangement pattern, indicating clonality
● 80% of B or T cell lymphomas with characteristic immunologic and clinical features have clonal IgH or TCR-gamma rearrangement by PCR (Mod Pathol 2000;13:1269)
● 10% of B cell and T cell lymphomas have both clonal IgH and TCR-gamma rearrangements
● Note: non-neoplastic tissue may be clonal, due to autoimmune diseases for B cell disorders or granulomatous diseases for T cell disorders; tissue with a small number of polyclonal B cells (skin, GI) may cause a pseudoclonal PCR profile; best to do multiple PCR and look for same rearranged band in every experiment

Gel images
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Clonally arranged B cell populations


Clonal T cell population


Reactive (not clonal) cell population

End of Lymphoma - B cell neoplasms > Molecular analysis - Theory


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