Immunology Today, rot. 3, No. 12, 1982
343
Chronic lymphocytic leukaemia and its relationship to normal B lymphopoiesis A. P. Johnstone Department of Immunology, St. George's Hospital Medical School, London SW17 ORE, U.K. The leukaemic cells from patients with chronic lymphocytic leukaemia have long been thought to represent circulating virgin B lymphocytes. In this article Alan Johnstone discusses the accumulated data from struclural and fi~nclional analyses which place the leukaemic cells at a stage intermediate between the pre-B cell and mature B lyrnphocyte, a stage not normally found in the circulation.
With the development of the concept of separate B and T lymphoid differentiation pathways, leukaemias could be classified according to the type of lymphocyte that the abnormal cells resembled and from which they were presumably derived. Using sophisticated technology, this approach has allowed the classification of acute lymphocytic leukaemias into several groups, with important consequences for diagnosis, prognosis and treatment of the disease I. Chronic lymphocytic leukaemia (CLL) differs from the acute leukaemias in several respects. It is a disease of the elderly, most patients being over 50 years old, and it is not particularly serious in its own right. The major clinical problems can be placed into three groups: interference with bone marrow function due to infiltration by leukaemic cells, resulting in anaemia and thrombocytopenia; autoimmune phenomena, particularly anaemia and thrombocytopenia; and defective cellular and humoral immune function with consequent recurrent infections. The circulating leukaemic cells have the morphCogy of small quiescent lymphocytes and they do not spontaneously proliferate when cultured in vitro. Leukaemic cells carry surface immunoglobulin (apart from the rare cases of T-cell CLL) and were classified as 'virgin' B lymphocytes as opposed to the more mature B lymphocytes and plasma cells responsible for some other neoplasias, c.g. multiple myeloma and macroglobulinaemia 2. Some of the stages in the generation of mature B lymphocytes from pluripotential stem cells have been elucidated 3,4. This review will describe our current knowledge of this transition and draw on several diverse lines of evidence to define the maturation stage represented by CLL cells. Normal B lymphopoiesis In mammals, B-cell differentiation begins in the foetal liver and bone m a r r o w and c o n t i n u e s throughout life in the marrow where other haemopoietic cells are also produced. Commitment to the Bcell lineage is first detectable when immunoglobulin Ix chains appear in the cytoplasm of large, cycling lymphoid cells in the liver of the 8-week human foetus 4
(Fig. l). Such cells, termed 'we-B', lacking light chain and surface i m m u n o g l o b u l i n , also c o m p r i s e approximately 5°70 of nucleated cells in the adult bone marrow. Large proliferating pre-B cells divide to give rise to small non-proliferating pre-B cells 3 which mature further to produce light chain and express low levels of surface tgM (immature B lymphocytes). These cells then undergo further development, including increased expression of surface immunoglobulin 3 and isotype switching 5, changing the expressed heavy chain from g through 8 to y and eL, sometimes expressing two or more isotypes simultaneously 4. The early parts of this differentiation and maturation pathway take place in primary lymphoid organs (marrow or foetal liver) whereas immature small lymphocytes can circulate to secondary, peripheral lymphoid tissue (spleen and lymph nodes) in order to become functionally mature 3. Blood is involved in conveying these immature lymphocytes but the majority of peripheral blood lymphocytes are probably recycling mature cells, both virgin and memory (i.e. previously act.ivated). Some of the characteristic B-cell surface molecules, such as H L A - D R antigens and Epstein-Barr virus receptors, are p~'esent throughout the B lineage from the pre-B stage 4. Conversely, receptors for the third component of complement (C3) and the Fc portion of IgG are only acquired at the immature lymphocyte stage. The expression of other phenotypic markers, both surface and cytoplasmic, is dynamically linked to the maturity of the cell (see below). Defining the stage of B-cell development represented by CLL is facilitated by comparison with normal foetal and newborn cord blood cells. Human beings are not fully immunocompetent at birth and it is clear that the neonatal B-cell system is immature 4,6,7, although abnormalities in antigenpresenting and immunoregulatory cells are also apparent 6,7.
Immunoglobulinp r o d u c t i o n The majority of CLL lymphocytes carry immunoglobulin, comprizing both heavy and light chains, on their surface and hence are derived from the B-cell Elsevier Biomedical Press 1982 0 ] 6 7 4 9 1 9 / 8 2 / 0 0 0 0 q ) 0 0 0 / $ 1 0(I
344
Immunology Today, vol. 3, No. 12, 1982
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343
Chronic lymphocytic leukaemia and its relationship to normal B lymphopoiesis A. P. Johnstone Department of Immunology, St. George's Hospital Medical School, London SW17 ORE, U.K. The leukaemic cells from patients with chronic lymphocytic leukaemia have long been thought to represent circulating virgin B lymphocytes. In this article Alan Johnstone discusses the accumulated data from struclural and fi~nclional analyses which place the leukaemic cells at a stage intermediate between the pre-B cell and mature B lyrnphocyte, a stage not normally found in the circulation.
With the development of the concept of separate B and T lymphoid differentiation pathways, leukaemias could be classified according to the type of lymphocyte that the abnormal cells resembled and from which they were presumably derived. Using sophisticated technology, this approach has allowed the classification of acute lymphocytic leukaemias into several groups, with important consequences for diagnosis, prognosis and treatment of the disease I. Chronic lymphocytic leukaemia (CLL) differs from the acute leukaemias in several respects. It is a disease of the elderly, most patients being over 50 years old, and it is not particularly serious in its own right. The major clinical problems can be placed into three groups: interference with bone marrow function due to infiltration by leukaemic cells, resulting in anaemia and thrombocytopenia; autoimmune phenomena, particularly anaemia and thrombocytopenia; and defective cellular and humoral immune function with consequent recurrent infections. The circulating leukaemic cells have the morphCogy of small quiescent lymphocytes and they do not spontaneously proliferate when cultured in vitro. Leukaemic cells carry surface immunoglobulin (apart from the rare cases of T-cell CLL) and were classified as 'virgin' B lymphocytes as opposed to the more mature B lymphocytes and plasma cells responsible for some other neoplasias, c.g. multiple myeloma and macroglobulinaemia 2. Some of the stages in the generation of mature B lymphocytes from pluripotential stem cells have been elucidated 3,4. This review will describe our current knowledge of this transition and draw on several diverse lines of evidence to define the maturation stage represented by CLL cells. Normal B lymphopoiesis In mammals, B-cell differentiation begins in the foetal liver and bone m a r r o w and c o n t i n u e s throughout life in the marrow where other haemopoietic cells are also produced. Commitment to the Bcell lineage is first detectable when immunoglobulin Ix chains appear in the cytoplasm of large, cycling lymphoid cells in the liver of the 8-week human foetus 4
(Fig. l). Such cells, termed 'we-B', lacking light chain and surface i m m u n o g l o b u l i n , also c o m p r i s e approximately 5°70 of nucleated cells in the adult bone marrow. Large proliferating pre-B cells divide to give rise to small non-proliferating pre-B cells 3 which mature further to produce light chain and express low levels of surface tgM (immature B lymphocytes). These cells then undergo further development, including increased expression of surface immunoglobulin 3 and isotype switching 5, changing the expressed heavy chain from g through 8 to y and eL, sometimes expressing two or more isotypes simultaneously 4. The early parts of this differentiation and maturation pathway take place in primary lymphoid organs (marrow or foetal liver) whereas immature small lymphocytes can circulate to secondary, peripheral lymphoid tissue (spleen and lymph nodes) in order to become functionally mature 3. Blood is involved in conveying these immature lymphocytes but the majority of peripheral blood lymphocytes are probably recycling mature cells, both virgin and memory (i.e. previously act.ivated). Some of the characteristic B-cell surface molecules, such as H L A - D R antigens and Epstein-Barr virus receptors, are p~'esent throughout the B lineage from the pre-B stage 4. Conversely, receptors for the third component of complement (C3) and the Fc portion of IgG are only acquired at the immature lymphocyte stage. The expression of other phenotypic markers, both surface and cytoplasmic, is dynamically linked to the maturity of the cell (see below). Defining the stage of B-cell development represented by CLL is facilitated by comparison with normal foetal and newborn cord blood cells. Human beings are not fully immunocompetent at birth and it is clear that the neonatal B-cell system is immature 4,6,7, although abnormalities in antigenpresenting and immunoregulatory cells are also apparent 6,7.
Immunoglobulinp r o d u c t i o n The majority of CLL lymphocytes carry immunoglobulin, comprizing both heavy and light chains, on their surface and hence are derived from the B-cell Elsevier Biomedical Press 1982 0 ] 6 7 4 9 1 9 / 8 2 / 0 0 0 0 q ) 0 0 0 / $ 1 0(I
344
Immunology Today, vol. 3, No. 12, 1982
T
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lineage
O-
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