BALB/c.CBA/N mice carrying the defective Btkxid gene are resistant to pristane-induced plasmacytomagenesis

Michael Potter, Judith S. Wax1, Carl T. Hansen2 and James J. Kenny3

Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Building 37, Room 2B04, 37 Convent Drive, MSC4255, Bethesda, MD 20892, USA
1 PerImmune, Inc., 1330 Piccard Drive, Rockville, MD 20850-4390, USA
2 Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD 20892-5590, USA
3 National Institute of Aging, National Institutes of Health, 4940 Eastern Avenue, MS28, Baltimore, MD 21224, USA

Correspondence to: M. Potter


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The X-chromosome from the CBA/N mouse which carries the defective Bruton's tyrosine kinase (Btk) allele (Xxid) has been introgressively backcrossed onto the plasmacytoma (PCT) induction-susceptible BALB/cAN. Inbred BALB/c.CBA/N-xid/xid (C.CBA/N) mice raised and maintained in our conventional colony were given three 0.5 ml injections of pristane and were highly refractory to PCT induction. Only one PCT was found among 59 mice followed for >=300 days. Twenty mice were examined at day 200 for foci of plasma cells in the oil granuloma. Ten mice had small foci of plasma cells, most of which were plasmacytotic, embedded in the inflammatory oil granuloma. In one there were multiple foci, but most of the mice had only one or two foci. F1 hybrid XxidY males derived from CBA/N females crossed to BALB/cAnPt were also resistant to PCT induction, while heterozygous and homozygous XY males were susceptible. C.CBA/N mice can develop extensive mucosal plasma cells as well as plasma cell accumulations in oil granuloma tissue, but the precursors of these plasma cells do not give rise to PCT in genetically susceptible hosts. The failure of C.CBA/N mice to develop PCT is probably due to the elimination of B cell clones that can be perpetuated by repeated exposure to thymus-independent type 2 antigens.

Keywords: B-1 lymphocytes, Bruton's tyrosine kinase, CBA/N, plasmacytoma, pristane, TI-2 antigens, xid


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In 1993 the genes for XLA (X-linked agammaglobulemia) in humans and xid (X-linked immunodeficiency) in mice were cloned and sequenced, and found to code for a non-receptor protein tyrosine kinase Bruton's agammaglobulinemia tyrosine kinase (Btk) (14). The wild-type gene product was in the Btk/Tec subfamily of src kinases that contained pleckstrin homology (PH), TH (Tec), SH2, SH3 and kinase domains (5). The xid mutation in the mouse produces a critical Arg to Cys replacement in the PH domain that blocks the activation of this kinase and its subsequent effector functions, leading to DNA synthesis (6 ,7), cell cycle completion in B cells and induction of anti-apoptotic proteins (811).

In humans the XLA mutations produce a severe immunodeficiency, a developmental arrest in the pre-B stage, and a loss of peripheral B cells and plasma cells (12). In the mouse the xid mutation is associated with defective immune responses to thymus-independent type 2 antigens (TI-2) (see reviews in 13,14). B cells that recognize the polyvalent TI-2 antigens are activated into DNA synthesis and cell division by cross-linking the sIgM receptors (B cell receptor). Most of these antigen–antibody interactions are associated with low binding affinities and polyreactivity (15). The epitopes on TI-2 antigens are widely distributed in nature and thus can be of autogenous origin (16), many are polysaccharides (13). Subsets of mature peripheral B cells that react to TI-2 antigens in the mouse are characterized by an IgMhigh, IgDlow, B220low, CD5+ or CD5 phenotype, and are located in the peritoneal cavity (PerC) and spleen (17). These B cells are commonly called B-1 cells, are thought to develop predominantly from fetal hematopoietic stem cells and are produced de novo until mice are ~30 days of age (15,18). Thereafter they are maintained by self-renewal of VHDHJH/VLJL rearranged cells (1921). In adult mice B cell lymphocytopoiesis is from de novo differentiation of hematopoietic stem cells from the bone marrow (19). The self renewal process and maintenance of B-1 cells in the mouse requires signaling through the B cell receptor (22).

Peritoneal plasmacytomas (PCT) are induced in genetically susceptible BALB/cAn mice by several different kinds of materials: solid plastic objects (23,24), paraffin oils, e.g. pristane (2,6,10,14 tetramethylpentadecane) (25), and silicone gels (26). The pristane model of plasmacytomagenesis has been the most extensively studied. Pristane is injected into the peritoneal space where it induces the formation of chronic oil granulomatous tissue, the microenvironment where PCT develop morphologically (27,28). PCT formation is usually preceded by the appearance of foci of proliferating plasma cells (28). Over 95% of the PCT have consistent chromosomal translocations that activate the c-myc oncogene, of which ~80% are T(12;15) and are 10–15% T(6;15) (see review in 29). All PCT so far studied appear to have a second consistent tumor suppressor-like mutation as they do not express functional transforming growth factor-ß receptors (30). The development of the PCT in peritoneal chronic inflammatory tissues raises the question about the relationship of B-1 lymphocytes to PCT development. The availability of an inbred BALB/c.CBA/N congenic strain that is homozygous for the defective Btkxid on a PCT induction-susceptible BALB/cAn background has provided the opportunity to determine if this defect affects pristane-induced peritoneal plasmacytomagenesis. In the present study we have attempted to induce PCT in BALB/cAn.CBA/N-xid/xid mice with pristane and found these mice to be highly resistant to PCT induction despite morphological evidence that abundant plasma cells develop in these mice.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The BALB/cAn.CBA/N-xid /xid (C.CBA/N) strain was originated by a breeding strategy that permitted the introduction of the CBA/N X chromosome onto a different inbred background (31). Essentially, CBA/N-xid/xid females were mated to BALB/c to obtain F1 hybrid males XxidY, which were then mated back to CBA/N to obtain backcross XxidXxid female progeny. These homozygous females were then mated to BALB/cAn to continue the introgressive backcrossing and the process repeated for 20 generations. In this scheme autosomal crossing over occurs, but there is no opportunity for crossing over between BALB/c and CBA/N X chromosomes. This raises the possibility that other PCT resistance genes of CBA X-chromosomal origin could also be introduced in these congenics. This congenic strain made by 20 introgressive backcrosses was then converted to a homozygous strain. C.CBA/N mice were introduced into our AAALAC approved barrier-protected conventional mouse colony at PerImmune (Rockville, MD) and continuously inbred. All mice were maintained on Purina Mouse Chow 5001 (PMI Feeds, St Louis, MO) and acidified tap water ad libitum. The mice were housed in shoe-box-type cages, four to five mice per cage. The bedding used in cages contained cedar shavings to control for mites. The colony harbors common potential pathogens such as Sendai virus, Mouse Hepatitis Virus and pin worms.

Pristane was purchased from Aldrich (Milwaukee, WI). To induce PCT the mice were injected with three 0.5 ml doses given i.p. on days 0, 60 and 120 performed under Animal Use Protocol no. 190. After day 120 ascites or peritoneal exudate was aspirated with 25 gauge needles every 3 weeks. Cytofuge preparations were made and the cells were stained with Wright's Giemsa stain. Plasmacytomas were diagnosed by finding >=10 atypical plasma cells per slide. In most cases two diagnoses per mouse were made. In most fully developed PCT the cytofuge reparations contained >100 PCT cells. When the mice were autopsied, the mesenteric and omental tissues were excised in large blocks after stripping away the intestines. These were then cut after fixation in Fekete's modification of Tellyesniczky's fixative (70% ethanol:formalin:glacial acetic acid in 20:2:1 parts) into 2–10 mm fragments. All of the 4 µm sections were stained with hematoxylin & eosin and scanned for the presence of plasmacytic foci or PCT. Selected cases were immunostained to determine the heavy chain class by methods previously described (28).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
C.CBA/N mice male and female mice were injected with pristane on days 0, 60 and 120. Of the 79 mice, 20 were autopsied on day 201, another 20 on day 303, and the remaining 39 mice were watched until day 397 for the development of ascites and the appearance of PCT cells in ascites, and then examined for evidence of plasmacytomagenesis (Table 1Go and Fig. 1Go). Tissue sections of the mesenteric and omental oil granuloma were surveyed for the presence of plasma cells, PCT and foci which contained aggregates of >=50 plasma cells (Fig. 2Go). Foci that contained differentiated plasma cells with round nuclei were classified as plasmacytotic foci (32) (Fig. 2B and DGo). Some of these that were still present when the tissue blocks were recut, stained for IgA. In contrast, the plasma cells in foci that contained atypical plasma cells (atypical foci) were larger in size and hyperchromatic, had more irregular nuclei, and resembled the plasma cells in fully developed PCT (Fig. 2AGo). The oil granulomatous tissue at 200 days was highly cellular with many macrophages, neutrophils and fibroblasts, and was typical of the inflammatory phase of oil granuloma development in BALB/cAn mice. By day 300 and after, the oil granulomata became progressively more sclerotic and calcified after 300 days. IgA cells were seen scattered through the granulomatous tissues and were abundant in the lamina propria sections of the gut of xid mice (Fig. 2CGo). IgA immunostained plasma cells in the lamina propria in ileal villi were counted. Only profiles of villi that included the base (crypt) and tip of the villus were used. Forty-two ileal villi from xid mice were counted and found to contain an average of 49 cells (range 30–90) per villus. IgA-producing cells in the lamina propria tissue of villi from pristane-injected wild-type BALB/cAn mice averaged 33.6 plasma cells per villus with a range of 18–64 cells. This suggested that pristane-treated xid mice contained more IgA than wild-type controls. The significance of this difference must await further study.


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Table 1. Plasmacytoma induction studies in BALB/cAn.CBA/N mice given three 0.5 ml i.p. injections of pristane on days 0, 60 and 120
 


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Fig. 1. Induction of PCT in C.CBA/N mice by pristane. Induction of PCT in C.CBA/N mice by three 0.5 ml injections of pristane on days 0, 60 and 120 (see Table 1Go). Gp-1 and Gp-2 refer to (Group 1) the 20 female mice autopsied on day 201, and (Group 2) the 10 males and 10 females autopsied on day 303. The controls were BALB/cAnPt control mice from eight experiments run during the period when the CBA/N studies were carried out. The mean incidence in the BALB/cAnPt controls at day 300 was 45%; however, the mean incidence for the individual experiments ranged from 30 to 60%. In three experiments carried to day 330 the incidence ranged from 45 to 60%.

 


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Fig. 2. Histological sections from C.CBA/N mice. Histological sections from C.CBA/N mice taken 201 days after the first of three 0.5 ml injections of pristane. Hematoxylin & eosin-stained section at x1000 through an atypical focus (A) and plasmacytotic focus (B). The cells and nuclei in the atypical focus are larger than those in plasmacytotic foci. A mitotic figure was found in the plasmacytotic focus. Immunohistochemical stains using a specific anti-IgA antiserum in the lamina propria of intestinal villi (C) and a plasmacytotic focus (D) showing the intense staining for IgA in the oil granuloma. We counted the number of IgA cells in 42 villi from five mice and found the mean number of plasma cells was 49 per villus.

 
Among the 20 mice autopsied on day 201, 10 (Table 1Go) had 22 plasmacytotic foci (each with >=50) composed of mature plasma cells (Fig. 2BGo) and in one, seven plasmacytotic foci were found. Two atypical foci were seen (Fig. 2AGo): one mouse had a single focus of atypical plasma cells and in the other the atypical focus was associated with a plasmacytotic focus. One mouse in the day 303 sample had multiple foci of differentiated plasma cells. A single advanced PCT was found at day 351; the cells in this tumor were atypical IgA-secreting plasma cells characteristic of PCT and extensively invaded the oil granulomatous tissue. Control BALB/cAnPt mice that were given similar doses of pristane from eight different experiments run during the same period as the C.CBA/N mice developed an overall incidence of 46% PCT (range 30–62.5%) by day 300. The results indicate that C.CBA/N mice were highly refractory to PCT induction by a potent PCT induction regimen but were able to develop typical oil granulomatous tissue that contained plasma cells and focal accumulations of plasma cells.

We previously found that CBA-T6/T6 and (CBA-T6/T6xBALB/c)F1 mice were resistant to PCT induction by pristane, indicating that CBA-T6/T6 carries strong resistance genes (33). To determine if the C.CBA/N congenic mouse carried PCT resistance genes other than xid, C.CBAN mice were reciprocally crossed with BALB/cAnPt (Table 1Go and Fig. 3Go) and injected with pristane. The XxidY males were resistant and resembled C.CBA/N males. XY males were the most susceptible. The high incidence of PCT in the XY males indicates that autosomal CBA/N resistance genes were not present in the C.CBA/N strain. The XXxid and XxidX females developed an intermediate incidence of PCT, 43 and 36% respectively. This partial resistance could be due to additional resistance genes on the CBA/N Xxid chromosome or to the effects of the Xxid chromosome. Our studies cannot distinguish between these two possibilities.



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Fig. 3. Induction of PCT in F1 hybrids of BALB/cAnPtxC.CBA/N. Induction of PCT in F1 hybrids of BALB/cAnPtxC.CBA/N (XY,X/xid) and C.CBA/NxBALB/cAnPt (xid/X and xid/Y) mice by three 0.5 ml injections of pristane on days 0, 60 and 120. The xid/Y male mice were resistant to PCT induction, while the XY were highly susceptible. Heterozygous X/xid females from both crosses showed an intermediate incidence of PCT (see Table 1Go).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
BALB/cAnCBA/N (xid/xid) mice are resistant to PCT induction by three 0.5 ml doses of pristane. Only one PCT was found among 59 mice followed for 300–397 days. To determine if the C.CBA/N congenic might carry autosomal resistance genes to PCT induction, BALB/cAnPt males were crossed to C.CBA/N and the F1 hybrid males (XxidY) were again found to be resistant to PCT induction, while the females (XxidX, XXxid) showed a substantial but partial susceptibility (36–43%). Overall, the results did not indicate the presence of autosomal resistance genes of CBA/N origin. The possibility of another weak PCT resistance gene on the X chromosome of CBA/N origin, however, could not be ruled out. The results indicate the Btkxid gene was principally responsible for the resistance to PCT induction.

Histological studies revealed an abundance of plasma cells in the lamina propria of the intestinal villi. Further, the oil granulomatous tissues examined at day 200 contained isolated plasma cells and in 10 of 20 mice at day 200 plasmacytotic foci were found, i.e. aggregates of >=50 plasma cells. Thus, plasma cell formation can occur in these immunodeficient mice at the very sites where plasma cells undergo progression to neoplasia.

How can the resistance to PCT induction in C.CBA/N mice be explained? The basic explanation is that the B lymphocyte precursors of PCT in wild-type BALB/cAn mice are missing in xid mice because of developmental clonal elimination mechanisms resulting from defective Btk activation.

The defective xid allele has been reported to interfere with the transmission of signals for DNA synthesis and completion of the cell cycle in response to antigen receptor cross-linking by TI-2 antigens (7,22). Although B cells from xid mice do respond weakly to B cell receptor cross-linking and enter the G1 phase, they fail to activate cyclin/cdk kinases (7) and complete the cell cycle (6). In addition, Btk-deficient cells do not up-regulate the anti-apoptotic proteins Bcl-2 (10) and Bcl-xL (6,34). Thus, B cells in xid mice which respond to cross-linking of their BCR via natural TI-2 antigens could become arrested in the cell cycle, trigger the apoptotic machinery and be eliminated as described and suggested by several studies (6,7,9,10).

An alternative way to explain how the xid mutation modifies the development of B cells is that all of the B cells produced in a xid mouse that reach the periphery are short lived and rapidly eliminated. In a recent re-evaluation of the effects of xid on B cell development, Klaus et al. (35) have provided evidence that all B cell compartments may be affected. This suggests the possibility that B cells in xid mice could produce only short-lived B cells and little long-term memory.

Specifically, then, does the xid mutation interfere with the clonal longevity in B-2 lymphocytes that are activated by T-dependent antigens? This question cannot yet be definitively answered. There is evidence that T-dependent responses in conventional B-2 cells are reduced in CBA/N mice (3640). When thymus-dependent immune responses were induced in (CBA/NxC57BL/6)F1 hybrids, Ridderstad et al. ( 39) found a 10-fold reduction in the primary responses in the male (XxidY) progeny, but qualitatively and quantitatively wild-type (normal) secondary responses. In other studies the btkxid mutation interfered with the formation of long-lived cells; however, the deficit in older mice was much reduced, indicating there was a recovery or a compensating B cell replacement mechanism in old xid mice (38).

One of the cardinal defects in xid mice is a deficiency of a subset of B cells that react to TI-2 antigens (i.e. B-1 cells). TI-2 antigens are of autogenous origin as well as being common antigens in ubiquitous microbial species. Thus, B-1 cells, which are self-replenishing (20,41) and activated naturally by these antigens, are clones that may have undergone repeated cycles of antigen activation and quiescence. Examples of clonal expansions of CD5+ clones have been described in NZB mice (42). Other direct evidence that clonal longevity exists is found in autoimmune mice where clonal history can be traced through Ig somatic hypermutation (43,44). This accumulation of successive Ig somatic mutations is assumed to result from repeated interactions with autoantigens and each mutation may occur in daughter cells of an original clone, separated in space and time. When the xid mutation was introduced into (NZWxNZB)F1 hybrid mice, it was found that immune complex glomerulonephritis and anti-DNA antibodies were dramatically reduced (45), suggesting that clonal evolution did not occur. If a similar process of repeated antigenic exposure occurs in BALB/cAn mice, then it becomes possible that a single clone could accumulate mutations affecting proliferative behavior (oncogenic diversification).

B-1 cells have been reported to be prone to develop clonal expansions both in autoimmune NZB (42) and C57BL/6 mice (46). This phenomenon may be linked to the self-renewing capabilities of B-1 cells in the mouse. The findings in the present study strongly suggest that the reduction in B cells that can respond to TI-2 antigens eliminates the lymphocytic precursors of the PCT cells. These appear to be B-1 cells.


    Acknowledgments
 
We thank Elizabeth Mushinski for preparing the immunostains.


    Abbreviations
 
BtkBruton's tyrosine kinase
PCTplasmacytoma
XLAX-linked agammaglobulinemia
PHpleckstrin homology
TI-2type 2 thymus-independent antigens
xidX-linked immunodeficient
PerCperitoneal cavity

    Notes
 
Transmitting editor: J. F. Kearney

Received 18 November 1998, accepted 12 March 1999.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R, . Bobrow, M., Edvard Smith, C. I. and Bentley, D. R. 1993. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226.[ISI][Medline]
  2. Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E. and Witte, O. N. 1993. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72:279.[ISI][Medline]
  3. Thomas, J. D., Sideras, P., Smith, C. I. E., Vorechovsky, I., Chapman, V. and Paul, W. E. 1993. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261:35.[ISI][Medline]
  4. Rawlings, D. J., Saffran, D. C., Tsukada, S., Largaespada, D. A., Grimaldi, J. C., Cohen, L., Mohr, R. N., Bazan, J. F., Howard, M., Copeland, N. G., Jenkins, N. A. and Witte, O. N. 1993. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 261:358.[ISI][Medline]
  5. Rawlings, D. J. and Witte, O. N. 1400 1995. The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function. Semin. Immunol. 7:237.[Medline]
  6. Solvason, N., Wu, W. W., Kabra, N., Lund-Johansen, F., Roncarolo, M. G., Behrens, T. W., Grillot, D. A., Nunez, G., Lees, E. and Howard, M. 1998. Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells. J. Exp. Med. 187:1081.[Abstract/Free Full Text]
  7. Brorson, K., Brunswick, M., Ezhevsky, S., Wei, D. G., Berg, R., Scott, D. and Stein, K. E. 1997. xid affects events leading to B cell cycle entry. J. Immunol. 159:135.[Abstract]
  8. Anderson, J. S., Teutsch, M., Dong, Z. and Wortis, H. H. 1996. An essential role for Bruton's [corrected] tyrosine kinase in the regulation of B cell apoptosis [published erratum appears in Proc. Natl Acad. Sci. USA 1500 1996; 93(26):15522]. Proc. Natl Acad. Sci. USA 93:10966.[Abstract/Free Full Text]
  9. Kenny, J. J., Fischer, R. T., Lustig, A., Dintzis, H., Katsumata, M., Reed, J. C. and Longo, D. L. 1996. bcl-2 alters the antigen-driven selection of B cells in mukappa but not in mu-only Xid transgenic mice. J. Immunol. 157:1054.[Abstract]
  10. Woodland, R. T., Schmidt, M. R., Korsmeyer, S. J. and Gravel, K. A. 1996. Regulation of B cell survival in xid mice by the proto-oncogene bcl-2. J. Immunol. 156:2143.[Abstract]
  11. Fang, W., Weintrab, B. C., Dunlap, B., Garside, P., Pape, K. A., Jenkins, M. K., Goodnow, C. C., Mueller, D. L. and Behrens, T. W. 1998. Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing. Immunity. 1600 9:35.[ISI][Medline]
  12. Rosen, F. S., Cooper, M. D. and Wedgwood, R. J. 1995. The primary immunodeficiencies. N. Engl. J. Med. 333:431.[Free Full Text]
  13. Bondada, S. and Garg, M. 1994. Thymus-independent antigens. In E. C. Snow, ed. Handbook of B and T Lymphocytes, p. 343. Academic Press, New York.
  14. Scher, I. 1982. CBA/N immune defective mice; evidence for the failure of a B cell subpopulation to be expressed. Immunol. Rev. 64:117.[ISI][Medline]
  15. Stall, A. M., Wells, S. M. and Lam, K. P. 1996. B-1 cells: unique origins and functions. Semin. Immunol. 8:45.[Medline]
  16. Mercolino, T. J., Arnold, L. W., Hawkins, L. A. and Haughton, G. 1988. Normal mouse peritoneum contains a large population of Ly-1+ (CD5) B cells that recognize phosphatidyl choline. J. Exp. Med. 168:687.[Abstract]
  17. Kroese, F. G. M., Butcher, E. C., Stall, A. M., Lalor, P. A., Adams, S. and Herzenberg, L. A. 1988. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int. Immunol. 1:75.
  18. Hardy, R. R., Li, Y. S. and Hayakawa, K. 1996. Distinctive developmental origins and specificities of the CD5+ B cell subset. Semin. Immunol. 8:37.[Medline]
  19. Herzenberg, L. A., Kantor, A. B. and Herzenberg, L. A. 1992. Layered evolution in the immune system. A model for the ontogeny and development of multiple lymphocyte lineages. Ann. NY Acad. Sci. 1800 651:1.
  20. Kantor, A. B., Stall, A. M., Adams, S., Watanabe, K. and Herzenberg, L. A. 1995. De novo development and self-replenishment of B cells. Int. Immunol. 7:55.[Abstract]
  21. Hayakawa, K., Hardy, R. R., Stall, A. M. and Herzenberg, L. A. 1986. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur. J. Immunol. 16:1313.[ISI][Medline]
  22. Satterthwaite, A. B., Li, Z. and Witte, O. 1998. Btk function in B cell development and response. Semin. Immunol. 10:309.[ISI][Medline]
  23. 1900 Merwin, R. M. and Redmon, L. W. 1963. Induction of plasma cell tumors and sarcomas in mice by diffusion chambers placed in the peritoneal cavity. J. Natl. Cancer Inst. 31:990.
  24. Potter, M., Wax, J. and Jones, G. M. 1997. Indomethacin is a potent inhibitor of pristane and plastic disc induced plasmacytomagenesis in a hypersusceptible BALB/c congenic strain. Blood 90:260.[Abstract/Free Full Text]
  25. Potter, M. and Wax, J. S. 1983. Peritoneal plasmacytomagenesis in mice: comparison of different pristane dose regimens. J. Natl. Cancer Inst. 71:391.[ISI][Medline]
  26. Potter, M., Morrison, S., Wiener, F. and Miller, F. W. 1994. Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J. Natl. Cancer Inst. 86:1058.[Abstract]
  27. Anderson, A. O., Wax, J. S. and Potter, M. 1985. Differences in the peritoneal response to pristane in BALB/cAnPt and BALB/cJ mice. Curr. Top. Microbiol. Immunol. 122:242.[ISI][Medline]
  28. Potter, M., Mushinski, E. B., Wax, J. S., Hartley, J. and Mock, B. A. 1994. Identification of two genes on chromosome 4 that determine resistance to plasmacytoma induction in mice. Cancer Res. 54:969.[Abstract]
  29. Potter, M. and Wiener, F. 1992. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13:1681.[Abstract]
  30. Amoroso, S. R., Huang, N., Roberts, A. B., Potter, M. and Letterio, J. J. 1998. Consistent loss of functional type beta transforming growth factor receptor expression in murine plasmacytomas. Proc. Natl Acad. Sci. USA 95:189 2100 .[Abstract/Free Full Text]
  31. Taurog, J. D., Raveche, E. S., Smathers, P. A., Glimcher, L. H., Huston, D. P., Hansen, C. T. and Steinberg, A. D. 1981. Studies of the pathogenesis of autoimmunity in NZB mice. Demonstration of independent B and T cell abnormalities and prevention of autoimmunity by deletion of a B cell subset. J. Exp. Med. 153:221.[Abstract]
  32. Potter, M., Wax, J. S., Anderson, A. O. and Nordan, R. P. 1985. Inhibition of plasmacytoma development in BALB/c mice by indomethacin. J. Exp. Med. 161:996.[Abstract]
  33. Potter, M. 1984. Genetics of susceptibility to plasmacytoma development in BALB/c mice. Cancer Surv. 3:247.[ISI]
  34. Choi, M. S., Holmann, M., Atkins, C. J. and Klaus, G. G. 1996. Expression of bcl-x during mouse B cell differentiation and following activation by various stimuli. Eur. J. Immunol. 2200 26:676.[ISI][Medline]
  35. Klaus, G. G., Holman, M., Johnson-Leger, C., Elgueta-Karstegal, C. and Atkins, C. 1997. A re-evaluation of the effects of X-linked immunodeficiency (xid) mutation on B cell differentiation and function in the mouse. Eur. J. Immunol. 27:2749.[ISI][Medline]
  36. Gershon, R. K. and Kondo, K. 1976. Deficient production of a thymus-dependent high affinity antibody subset in mice (CBA/N) with an X-linked B lymphocyte defect. J. Immunol. 117:701.[ISI][Medline]
  37. Sprent, J., Bruce, J., Ron, Y. and Webb, S. R. 1985. Physiology of B cells in mice with X-linked immunodeficiency. I. Size, migratory properties, and turnover of the B cell pool. J. Immunol. 134:1442.[Abstract/Free Full Text]
  38. Oka, Y., Rolink, A. G., Andersson, J., Kamanaka, M., Uchida, J., Yasui, T., Kishimoto, T., Kikutani, H. and Melchers, F. 2300 1996. Profound reduction of mature B cell numbers, reactivities and serum Ig levels in mice which simultaneously carry the XID and CD40 deficiency genes. Int. Immunol. 8:1675.[Abstract]
  39. Ridderstad, A., Nossal, G. T. and Tarlinton, D. M. 1996. The xid mutation diminishes memory B cell generation but does not affect somatic hypermutation and selection. J. Immunol. 157:3357.[Abstract]
  40. Scher, I., Berning, A. K. and Asofsky, R. 1979. X-linked B lymphocyte defect in CBA/N mice. IV. Cellular and environmental influences on the thymus dependent IgG anti-sheep red blood cell response. J. Immunol. 123:477.[ISI][Medline]
  41. Hayakawa, K., Hardy, R. R., Parks, D. R. and Herzenberg, L. A. 1983. The `Ly-1 B' cell subpopulation in normal immunodefective, and autoimmune mice. J. Exp. Med. 157:202.[Abstract]
  42. Stall, A. M. 1988. Ly-1 B cell clones similar to human chronic lymphocytic leukemias routinely develop in older normal mice and young autoimmune (New Zealand Black-related) animals. Proc. Natl Acad. Sci. USA 85:7312.[Abstract]
  43. Shlomchik, M. J., Marshak-Rothstein, A., Wolfowicz, C. B., Rothstein, T. L. and Weigert, M. G. 1987. The role of clonal selection and somatic mutation in autoimmunity. Nature 328:895.
  44. Schroder, A. E., Greiner, A., Seyfert, C. and Berek, C. 1996. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 93:221.[Abstract/Free Full Text]
  45. Steinberg, B. J., Smathers, P. A., Frederikson, K. and Steinberg, A. D. 1982. Ability of the xid gene to prevent autoimmunity in (NZBxNZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. J. Clin. Invest. 70:587.[ISI][Medline]
  46. LeMaoult, J., Delassus, S., Dyall, R., Nikolic-Zugic, J., Kourilsky, P. and Weksler, M. E. 1997. Clonal expansions of B lymphocytes in old mice. J. Immunol. 159:3866.[Abstract]