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. 1993 Nov 1;178(5):1507–1515. doi: 10.1084/jem.178.5.1507

Suppression of B lymphopoiesis during normal pregnancy

PMCID: PMC2191236  PMID: 8228804

Abstract

We describe a dramatic reduction in numbers and activity of committed B lymphocyte precursors in the bone marrow of normal pregnant mice. Changes in cells responsive to IL-7 were evident as early as 6.5 d of pregnancy and values were < 10% of normal at parturition. B lineage precursors, identified by display of CD45R and absence of surface IgM, were also substantially depressed, and subpopulations representing different stages in the B lineage were assessed by three-color flow cytometry. Early pro-B cells are medium to large in size and have been previously characterized by low expression of the heat-stable antigen (HSA). This category of cells was not reduced, and in fact may have been slightly elevated, during pregnancy. In contrast, all subsequent populations of B lineage precursors, defined by patterns of expression of heat-stable and CD43 antigens, were substantially depressed. The immediate precursors of B cells (small pre-B cells) were identified by small size, expression of CD45R, absence of CD43, and lack of surface IgM. These were the most reduced of any phenotypically defined population in bone marrow. Numbers of newly formed B cells, characterized by the presence of sIgM, but not sIgD, were also diminished. However, B cells with a mature phenotype (sIgM+, sIgD+) were present in normal to somewhat elevated numbers. Mitogen-responsive B cells clonable in a semisolid agar assay were not significantly affected. A bromodeoxyuridine (BrdU) labeling technique was used to evaluate mitotic activity, which revealed an increased proportion of long-lived lymphocytes in the bone marrow of pregnant mice. These observations indicate that B lymphopoiesis is markedly downregulated during pregnancy and that all precursor populations beyond the early pro-B cell stage are affected. The pregnancy-related changes in bone marrow were selective for B lineage precursors, as cells expressing myeloid and erythroid markers were not reduced. In spleen, evidence was obtained for partial depletion of one subset of B cells. These cells, which have been reported to be recent immigrants from marrow, are characterized as having high levels of sIgM and HSA. Changes in other major B lymphocyte subsets in the spleen were less remarkable. When considered with results from the BrdU labeling procedure, the findings indicate that both production and export of lymphocytes from marrow may be substantially decreased. Numbers of B cell precursors were higher in postpartum animals whose litters were removed at birth, suggesting that lactation may prolong regeneration of lymphocyte production.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. ASPINALL R. L., MEYER R. K., RAO M. A. Effect of various steroids on the development of the bursa Fabricii in chick embryos. Endocrinology. 1961 Jun;68:944–949. doi: 10.1210/endo-68-6-944. [DOI] [PubMed] [Google Scholar]
  2. Abboud S. L., Bethel C. R., Aron D. C. Secretion of insulinlike growth factor I and insulinlike growth factor-binding proteins by murine bone marrow stromal cells. J Clin Invest. 1991 Aug;88(2):470–475. doi: 10.1172/JCI115327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allman D. M., Ferguson S. E., Cancro M. P. Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J Immunol. 1992 Oct 15;149(8):2533–2540. [PubMed] [Google Scholar]
  4. Barr I. G., Khalid B. A., Pearce P., Toh B. H., Bartlett P. F., Scollay R. G., Funder J. W. Dihydrotestosterone and estradiol deplete corticosensitive thymocytes lacking in receptors for these hormones. J Immunol. 1982 Jun;128(6):2825–2828. [PubMed] [Google Scholar]
  5. DOUGHERTY T. F. Effect of hormones on lympatic tissue. Physiol Rev. 1952 Oct;32(4):379–401. doi: 10.1152/physrev.1952.32.4.379. [DOI] [PubMed] [Google Scholar]
  6. Dardenne M., Kelly P. A., Bach J. F., Savino W. Identification and functional activity of prolactin receptors in thymic epithelial cells. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9700–9704. doi: 10.1073/pnas.88.21.9700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dardenne M., Savino W., Gagnerault M. C., Itoh T., Bach J. F. Neuroendocrine control of thymic hormonal production. I. Prolactin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells. Endocrinology. 1989 Jul;125(1):3–12. doi: 10.1210/endo-125-1-3. [DOI] [PubMed] [Google Scholar]
  8. Ehlich A., Schaal S., Gu H., Kitamura D., Müller W., Rajewsky K. Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell. 1993 Mar 12;72(5):695–704. doi: 10.1016/0092-8674(93)90398-a. [DOI] [PubMed] [Google Scholar]
  9. Forsberg J. G. Short-term and long-term effects of estrogen on lymphoid tissues and lymphoid cells with some remarks on the significance for carcinogenesis. Arch Toxicol. 1984 Jul;55(2):79–90. doi: 10.1007/BF00346044. [DOI] [PubMed] [Google Scholar]
  10. Förster I., Vieira P., Rajewsky K. Flow cytometric analysis of cell proliferation dynamics in the B cell compartment of the mouse. Int Immunol. 1989;1(4):321–331. doi: 10.1093/intimm/1.4.321. [DOI] [PubMed] [Google Scholar]
  11. Girasole G., Jilka R. L., Passeri G., Boswell S., Boder G., Williams D. C., Manolagas S. C. 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest. 1992 Mar;89(3):883–891. doi: 10.1172/JCI115668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hardy R. R., Carmack C. E., Shinton S. A., Kemp J. D., Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hayashi S., Kunisada T., Ogawa M., Sudo T., Kodama H., Suda T., Nishikawa S., Nishikawa S. Stepwise progression of B lineage differentiation supported by interleukin 7 and other stromal cell molecules. J Exp Med. 1990 May 1;171(5):1683–1695. doi: 10.1084/jem.171.5.1683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holmdahl R. Estrogen exaggerates lupus but suppresses T-cell-dependent autoimmune disease. J Autoimmun. 1989 Oct;2(5):651–656. doi: 10.1016/s0896-8411(89)80004-6. [DOI] [PubMed] [Google Scholar]
  15. Hooghe R., Delhase M., Vergani P., Malur A., Hooghe-Peters E. L. Growth hormone and prolactin are paracrine growth and differentiation factors in the haemopoietic system. Immunol Today. 1993 May;14(5):212–214. doi: 10.1016/0167-5699(93)90165-h. [DOI] [PubMed] [Google Scholar]
  16. ITO T., HOSHINO T. Studies of the influences of pregnancy and lactation on the thymus in the mouse. Z Zellforsch Mikrosk Anat. 1962;57:667–678. doi: 10.1007/BF00410229. [DOI] [PubMed] [Google Scholar]
  17. Ishihara K., Wood W. J., Jr, Damore M., Hermanson G. G., Wall R., Kincade P. W. B29 gene products complex with immunoglobulins on B lymphocytes. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):633–637. doi: 10.1073/pnas.89.2.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jacob J., Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med. 1992 Sep 1;176(3):679–687. doi: 10.1084/jem.176.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jungers P., Dougados M., Pélissier C., Kuttenn F., Tron F., Lesavre P., Bach J. F. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum. 1982 Jun;25(6):618–623. doi: 10.1002/art.1780250603. [DOI] [PubMed] [Google Scholar]
  20. Jyonouchi H., Kincade P. W., Good R. A., Gershwin M. E. B lymphocyte lineage cells in newborn and very young NZB mice: evidence for regulatory disorders affecting B cell formation. J Immunol. 1983 Nov;131(5):2219–2225. [PubMed] [Google Scholar]
  21. Jyonouchi H., Kincade P. W., Landreth K. S., Lee G., Good R. A., Gershwin M. E. Age-dependent deficiency of B lymphocyte lineage precursors in NZB mice. J Exp Med. 1982 Jun 1;155(6):1665–1678. doi: 10.1084/jem.155.6.1665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jyonouchi H., Kincade P. W. Precocious and enhanced functional maturation of B lineage cells in New Zealand Black mice during embryonic development. J Exp Med. 1984 Apr 1;159(4):1277–1282. doi: 10.1084/jem.159.4.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kincade P. W. Experimental models for understanding B lymphocyte formation. Adv Immunol. 1987;41:181–267. doi: 10.1016/s0065-2776(08)60032-2. [DOI] [PubMed] [Google Scholar]
  24. Kincade P. W., Lee G., Watanabe T., Sun L., Scheid M. P. Antigens displayed on murine B lymphocyte precursors. J Immunol. 1981 Dec;127(6):2262–2268. [PubMed] [Google Scholar]
  25. Kincade P. W. Molecular interactions between stromal cells and B lymphocyte precursors. Semin Immunol. 1991 Nov;3(6):379–390. [PubMed] [Google Scholar]
  26. Kincade P. W., Ralph P., Moore M. A. Growth of B-lymphocytes clones in semisolid culture is mitogen dependent. J Exp Med. 1976 May 1;143(5):1265–1270. doi: 10.1084/jem.143.5.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Landreth K. S., Engelhard D., Beare M. H., Kincade P. W., Kapoor N., Good R. A. Regulation of human B lymphopoiesis: effect of a urinary activity associated with cyclic neutropenia. J Immunol. 1985 Apr;134(4):2305–2309. [PubMed] [Google Scholar]
  28. Landreth K. S., Kincade P. W., Lee G., Medlock E. S. Phenotypic and functional characterization of murine B lymphocyte precursors isolated from fetal and adult tissues. J Immunol. 1983 Aug;131(2):572–580. [PubMed] [Google Scholar]
  29. Landreth K. S., Narayanan R., Dorshkind K. Insulin-like growth factor-I regulates pro-B cell differentiation. Blood. 1992 Sep 1;80(5):1207–1212. [PubMed] [Google Scholar]
  30. Le Douarin N. M., Michel G., Baulieu E. E. Studies of testosterone-induced involution of the bursa of Fabricius. Dev Biol. 1980 Mar 15;75(2):288–302. doi: 10.1016/0012-1606(80)90164-5. [DOI] [PubMed] [Google Scholar]
  31. Lee G., Namen A. E., Gillis S., Ellingsworth L. R., Kincade P. W. Normal B cell precursors responsive to recombinant murine IL-7 and inhibition of IL-7 activity by transforming growth factor-beta. J Immunol. 1989 Jun 1;142(11):3875–3883. [PubMed] [Google Scholar]
  32. MEYER R. K., RAO M. A., ASPINALL R. L. Inhibition of the development of the bursa of Fabricius in the embryos of the common fowl by 19-nortestosterone. Endocrinology. 1959 Jun;64(6):890–897. doi: 10.1210/endo-64-6-890. [DOI] [PubMed] [Google Scholar]
  33. MUND A., SIMSON J., ROTHFIELD N. Effect of pregnancy on course of systemic lupus erythematosus. JAMA. 1963 Mar 16;183:917–920. doi: 10.1001/jama.1963.03700110049009. [DOI] [PubMed] [Google Scholar]
  34. McMurray R., Keisler D., Kanuckel K., Izui S., Walker S. E. Prolactin influences autoimmune disease activity in the female B/W mouse. J Immunol. 1991 Dec 1;147(11):3780–3787. [PubMed] [Google Scholar]
  35. Mountz J. Animal models of systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol. 1990 Oct;2(5):740–748. doi: 10.1097/00002281-199002050-00010. [DOI] [PubMed] [Google Scholar]
  36. Murphy W. J., Durum S. K., Anver M. R., Longo D. L. Immunologic and hematologic effects of neuroendocrine hormones. Studies on DW/J dwarf mice. J Immunol. 1992 Jun 15;148(12):3799–3805. [PubMed] [Google Scholar]
  37. Norton J. M., Wira C. R. Dose-related effects of the sex hormones and cortisol on the growth of the bursa of Fabricius in chick embryos. J Steroid Biochem. 1977 Sep;8(9):985–987. doi: 10.1016/0022-4731(77)90197-2. [DOI] [PubMed] [Google Scholar]
  38. Novotny E. A., Raveche E. S., Sharrow S., Ottinger M., Steinberg A. D. Analysis of thymocyte subpopulations following treatment with sex hormones. Clin Immunol Immunopathol. 1983 Aug;28(2):205–217. doi: 10.1016/0090-1229(83)90155-1. [DOI] [PubMed] [Google Scholar]
  39. Ogawa M., Matsuzaki Y., Nishikawa S., Hayashi S., Kunisada T., Sudo T., Kina T., Nakauchi H., Nishikawa S. Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med. 1991 Jul 1;174(1):63–71. doi: 10.1084/jem.174.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Okuyama R., Abo T., Seki S., Ohteki T., Sugiura K., Kusumi A., Kumagai K. Estrogen administration activates extrathymic T cell differentiation in the liver. J Exp Med. 1992 Mar 1;175(3):661–669. doi: 10.1084/jem.175.3.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Opstelten D., Osmond D. G. Regulation of pre-B cell proliferation in bone marrow: immunofluorescence stathmokinetic studies of cytoplasmic mu chain-bearing cells in anti-IgM-treated mice, hematologically deficient mutant mice and mice given sheep red blood cells. Eur J Immunol. 1985 Jun;15(6):599–605. doi: 10.1002/eji.1830150613. [DOI] [PubMed] [Google Scholar]
  42. Osmond D. G. B cell development in the bone marrow. Semin Immunol. 1990 May;2(3):173–180. [PubMed] [Google Scholar]
  43. Osmond D. G., Kim N., Manoukian R., Phillips R. A., Rico-Vargas S. A., Jacobsen K. Dynamics and localization of early B-lymphocyte precursor cells (pro-B cells) in the bone marrow of scid mice. Blood. 1992 Apr 1;79(7):1695–1703. [PubMed] [Google Scholar]
  44. Osmond D. G., Priddle S., Rico-Vargas S. Proliferation of B cell precursors in bone marrow of pristane-conditioned and malaria-infected mice: implications for B cell oncogenesis. Curr Top Microbiol Immunol. 1990;166:149–157. doi: 10.1007/978-3-642-75889-8_19. [DOI] [PubMed] [Google Scholar]
  45. Osmond D. G. The turnover of B-cell populations. Immunol Today. 1993 Jan;14(1):34–37. doi: 10.1016/0167-5699(93)90322-C. [DOI] [PubMed] [Google Scholar]
  46. Park Y. H., Osmond D. G. Dynamics of early B lymphocyte precursor cells in mouse bone marrow: proliferation of cells containing terminal deoxynucleotidyl transferase. Eur J Immunol. 1989 Nov;19(11):2139–2144. doi: 10.1002/eji.1830191125. [DOI] [PubMed] [Google Scholar]
  47. Park Y. H., Osmond D. G. Phenotype and proliferation of early B lymphocyte precursor cells in mouse bone marrow. J Exp Med. 1987 Feb 1;165(2):444–458. doi: 10.1084/jem.165.2.444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Phuc L. H., Papiernik M., Berrih S., Duval D. Thymic involution in pregnant mice. I. Characterization of the remaining thymocyte subpopulations. Clin Exp Immunol. 1981 May;44(2):247–252. [PMC free article] [PubMed] [Google Scholar]
  49. Pietrangeli C. E., Osmond D. G. Regulation of B-lymphocyte production in the bone marrow: role of macrophages and the spleen in mediating responses to exogenous agents. Cell Immunol. 1985 Aug;94(1):147–158. doi: 10.1016/0008-8749(85)90092-9. [DOI] [PubMed] [Google Scholar]
  50. Pope R. M. Immunoregulatory mechanisms present in the maternal circulation during pregnancy. Baillieres Clin Rheumatol. 1990 Apr;4(1):33–52. doi: 10.1016/s0950-3579(05)80242-0. [DOI] [PubMed] [Google Scholar]
  51. Rodriguez-Tarduchy G., Collins M. K., García I., López-Rivas A. Insulin-like growth factor-I inhibits apoptosis in IL-3-dependent hemopoietic cells. J Immunol. 1992 Jul 15;149(2):535–540. [PubMed] [Google Scholar]
  52. Russell D. H., Mills K. T., Talamantes F. J., Bern H. A. Neonatal administration of prolactin antiserum alters the developmental pattern of T- and B-lymphocytes in the thymus and spleen of BALB/c female mice. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7404–7407. doi: 10.1073/pnas.85.19.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Screpanti I., Meco D., Morrone S., Gulino A., Mathieson B. J., Frati L. In vivo modulation of the distribution of thymocyte subsets: effects of estrogen on the expression of different T cell receptor V beta gene families in CD4-, CD8- thymocytes. Cell Immunol. 1991 May;134(2):414–426. doi: 10.1016/0008-8749(91)90314-2. [DOI] [PubMed] [Google Scholar]
  54. Screpanti I., Morrone S., Meco D., Santoni A., Gulino A., Paolini R., Crisanti A., Mathieson B. J., Frati L. Steroid sensitivity of thymocyte subpopulations during intrathymic differentiation. Effects of 17 beta-estradiol and dexamethasone on subsets expressing T cell antigen receptor or IL-2 receptor. J Immunol. 1989 May 15;142(10):3378–3383. [PubMed] [Google Scholar]
  55. Strasser A., Rolink A., Melchers F. One synchronous wave of B cell development in mouse fetal liver changes at day 16 of gestation from dependence to independence of a stromal cell environment. J Exp Med. 1989 Dec 1;170(6):1973–1986. doi: 10.1084/jem.170.6.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sundblad A., Marcos M., Huetz F., Freitas A., Heusser C., Portnoï D., Coutinho A. Normal serum immunoglobulins influence the numbers of bone marrow pre-B and B cells. Eur J Immunol. 1991 May;21(5):1155–1161. doi: 10.1002/eji.1830210510. [DOI] [PubMed] [Google Scholar]
  57. Thompson E. A., Jr The effects of estradiol upon the thymus of the sexually immature female mouse. J Steroid Biochem. 1981 Feb;14(2):167–174. doi: 10.1016/0022-4731(81)90170-9. [DOI] [PubMed] [Google Scholar]
  58. Xenocostas A., Osmond D. G., Lapp W. S. The effect of the graft-versus-host reaction on B lymphocyte production in bone marrow of mice. Depressed genesis of early progenitors prior to mu heavy chain expression. Transplantation. 1991 May;51(5):1089–1096. doi: 10.1097/00007890-199105000-00031. [DOI] [PubMed] [Google Scholar]

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