The development of human B lymphocytes can be charted with the detection of pro-(CD24+/surface IgM-) and pre-B cells (cytoplasmic IgM+/surface IgM-) in the fetal liver and omentum as early as 8 weeks of gestation (Hardy 2003; Holladay and Smialowicz 2000; Holt and Jones 2000). These cells in the liver express CD20 but not CD21 or CD22. Assays for N region addition indicate that early B cells lack terminal deoxynucleotide transferase (TdT) until the 8th or 9th week of gestation (Hardy 2003). Surface IgM becomes apparent on liver B cells by 10 to 12 weeks, and surface IgD can be detected from 13 weeks of gestation. B cells can be found in the spleen between 13 to 23 weeks of gestation; these cells strongly express IgM on their cell surface. Likewise, B cells can be detected in the LN by IgM+ staining from 16 to 17 weeks of gestation (Holt and Jones 2000). B cells positive for CD19, CD20, CD21, CD22, HLA-DR, IgM, and IgD can be detected in the peripheral circulation as early as 12 weeks of gestation (Bofill et al. 1985; Holt and Jones 2000). A higher percentage of fetal B cells express CD19 compared to adult B cells (Berry et al. 1992); CD20 expression by these CD19+ B cells was not significantly different in the two populations (De Waele et al. 1988). Interestingly, the CD19+ CD20+ B cell population declines in the fetus during the period in which fetal circulation of maternally derived IgG dramatically increases. Maternal IgG at 22 weeks of gestation rises from 10 to 20% of adult levels to 100% of adult levels by 26 weeks of gestation (Gitlin and Biasucci 1969).

The cytokine requirements for human B cell maturation continue to be elucidated. Surprisingly, B-precursor growth in humans is not dependent on IL-7, although B cell formation in adult murine bone marrow is completely dependent on this cytokine (Carvalho et al. 2001; Pribyl and Lebien 1996). In addition, the lack of cytokine common gamma chain (gc) has been shown to block B-cell development in mice but, in humans, the blockage is of T-cell development (Gougeon et al. 1990;

Noguchi et al. 1993). Clear differences exist in cytokine dependency between mouse and human lymphopoiesis (Hardy 2003).

CD5+ B cells can be found in both the human peritoneal cavity and pleural cavity at 15 weeks of gestation (Namikawa et al. 1986). CD5+ B cells are largely T-independent, and they produce polyreactive antibodies that may play an important role in the primary immune response of newborns. Fetal circulation has been reported to have a higher percentage of CD5+ B cells than adult circulation (Bofill et al. 1985; Hao and Rajewsky 2001; Tucci et al. 1991). Indeed, the CD5 marker has been reported to be on the majority of B cells in fetal LN, spleen, and liver (Hannet et al. 1992).

T-dependent B cell responses lag behind CD5+ B cell production. Fetal LN lack germinal center B cells, presumably due to a lack of antigen. Primary nodule development in fetal LN at week 17 precedes development of primary nodules in the spleen at 24 weeks of gestation. B cells do not become abundant in the bone marrow until 16-20 weeks of gestation (Holt and Jones 2000). Although the bone marrow is the predominant site for B lymphopoiesis in adults (Kane et al. 1999; Landreth 1993), the liver and spleen are major sites in the fetus (Cooper 1981; Hardy 2003).

B cells bearing surface immunoglobulin of all classes have been reported to reach adult levels by 14 to 15 weeks of gestation (Anderson et al. 1981). However, by parturition, no IgG- or IgA-producing cells can be identified (Holladay and Smialowicz 2000). Early IgG and IgM synthesis occurs in the spleen with large amounts of both antibodies being produced by the spleen as early as 10 weeks of gestation. Maximal levels are reached by 17 to 18 weeks of gestation (Holt and Jones 2000). IgE synthesis occurs at 11 weeks of gestation in fetal liver and lung, and by 21 weeks in the spleen (Miller et al. 1973).

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