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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3417-3418.
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IMMUNOBIOLOGY
Comment on Weller et al, page 3647
IgM memory B cells: origin, mutation, and mobilization by polysaccharide vaccination
Alexander H. Lucas
CHILDREN'S HOSPITAL OAKLAND RESEARCH INSTITUTE
Weller and colleagues show that human peripheral blood IgM+CD27+ B lymphocytes, known as IgM memory B cells, derive from the splenic marginal zone, mutate their immunoglobulin genes in early ontogeny, and respond to polysaccharide antigen, a T-cell–independent antigenic stimulus.
In humans, B lymphocytes expressing cell surface immunoglobulin M (IgM) and CD27 comprise a significant proportion of the B-cell population in the peripheral circulation. These cells have been termed IgM memory B cells because, like conventional class-switched memory cells, they possess somatically hypermutated variable region genes and express CD27.1 The splenic marginal zone (MZ) has been implicated as a source of circulating IgM memory B cells, as their representation in the peripheral circulation is reduced in asplenic subjects, and their progressive appearance in the peripheral circulation during the first and second year of life correlates with the development of the splenic MZ.2 Weller and colleagues provide further evidence that the IgM memory population can derive from the splenic MZ. First, they show that blood IgM memory B cells phenotypically resemble splenic MZ B cells in being IgMhiIgDloCD21hiCD1chi. Second, they use gene expression profiling to show that the set of genes expressed in splenic MZ B cells closely parallels that of IgM memory peripheral B cells and differs from the set of genes expressed in naive and class-switched memory B cells. Third, using CDR-3 spectratyping, they demonstrate that a particular B-cell clone is mobilized in both splenic and blood populations following vaccination with pneumococcal and meningococcal polysaccharides. Interestingly, this clone had mutations prior to vaccination and acquired further mutations after vaccination. This result is consistent with previous studies indicating that MZ B cells participate in responses to T-cell–independent polysaccharide antigens and to encapsulated bacterial pathogens.2,3 In keeping with the findings of Kreutzmann et al,2 Weller and colleagues observed a diminution of blood IgM memory B cells in asplenic adults. However, unlike Kreutzmann et al,2 they did not observe this diminution in asplenic children, and therefore IgM memory B cells in children can be generated in extrasplenic sites.
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CD1c is strongly expressed by splenic marginal zone B cells in humans. See the complete figure in the article beginning on page 3647.
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Weller et al confirm that the immunoglobulin genes of IgM memory B cells are heavily mutated, and importantly, they show that this mutation occurs as early as 12 months of age. Previous work by Weller et al4 has shown that hyper IgM patients having defective CD40L lacked germinal centers and did not have class-switched memory B cells. Nonetheless, these patients possessed IgM memory B cells with mutated immunoglobulin variable region genes. Thus, they proposed a second pathway of B-cell hypermutation that occurs in the absence of classical cognate T-cell–B-cell interaction, and they suggested this mutation may occur as part of an intrinsic developmental pathway as is known to occur in sheep.
MZ B cells (and B1 B cells) are rapidly mobilized in response to blood-borne encapsulated bacteria,3 and Kearney and colleagues (Martin et al,3 and Lopes-Carvalho and Kearney5) have suggested that this represents an innate-like immune response capable of producing IgM antibodies at a time when the conventional adaptive response is still developing. It is intriguing to consider the possibility that in humans, 2 distinct B-cell developmental programs exist: one that relies upon antigen-driven cognate T–B-cell interactions and germinal center formation to generate a mutated, high-affinity adaptive antibody response and memory, and another that uses an antigen-independent hypermutation process to generate a prediversified set of B-cell receptors that mediate rapid innate IgM responses to bacterial and viral pathogens.
References
- Klein U, Rajewsky K, Küppers R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998;188: 1679-1689.[Abstract/Free Full Text]
- Kreutzmann S, Manuela M, Weber H, et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med. 2003;197: 939-945.[Abstract/Free Full Text]
- Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity. 2001;14: 617-629.[CrossRef][Medline]
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- Weller S, Faili A, Garcia C, et al. CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc Natl Acad Sci U S A. 2001;98: 1166-1170.[Abstract/Free Full Text]
- Lopes-Carvalho T, Kearney JF. Development and selection of marginal zone B cells. Immunol Rev. 2004;197: 192-205.[CrossRef][Medline]
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Related Article in Blood Online:
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Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire
- Sandra Weller, Moritz C. Braun, Bruce K. Tan, Andreas Rosenwald, Corinne Cordier, Mary Ellen Conley, Alessandro Plebani, Dinakhanta S. Kumararatne, Damien Bonnet, Olivier Tournilhac, Gil Tchernia, Birte Steiniger, Louis M. Staudt, Jean-Laurent Casanova, Claude-Agnès Reynaud, and Jean-Claude Weill
Blood 2004 104: 3647-3654.
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