Human splenic IgM immunoglobulin transcripts are mutated at high frequency

Insel, Richard A.; Varade, William S.; Marin, Elides

doi:10.1016/0161-5890(94)90116-3

Cited by 21 publications

(12 citation statements)

References 48 publications

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“…Evidence supporting these conclusions was provided by studies that detected mutated Ig transcripts in human spleen (29) (Fig. 1a), PB (30), and tonsil (11), albeit to a lower extent than IgG ϩ B cells.…”

Section: Igdmentioning

confidence: 55%

Human IgM+CD27+ B Cells: Memory B Cells or “Memory” B Cells?

Tangye

Good

2007

The Journal of Immunology

216

200

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Memory B cells are generated in germinal centers (GC) and contribute to serological immunity by rapidly differentiating into plasma cells. Human memory B cells can be identified by the expression of CD27. These cells exhibit more rapid responses than naive (CD27−) B cells following stimulation in vitro, consistent with the heightened kinetics of secondary responses in vivo. CD27+ B cells express mutated Ig V region genes; however a significant proportion continue to express IgM, suggesting the existence of IgM+ memory B cells. The observation that mutated IgM+CD27+ B cells are generated in humans who cannot form GC led to the conclusions that these cells are generated independently of GC and thus are not memory cells and that they mediate responses to T cell-independent Ag. Although some studies support the idea that IgM+CD27+ B cells participate in T cell-independent responses, many others do not. In this review we will provide alternate interpretations of the biology of IgM+CD27+ B cells and propose that they are indeed memory cells.

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Section: Igdmentioning

confidence: 55%

Human IgM+CD27+ B Cells: Memory B Cells or “Memory” B Cells?

Tangye

Good

2007

The Journal of Immunology

216

200

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“…van Es et al, Insel et al and Pascual et al [15][16][17] have demonstrated unequivocally that m-chainassociated V H 6 can be mutated. van Es et al found mutation rates in adult IgM-associated V H 6 averaging 10 mutations per clone [15], while Pascual et al [17] found on average 5 .…”

Section: Discussionmentioning

confidence: 97%

Somatic hypermutation of immunoglobulin genes in human neonates

Ridings

Nicholson

Goldsworthy³

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThe antibody response in the young infant is limited in several ways; in particular, responses generally are of low affinity and restricted to IgM. This raises the question whether the affinity maturation process, consisting of somatic mutation of immunoglobulin genes coupled with selection of high-affinity variants, is operative in the neonate. Re-arranged V H 6 genes were amplified by polymerase chain reaction (PCR) from cord blood and from peripheral blood of infants. Heteroduplex analysis detected mutation in only 2/18 cord blood samples, while mutations were seen from about 10 days of age onwards. Cloning and sequencing of mutated neonatal V H 6 genes showed that mutated sequences contained relatively few mutations (one to three mutations per sequence) compared with published values of about 10 in adult IgM sequences. Selection was not evident in the majority of neonatal samples. Thus mutation can occur in the human neonate, but is minimal and generally not accompanied by selection. The age at which affinity maturation develops effectively is yet to be defined.

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“…Unlike G15, which is germ line, G14 and G19 have somatic mutations in their CDR1 and CDR2 sequences. Somatic mutations among V H 6-expressing B-cell transcripts have been attributed to antigen-driven mechanisms, which can occur in IgM and be CD40 ligand independent (28,57). Hence, the expressed V H 6 repertoire can be shaped by antigen selection in a T-cell-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the putative germ line genes of the MAbs, the replacement-to-silent (R/S) mutation ratios were as follows: for the G14 V H , 5:1 (five replacements [one CDR1, one CDR2, and three CDR3); for the G19 V H , 6:0 (one CDR1, two CDR2, and three CDR3); for the G14 V, 2:0 (one CDR1 and one CDR3); and for the G19 V, 5:0 (four CDR1 and one CDR3). The R/S ratios in the CDRs indicate that the G14 and G19 somatic mutations were likely to have been selected by antigen (28). Comparison of the CDR1 and CDR2 sequences of the MAbs to previously reported human and murine IgMs to GXM are shown in Table 2.…”

Section: Mabs and Mab Gene Usementioning

confidence: 99%

Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies toCryptococcus neoformansGlucuronoxylomannan Manifest Different Specificities and Gene Use Profiles

Maitta¹,

Datta²,

Chang³

et al. 2004

Infect Immun

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The features of protective murine antibodies to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been rigorously investigated; however, the characteristics of protective human antibodies to GXM have not been defined. We produced monoclonal antibodies (MAbs) from XenoMouse mice (transgenic mice that express human immunoglobulin M [IgM], IgG2, and ) which were immunized with a C. neoformans serotype D strain 24067 GXM-diphtheria toxoid conjugate. This study reports the specificity and efficacy of three human IgM MAbs, G14, G15, and G19, generated from these mice. Each MAb was specific for GXM, but G14 and G19 had different specificity based on their binding to serotype A strain H99 and SB4 GXMs, to which G15 did not bind. Nucleic acid sequence analysis revealed that G15 uses V H 3-64 in the germ line configuration. G14 and G19 use V H 6-1, which has somatic mutations. All of the MAbs use V DPK22/A27. Studies of MAb efficacy in BALB/c mice showed that administration of 0.1 mg, but not 1 or 0.01 mg, of G15 prolonged survival against lethal C. neoformans strain 24067 challenge, whereas G14 and G19 were not protective at any dose. This panel of MAbs illustrates that serotype D GXM has epitopes that elicit human antibodies that can be either protective or nonprotective. Our findings suggest that V H gene use may influence GXM specificity and efficacy, and they provide insights into the possible contribution that V H gene use may have in resistance and susceptibility to cryptococcosis.

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Human splenic IgM immunoglobulin transcripts are mutated at high frequency

Cited by 21 publications

References 48 publications

Human IgM+CD27+ B Cells: Memory B Cells or “Memory” B Cells?

Human IgM+CD27+ B Cells: Memory B Cells or “Memory” B Cells?

Somatic hypermutation of immunoglobulin genes in human neonates

Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies toCryptococcus neoformansGlucuronoxylomannan Manifest Different Specificities and Gene Use Profiles

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