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PubMed2001

Resistance to CD95-mediated apoptosis in breast cancer is not due to somatic mutation of the CD95 gene.

Resistance to CD95 (Apo-1/Fas)-mediated apoptosis is a typical feature of breast cancer cells. Recent studies identified deleterious mutations of the CD95 gene not only in a variety of B cell lymphomas but also in a number of solid tumor entities. Therefore, we amplified and sequenced selected regions of the CD95 gene from 48 breast cancer cases and 10 cell lines but no mutation was found. In the presence of both polymorphic alleles, loss of heterozygosity was excluded in 27 informative cases. We conclude, that relevant somatic mutations of the CD95 gene occur, if at all, at a low frequency and are not the primary cause for resistance to CD95-mediated apoptosis in breast cancer.

Apoptosis↗

PubMed2002

Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors.

Lysyl oxidase (LOX), a copper-dependent amine oxidase, has been implicated in tumor suppression and cell growth regulation. The chromosomal locus of LOX, 5q23, is affected by loss of heterozygosity (LOH) in colon cancer, suggesting that the LOX gene could be affected by LOH and consequently, loss or reduction of LOX function contribute to the tumorigenic process. Identification of microsatellite markers within the LOX locus has allowed us to map the LOX gene within the 5q23.1 region. Analysis of this locus and flanking loci in matched tumor and blood DNA samples from a panel of colorectal cancer patients, demonstrated that 38% (16/42) of informative samples were affected by LOH or allelic imbalance. Furthermore, 75% (6/8) of these tumor samples were shown to have significantly reduced LOX mRNA levels. Similar reduction in LOX levels were detected in a panel of matched normal colon and colon tumor samples. Tumor samples demonstrating LOH by RFLP, were subject to mutational analysis, including RT-PCR, exonic deletion detection by PCR, cDNA and genomic DNA sequencing, and were found to have a spectrum of alterations and mutations affecting the LOX gene. These results confirm that loss or reduction of LOX function during tumor development is a direct consequence of somatic mutations and is associated with colon tumor pathogenesis.

Adenocarcinoma↗

PubMed1990

Somatic mutations in antibodies expressed by germinal centre B cells early after primary immunization.

We have studied the maturation of the immune response by looking at the generation of antibody diversity in germinal centre B cells. Mice were immunized with the antigen 2-phenyloxazolone. Germinal centre B cells, defined by their strong binding to peanut agglutinin (PNA(hi], were sorted from the spleen and fused. Ten days after immunization high numbers of antigen specific hybridoma lines were obtained from the PNA(hi) subset of B cells, suggesting that the small fraction of B cells which are PNA(hi) harbour the antigen activated population. The majority of the day 10 sequences from PNA(hi) cells were shown to be mutated. However, in contrast to results from later stages of the immune response, most of the mutations found were silent. The preferential expansion of B cell clones expressing the mutations characteristic of the mature response was not observed at this stage. Among these hybridoma lines was at least one which, apparently through somatic mutation, had lost the ability to bind antigen. We conclude that in the micro-environment of the germinal centre the B cell repertoire is diversified by hypermutation.

Animals↗

PubMed2000

Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas.

B cell diffuse large cell lymphoma (B-DLCL) is a heterogeneous group of tumors, based on significant variations in morphology, clinical presentation, and response to treatment. Gene expression profiling has revealed two distinct tumor subtypes of B-DLCL: germinal center B cell-like DLCL and activated B cell-like DLCL. In a separate study, we determined that B-DLCL can also be subdivided into two groups based on the presence or absence of ongoing Ig gene hypermutation. Here, we evaluated the correlation between these B-DLCL subtypes established by the two different methods. Fourteen primary B-DLCL cases were studied by gene expression profiling using DNA microarrays and for the presence of ongoing mutations in their Ig heavy chain gene. All seven cases classified as germinal center B cell-like DLCL by gene expression showed the presence of ongoing mutations in the Ig genes. Five of the seven cases classified by gene expression as activated B cell-like DLCL had no ongoing somatic mutations, whereas, in the remaining two cases, a single point mutation was observed in only 2 of 15 and 21 examined molecular clones of variable heavy (V(H)) chain gene, respectively. These two cases were distantly related to the rest of the activated B cell-like DLCL tumors by gene expression. Our findings validate the concept that lymphoid malignancies are derived from cells at discrete stages of normal lymphocyte maturation and that the malignant cells retain the genetic program of those normal cells.

Biopsy↗

PubMed1994

Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid.

It has recently been shown that somatic and germ line mutations of the TSH receptor gene cause autonomous hyperfunctioning thyroid adenomas and nonautoimmune toxic thyroid hyperplasia by constitutive activation of the TSH receptor. A "saturated" map of these mutations is a prerequisite for a systematic screening for these clinically important mutations. In this context, it is also of interest to determine whether different amino acid substitutions at the same residue cause constitutive activation of the TSH receptor, as suggested by site-directed mutagenesis of the alpha 1 beta-adrenergic receptor. We, therefore, screened further hyperfunctioning autonomous adenomas of the thyroid for constitutively activating mutations. We identified two new somatic mutations, changing alanine in position 623 to valine (A623V) and threonine in position 632 to isoleucine (T632I). Both mutations constitutively activated cAMP when transiently expressed in COS cells. Together with neighboring mutations, the T632I mutation demonstrates the importance of transmembrane domain VI for the activation of the TSH receptor and characterizes it as a hot spot for constitutively activating mutations. The previously identified A623I and the newly identified A623V mutations demonstrate that several amino acid substitutions at the same residue can cause constitutive activation of the TSH receptor.

Adenoma↗

PubMed1999

Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. Genes Chromosomes Cancer 25:75-81, 1999.

Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan K, Fan YW, Chan ASY, Leung SY. 1999. Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. Genes Chromosomes Cancer 25:75-81, 1999. It has come to our attention that the three patients described in the article above, were also included in a report by Leung et al., American Journal of Pathology, 153:1181-1189, 1998. Reference to the American Journal of Pathology article was inadvertently omitted

Journal Article↗

PubMed2005

A comparison of somatic mutational spectra in healthy study populations from Russia, Sweden and USA.

A comparison of mutation spectra at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene of peripheral blood T-lymphocytes may provide an insight into the aetiology of somatic mutation contributing to carcinogenesis and other diseases. To increase the knowledge of mutation spectra in healthy people, we have analysed HPRT mutant T-cells of 50 healthy Russians originally recruited as controls in a study involving Chernobyl clean-up workers [I.M. Jones, H.Galick, P.Kato et al. (2002) Radiat. Res., 158, 424-442]. Reverse transcriptase-polymerase chain reactions and DNA sequencing identified 161 independent mutations among 176 thioguanine-resistant mutants. Forty mutations affected splicing mechanisms and 27 deletions or insertions of 1-60 nt were identified. Ninety-four single base substitutions were identified, including 62 different mutations at 55 different nucleotide positions, of which 19 had not been reported previously in human T-cells. Comparison of this base substitution spectrum with mutation spectra in a USA [K.J.Burkhart-Schultz, C.L. Thompson and I.M. Jones (1996) Carcinogenesis, 17, 1871-1883] and two Swedish populations [A.Podlutsky, A.-M.Osterholm, S.-M.Hou, A. Hofmaier and B. Lambert (1998) Carcinogenesis, 19, 557-566; A.Podlutsky, S.M.Hou, F.Nyberg, G. Pershagen and B. Lambert (1999) Mutat. Res., 431, 325-39] revealed similarity in the type, frequency and distribution of mutations in the four spectra, consistent with aetiologies inherent in human metabolism. There were 15-19 identical mutations in the three pairwise comparisons of Russian with USA and Swedish spectra. Intriguingly, there were 21 mutations unique to the Russian spectrum, and comparison by the Monte Carlo method of W.T. Adams and T.R. Skopek [(1987) J. Mol. Biol., 194, 391-396] indicated that the Russian spectrum was different from both Swedish spectra (P = 0.007, 0.002), but not different from the USA spectrum (P = 0.07) when Bonferroni correction for multiple comparisons was made (P < 0.008 required for significance). Age and smoking did not account for these differences. Other factors causing mutational differences need to be explored.

Adult↗

PubMed1998

Independent occurrence of somatic mutations in mitochondrial DNA of human skin from subjects of various ages.

The incidence (frequency of occurrence) and abundance (percentage of mutant out of total mtDNA population) of two different somatic mtDNA mutations in human skin were investigated in 44 subjects ranging from 19 to 87 years of age. Using quantitative allele-specific polymerase chain reaction (AS-PCR) to analyse the A-->G base substitution at nucleotide 3243, 50% of the samples showed detectable levels of that particular mutation, with abundances ranging from 0.01% to 0.12%. In the same set of skin samples, the overall incidence of the 4977 bp "common" deletion was also approximately 50%. Where detected, the abundance of this deletion ranged from 0.0002% to 0.1%. Comparative analyses of the incidence and abundance of these two mutations, collectively and in individual skin samples, led to these two conclusions: (1) there is independent occurrence of these two mtDNA mutations in human skin, and (2) whereas the 4977 bp deletion shows an age-associated accumulation in human skin, no age association is apparent for the 3243 A-->G base substitution. Furthermore, in general, there is a much lower incidence of somatic mutations in mtDNA of human skin as compared to that in postmitotic tissues such as skeletal muscle.

Adult↗

PubMed1977

Mutagenic effectiveness and efficiency of sodium azide versus ethyl methanesulfonate in maize: induction of somatic mutations at the yg2 locus by treatment of seeds differing in metabolic state and cell population.

This study was conducted to compare the effectiveness and efficiency of sodium azide tNaN3) and ethyl methanesulfonate (EMS) for inducing somatic mutations at the yg2 locus in maize seeds of two different metabolic states and cell populations. Dormant or presoaked (72 h at 20 degrees C) seeds heterozygous for yg2 locus were treated with different concentrations of either EMS or NaN3. The cell populations with respect to the percentage of cells in G1, S, G2, and M were also determined for seeds of the two metabolic states. Dormant seeds possessed a higher percentage of cells in G1 and the presoaked seeds a higher percentage of cells in S, G2, and M. The frequency of yg2 sectors in leaves 4 and 5 increased with increasing concentration of both mutagens in both dormant and presoaked seeds. Both mutagens were more effective and efficient in the presoaked seeds. NaN3 was more effective than EMS in terms of number of sectors induced per unit of dose. However, EMS was more efficient as determined by sectors induced per unit of seedling injury and clearly had the ability to induce much higher sector frequencies (more than 10 times greater) than NaN3. The low ability of NaN3 (compared to EMS) to induce mutant sectors may be related to the cells not being treated at the optimum time during the cell cycle, but it is more likely due to its low effectiveness for inducing chromosome aberrations.

Azides↗

PubMed2006

Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs.

Mitochondrial defects have long been suspected to play an important role in the development of cancer. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations positively contribute to the development of cancer remained unclear. To clarify the role of mutant mtDNA excluding effects by the nuclear background, we focus on a method of transmitochondrial cybrids. Tumors were formed by transplanting cybrids with or without mutant mtDNA into nude mice and compared each size, revealing that mutant cybrids enhanced tumorigenesis. Next, we discuss a method for excluding the possibility of secondary nuclear mutations that may affect tumorigenesis. Mitochondrial genes that had been converted from mitochondrial to nuclear codons and equipped with a mitochondrial-targeting sequence were introduced into the nucleus of mutant cybrids. The gene products complemented the dysfunction, and reduced the promotion of tumors. By these methods, we concluded that mutant mitochondria positively and directly contribute to tumorigenesis. Since apoptosis occurred less frequently in the mutant versus wild-type cybrids in tumors, pathogenic mtDNA mutations contribute to the promotion of tumors by preventing apoptosis. Finally, we discuss the role of mutant mtDNA in conferring tolerance against anticancer drugs.

Animals↗

PubMed2001

Differences in susceptibility to colonic stem cell somatic mutation in three strains of mice.

Different species and different strains of animals commonly show very different sensitivities to carcinogenic regimes, which are often unexplained. A major possible contributory factor is variation in susceptibility to mutation, but this has not been directly demonstrated. This study therefore quantified the colonic stem cell mutation frequency in three strains of mice using two carcinogens. Stem cell mutations were identified using loss of function of glucose 6-phosphate dehydrogenase (G6PD) in individual crypts, a technique validated by several previous studies. The carcinogens dimethylhydrazine (DMH) and ethyl nitrosurea (ENU) were given to Balb/C, C57BL/6J, and C3H mice. In response to DMH, Balb/C mice were most susceptible, with approximately double the stem cell mutation frequency found in C3H and more than ten-fold that found in C57BL/6J (3.3+/-0.71 vs. 1.5+/-0.52 vs. 0.28+/-0.8x10(-4)). In response to ENU, Balb/C mice and C3H mice were equally susceptible, showing a stem cell mutation frequency approximately twice that of C57BL/6J (3.1+/-0.4 vs. 3.1+/-0.65 vs. 1.63+/-0.28x10(-4)). The observed differences among the strains with respect to somatic mutation following DMH treatment are likely to be due to the previously documented differences in metabolic conversion to the active metabolite. However, as ENU is a directly acting, rapidly inactivated mutagen, strain differences in response to ENU are unlikely to be due to strain-dependent metabolism of the mutagen and are likely to reflect differences in DNA repair efficiency, or possibly in stem cell kinetics among the strains studied. Susceptibility to the induction of colonic stem cell mutation is an important factor in susceptibility to carcinogens, whether due to differences in DNA repair or to other factors. Direct quantification of stem cell mutation frequency allows the separate identification of this component of the carcinogenic cascade and shows that it can make a major contribution to the differing susceptibility of different mouse strains.

1,2-Dimethylhydrazine↗

PubMed1995

Human aging is associated with stochastic somatic mutations of mitochondrial DNA.

Deletions and point mutations of mitochondrial DNA (mtDNA), which are characteristic of various human mitochondrial diseases, have been identified mainly in postmitotic tissues like brain, heart and skeletal muscle of healthy humans of advanced age but not in young people. An exponential increase with age was described for deletions of mtDNA. This paper reviews the molecular basis and experimental results on mutations of mtDNA in patients with mitochondrial diseases and in aged individuals. In addition new data on the exponential increase of point mutations of mtDNA, characteristic for MERRF and MELAS disease, in extraocular muscle from elderly humans are shown. Finally the 'mitochondrial hypothesis on aging' based on stochastic somatic mutations of mtDNA is presented.

Aging↗

PubMed1992

Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster.

Sixteen pyrrolizidine alkaloids (PAs) were examined for their genotoxic potency in the wing spot test of Drosophila melanogaster following oral application. This in vivo assay tests for the induction of somatic mutation and mitotic recombination in cells of the developing wing primordia. All PAs tested except the C9-monoester supinine were clearly genotoxic. Depending on their chemical structure, however, genotoxicity of the PAs varied widely in a range encompassing about three orders of magnitude. In general, macrocyclic diester-type PAs were the most and 7-hydroxy C9-monoester types the least genotoxic representatives studied, while open diesters were intermediate in this respect. Stereoisomeric PAs mostly showed similar, but sometimes also clearly unequal genotoxicity. An increasing number of hydroxy groups in the PA molecule seemed to reduce its genotoxic potency. With respect to the structure/activity relationships, there appears to be a good correlation between hepatotoxicity of PAs in experimental rodents and genotoxicity in the wing spot test of Drosophila. This suggests that PAs are bioactivated along similar pathways in the mammalian liver and in the somatic cells of Drosophila. The genotoxic potential of PAs in the Drosophila wing spot test and their carcinogenic potential in mammals also seem correlated, although the information in the literature on carcinogenicity of the non-macrocyclic PAs with moderate to low genotoxic potency is concededly limited. Comparisons with other genotoxicity tests suggest that the wing spot test is particularly suitable for genotoxins like PAs, on the one hand because of the versatile metabolic bioactivation system of Drosophila and on the other hand also because of its excellent sensitivity to the crosslinking agents among the genotoxins.

Animals↗

PubMed1993

An analysis of idiotype expression in a high-affinity, somatically mutated variant of a germline-encoded anti-p-azobenzenearsonate antibody.

Using two polyclonal (rabbit) and two monoclonal anti-idiotype (anti-Id) reagents, we investigated structural correlates of the Id of mAb 36-71, a somatically mutated member of the CRIA Id family that has an exceptionally high affinity for the p-azobenzenearsonate (Ars) hapten. The two monoclonal anti-Ids reacted principally with the L chain of 36-71. The polyclonal anti-Ids interacted with both the H and L chain. The amino acid sequences of the VH and VL regions of 36-71 differ in eight and 11 positions respectively from those of the anti-Ars mAb 36-65, an unmutated prototype of the CRIA family. In the presence of 36-71L only three substitutions in 36-65 VH, introduced by mutagenesis, sufficed to restore full expression of the 36-71 Id. The same three substitutions had previously been shown to increase the affinity of 36-65 by a factor of 200, to a level equivalent to that of 36-71. X-ray crystallography had indicated that two of these substitutions introduce conformational changes consistent with the increase in affinity. We propose that these conformational changes may also account for the critical role of the three amino acids in Id expression. We also found that 36-65 is a very poor inhibitor of the interaction of 36-71 with its polyclonal anti-Ids, despite identity of the hapten-contacting residues in the two mAbs and evidence (from hapten inhibition) that the hapten-binding region is part of an important Id. Again, a difference in conformation at the binding site of the two mAbs could account for these observations.

Amino Acid Sequence↗

PubMed1996

Induction of somatic mutation and recombination by four inhibitors of eukaryotic topoisomerases assayed in the wing spot test of Drosophila melanogaster.

Four inhibitors of eukaryotic topoisomerases were investigated for genotoxic effects in the wing spot test of Drosophila melanogaster. As a somatic mutation and recombination test (SMART) this assay assesses mitotic recombination and mutational events of various kinds. We studied camptothecin as a topoisomerase I inhibitor, as well as ellipticine as an intercalating inhibitor and teniposide and etoposide as two non-intercalating inhibitors of topoisomerase II. Wing spots were induced in flies trans-heterozygous for the recessive wing cell markers multiple wing hairs (mwh) and flare (flr3) as well as in flies heterozygous for mwh and the multiply inverted TM3 balancer chromosome. All four compounds proved significantly genotoxic in this test. The spot induction frequencies formally standardized to the millimolar unit of exposure dose decreased in the order camptothecin > teniposide > ellipticine greater, similar etoposide in the mwh/flr3 inversion-free genotype. In the mwh/TM3 genotype, in which mitotic crossing over is suppressed because of the inversion-heterozygosity, the observed spot frequencies were considerably reduced, but to different extents. In this genotype, spot induction by ellipticine was not statistically significant, and it was determined that >99% of the spots are due to mitotic recombination in mwh/flr3 flies. For the other compounds, spot induction in the inversion-heterozygous genotype was significant. The relative contribution of recombination to total spot induction in the inversion-free genotype was 88% for camptothecin. It was significantly lower for the two epipodophyllotoxins teniposide (71%) and etoposide (59%). Only suggestions can be proffered at present as to how these proportions could be related to the primary damage produced by the respective compounds on the chromosomes.

Animals↗

PubMed1999

Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

Loss of heterozygosity (LOH) of loci on chromosome 18q occurs in a majority of colorectal cancers. The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS). The gene product functions as a cytoplasmic mediator in the signaling pathway of transforming growth factor beta (TGF-beta). To investigate the potential role of DPC4/SMAD4 gene in colorectal cancers, we examined 73 tumors of clinical stages II or III from Japanese patients, for LOH at 18q21 and also for subtle mutations anywhere within the coding region of DPC4/SMAD4. LOH was identified in 50 (78%) of the 64 tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in seven of those tumors: two frameshift mutations, a 1-bp deletion (326 del T) in exon 8 and a 1-bp insertion (50-51 ins A) in exon 1; two nonsense mutations, Arg445Ter in exon 10 and Glu538Ter in exon 11; and three missense mutations, Asn129Lys in exon 2, Tyr95Asn in exon 2, and Asp355Glu in exon 8. Three of the seven mutations were observed in the mad homology 1 (MH1) domain encoded by exons 1 and 2. In all of the tumors carrying intragenic mutations of one allele, LOH analysis had shown that the other allele was missing. The results demonstrated that inactivation of both alleles of the DPC4/SMAD4 gene occurs in a substantial proportion of advanced colorectal cancers, and that the DPC4/SMAD4 gene probably exerts a tumor-suppressor effect for colorectal carcinogenesis that fulfills the criterion of the two-hit concept proposed by Knudson [A.G. Knudson, Hereditary cancer, oncogenes, and anti-oncogenes, Cancer Res. 45 (1985) 1437-1443.].

Alleles↗

PubMed1999

The IgG2a/IgA produced by the murine T560 B lymphoma that arose during a graft-versus-host reaction is polyreactive and somatically mutated.

In mice undergoing a graft-versus-host (GVH) reaction, donor T cells responding to the host's MHC antigens induce polyclonal activation of the host's B cells and secretion of their antibodies and autoantibodies. T560, a CD5- B lymphoma that arose in the gut-associated lymphoid tissue (GALT) of a (B10 x B10.H2aH4(b)pWts) F1 hybrid mouse that had been injected with parental B10.H2aH4b splenocytes, is of particular interest because it produces switched, heavily mutated, but, nevertheless, polyreactive immunoglobulin. T560 bears and contains IgG2a but switches to IgA spontaneously. The T560 Ig variable region is encoded by a V186.2-related VH gene, juxtaposed to DFL 16 and J(H)1, and by a Vkappa gene of the Vkappa 4/5 group juxtaposed to Jkappa1. Both VH and VK are heavily mutated. The IgA binds to polystyrene, to p-azophenyl-phosphorylcholine (PC)-conjugated keyhole limpet hemocyanin (KLH) (PC-KLH), to 2,4,6 trinitrophenylated (TNP)-KLH and to human TNF-beta but not to KLH, human TNF-alpha, or any of several other Ags tested. Hapten inhibition experiments indicate that the polystyrene, PC- and TNP-binding sites do not overlap. The switched isotypes and heavy load of somatic mutations found in the T560 IgG2a/IgA suggest that T cell-dependant somatic selection of the T560 precursor B cell may have been superimposed on polyclonal B cell activation originally associated with the GVH.

Amino Acid Sequence↗

PubMed1999

Analysis of immunoglobulin E VH transcripts in a bronchial biopsy of an asthmatic patient confirms bias towards VH5, and indicates local clonal expansion, somatic mutation and isotype switch events.

Immunoglobulin E (IgE)-dependent mechanisms play a pivotal role in mediating allergic disease. Previously, VH-Cepsilon transcripts from blood or spleen of atopic asthmatics have been analysed for VH gene usage and patterns of somatic mutation. An over-representation of the minor VH5 family has been observed, consistent with a superantigen drive. As local mucosal events in IgE production may be more significant in the disease process, we have analysed VH-Cepsilon transcripts from a bronchial biopsy of a patient with severe asthma. VH5 predominance was confirmed with 10 of 30 unique clones derived from this family. Repeated sequences, some with intraclonal variation, revealed clonal expansion and continuing mutational activity at the site. Unexpectedly, three unmutated VH-Cepsilon sequences were found, indicating that isotype switching to IgE can occur without mutation. Detection of a sister clone with extensive mutations was again consistent with local mutational activity. Evidence for local isotype switching was obtained by identification of clonally related immunoglobulin M (IgM), immunoglobulin G (IgG) and immunoglobulin E (IgE) sequences. However, in contrast to findings in blood, no IgG4 transcripts clonally related to IgE were detected, suggesting that the balance between synthesis of IgG4 and IgE may differ between systemic and local sites. These data confirm a VH5 bias in IgE, and support the concept that IgE-synthesizing B cells arise via local differentiation.

Adult↗