Showing papers by "Jo Spencer published in 2002"
TL;DR: Measurements indicated that selection of Ig genes may decrease in Peyer's patch GC but increase in splenic GC with age, and tissue‐specific differences highlight the importance of considering the activation and effector sites when studying immune senescence.
Abstract: The elderly produce increased levels of antibodies to autologous antigens and are less able to make high-affinity antibodies to foreign antigens. Ig gene hypermutation is integral to the affinity maturation process but previous studies of hypermutation with age have yielded conflicting results. The cells studied have represented post-germinal center (GC) populations and, therefore, the results may be complicated by possible differences in activation history. We studied Ig genes from GC B cells to elucidate which factors in the affinity maturation process change with age. Age-related changes in the pattern of hypermutation were seen, although the analysis of variable region heavy chain (VH) genes and their lineage trees shows that an alteration in the mechanism of somatic hypermutation is unlikely. The changes are due to founder cell effects and/or the process of selection. Striking tissue-specific differences were seen. All measurements indicated that selectionof Ig genes may decrease in Peyer's patch GC but increase in splenic GC with age. These tissue-specific differences highlight the importance of considering the activation and effector sites when studying immune senescence.
92 citations
TL;DR: It is shown that S. flexneri infection of human monocyte‐derived dendritic cells (DC) also results in rapid IpaB‐dependent death, which is likely to have adverse consequences for generation of adaptive immunity.
Abstract: Shigella flexneri infection of macrophages (MPhi) leads to activation of caspase-1 by the IpaB virulence factor, which induces rapid cell death and release of mature IL-1beta. Here we show that S. flexneri infection of human monocyte-derived dendritic cells (DC) also results in rapid IpaB-dependent death. Cytotoxicity is only partially blocked by the caspase-1 inhibitor YVAD, but completely blocked by the pan-caspase inhibitor z-VAD. Cytotoxicity is also partially blocked by glycine without affecting caspase-1-dependent IL-1beta processing, and treatment with glycine and YVAD completely blocks cytotoxicity, implying that glycine inhibits a caspase-1-independent cytotoxic mechanism. S. flexneri infection of LPS-pre-treated DC and Mphi results in comparable release of mature IL-1beta, although DC release significantly less IL-18 than MPhi. IL-1beta release from infected DC occurs within 3 h of the initial LPS pre-stimulation signal, implying that infection of DC will contribute towards induction of the early inflammatory response. The rapid death of DC during the early stages of shigellosis is likely to have adverse consequences for generation of adaptive immunity.
76 citations
TL;DR: Overall, this study suggested that human peritoneal B cell are either peripheral or mixed in origin; they are unlikely to represent an inductive compartment for the mucosal B cell system.
Abstract: The contribution of peritoneal B cells to the intestinal lamina propria plasma cell population is well documented in mice, but unknown in humans. We have analyzed immunoglobulin (Ig) genes of human peritoneal B cells, because such genes show distinctive characteristics in mucosal B cells, particularly highly mutated variable regions. Here, we report the characteristics of variable region genes used by IgM, IgA and IgG in peritoneal cells. We focused on the properties of IgV(H)4-34 to allow comparisons of like-with-like between different isotypes and cells from different immune compartments. We observed that the IgM genes were mostly unmutated, and that the mutated subset had less mutations than would be expected in a mucosal B cell population. Likewise, the IgV(H)4-34 genes used by IgA and IgG from peritoneal B cells had significantly lower numbers of mutations than observed in the mucosal counterparts. Other trends observed, while not reaching statistical significance, followed the trend of peripheral B cells. The peritoneal B cell population had more IgA1 than IgA2 sequences, and there was no dominance of J(H)4 in the IgA from peritoneum or spleen, in contrast to the mucosal sequences. Overall, this study suggested that human peritoneal B cell are either peripheral or mixed in origin; they are unlikely to represent an inductive compartment for the mucosal B cell system.
38 citations
TL;DR: The clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC suggest a peripheral response is expressed and expanded in the colonic mucosa, and it is shown that JH1 usage was characteristic of the peripheral repertoire.
Abstract: Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltrated with plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosal response which has switched to IgG or a peripheral response which may have been initiated by peripheral antigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotype switched variants in UC is not known. Aims: To investigate the clonal distribution of mucosal IgG in UC and to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. To investigate characteristics which may discriminate between the mucosal and peripheral repertoire in the normal mucosa and in UC. Patients: Blood and normal and diseased mucosa from two patients with UC were studied. Methods: Immunoglobulin gene analysis and clone specific polymerase chain reaction were used to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC. Results: The IgG response in the mucosa of UC patients included widespread clones of cells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa. Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosa and blood. This suggests that these clones home preferentially to the diseased mucosa. We showed that J H 1 usage was characteristic of the peripheral repertoire, and that examples of J H 1 usage were observed in mucosal IgG in UC. Conclusions: Overall, these data are consistent with a model of UC in which a peripheral response is expressed and expanded in the colonic mucosa.
31 citations
TL;DR: It is shown that mature, dividing B cells are present in human fetal intestine, and Ig VHDJH gene sequencing can confirm clonal identity of B cells, and local accumulation of related cells in each case is confirmed.
Abstract: B cells are present in human fetal intestine from approximately 14 weeks of gestation. Here we show that this population includes mature, dividing B cells. These are large cells with dendritic processes, resembling human thymic B cells. In addition, we observed IgM+, light chain-, and CD20- cells and local expression of V pre-B, demonstrating that the human fetal intestine is a site of B cell development. Ig V(H)DJ(H) gene sequencing can confirm clonal identity of B cells. Identification of the same IgV(H)4-34 sequence in serial sections in two fetuses confirmed local accumulation of related cells in each case. IgV(H)4-34 was also amplified from an additional two samples, and the D and J repertoire compared with a unique database of unselected V(H)4-34 genes from postnatal gut. Distinguishing characteristics of Ig lambda genes in postnatal gut were also studied in the fetus. According to these parameters, fetal and postnatal B cells are unrelated.
21 citations
TL;DR: In the human gut, IgM is encoded by mutated genes and is therefore associated with secondary immune responses, alongside IgA and IgG, and it is perhaps not surprising that it can compensate functionally in IgA deficiency.
Abstract: The relationship between mucosal IgM and IgA has recently been addressed in murine systems to investigate how IgA secreting plasma cells localise in the intestine and to determine if switching from IgM to IgA occurs in the microenvironment of the gut mucosa
The gut is the major site of antibody production in humans. The most abundant isotype produced is IgA, but the importance of IgA has been questioned. On the one hand, in IgA deficient patients, IgM can compensate functionally1,2; on the other hand, it might be argued that such flexibility is an absolute requirement because the system is indispensable.3 The relationship between IgM and IgA in humans has been studied by analysis of the immunoglobulin genes used by plasma cells. Such studies can give information on the history of the B cells that generated them because they contain a unique fingerprint acquired during B cell development that enables the identification of related cells. Investigations of human mucosal plasma cells have shown that in humans, clonally related IgM+ and IgA+ plasma cells that probably secrete antibody with the same specificity can occupy the same mucosal microenvironment.4–7 In addition, immunoglobulin genes become mutated if the cell has been selected for the production of high affinity antibody. In the human gut, IgM is encoded by mutated genes4 and is therefore associated with secondary immune responses, alongside IgA and IgG, and it is perhaps not surprising that it can compensate functionally in IgA deficiency.
In mice the situation appears to be quite …
12 citations