Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Extrafollicular differentiation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2003

Germinal centers regulate human Th2 development.

In the present study we demonstrate that all CD4(+) T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-gamma, after in vitro activation. CD4(+) T cells, which express only intermediate levels of CXCR5, instead develop into IFN-gamma-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2(+) Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57(+) GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4(+) T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.

B-Lymphocyte Subsets↗
PubMed2006

Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation.

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.

Animals↗
PubMed1997

Viral superantigen drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

Mouse mammary tumor virus (MMTV[SW]) encodes a superantigen expressed by infected B cells. It evokes an antibody response specific for viral envelope protein, indicating selective activation of antigen-specific B cells. The response to MMTV(SW) in draining lymph nodes was compared with the response to haptenated chicken gamma globulin (NP-CGG) using flow cytometry and immunohistology. T cell priming occurs in both responses, with T cells proliferating in association with interdigitating dendritic cells in the T zone. T cell proliferation continues in the presence of B cells in the outer T zone, and B blasts then undergo exponential growth and differentiation into plasma cells in the medullary cords. Germinal centers develop in both responses, but those induced by MMTV(SW) appear later and are smaller. Most T cells activated in the T zone and germinal centers in the MMTV(SW) response are superantigen specific and these persist for weeks in lymph nodes draining the site MMTV(SW) injection: this contrasts with the selective loss of superantigen-specific T cells from other secondary lymphoid tissues. The results indicate that this viral superantigen, when expressed by professional antigen-presenting cells, drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

Animals↗
PubMed2002

Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals.

CD40 is essential for efficient humoral immune responses. CD40 has two cytoplasmic domains required for binding of tumor necrosis factor receptor-associated factors (TRAF). The TRAF6-binding site is within the membrane proximal cytoplasmic (Cmp) region, while a PXQXT motif in the membrane distal cytoplasmic (Cmd) region needs to engage TRAF2/3/5. To dissect CD40 signals necessary for B cell differentiation, we generated transgenic mice expressing wild-type and mutant human CD40 (hCD40) molecules in a mouse CD40-deficient (mCD40(-/-)) background. The B cell-specific expression of hCD40 in mCD40(-/-) mice resulted in T-dependent antibody responses including germinal center (GC) formation. Mutant hCD40 molecules that carry either a point mutation of the TRAF2/3/5-binding site or a deletion of the Cmd region rescued extrafollicular B cell differentiation but not GC formation. A mutant hCD40 that comprises of only the TRAF2/3/5-binding site in the cytoplasmic region also rescued low but significant titers of antigen-specific IgG1 without GC formation. These results demonstrated that two distinct signals either from the Cmp or from the Cmd region induced the extrafollicular B cell differentiation and Ig class switching; however, GC formation required both. We conclude that combinations of these two signals determine which of the extrafollicular or the follicular (GC) differentiation pathway B cells enter.

Animals↗
PubMed2001

Extrafollicular plasmablast B cells play a key role in carrying retroviral infection to peripheral organs.

B cells can either differentiate in germinal centers or in extrafollicular compartments of secondary lymphoid organs. Here we show the migration properties of B cells after differentiation in murine peripheral lymph node infected with mouse mammary tumor virus. Naive B cells become activated, infected, and carry integrated retroviral DNA sequences. After production of a retroviral superantigen, the infected B cells receive cognate T cell help and differentiate along the two main differentiation pathways analogous to classical Ag responses. The extrafollicular differentiation peaks on day 6 of mouse mammary tumor virus infection, and the follicular one becomes detectable after day 10. B cells participating in this immune response carry a retroviral DNA marker that can be detected by using semiquantitative PCR. We determined the migration patterns of B cells having taken part in the T cell-B cell interaction from the draining lymph node to different tissues. Waves of immigration and retention of infected cells in secondary lymphoid organs, mammary gland, salivary gland, skin, lung, and liver were observed correlating with the two peaks of B cell differentiation in the draining lymph node. Other organs revealed immigration of infected cells at later time points. The migration properties were correlated with a strong up-regulation of alpha(4)beta(1) integrin expression. These results show the migration properties of B cells during an immune response and demonstrate that a large proportion of extrafolliculary differentiating plasmablasts can escape local cell death and carry the retroviral infection to peripheral organs.

Animals↗
PubMed1999

Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses.

The effect of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) on the activation and differentiation of normal B cells was investigated. B cells of transgenic mice expressing LMP1 under the control of immunoglobulin promoter/enhancer displayed enhanced expression of activation antigens and spontaneously proliferated and produced antibody. Humoral immune responses of LMP1 transgenic mice in CD40-deficient or normal backgrounds revealed that LMP1 mimics CD40 signals to induce extrafollicular B cell differentiation but, unlike CD40, blocks germinal center formation. Thus, these specific properties of LMP1 may determine the site of primary B cell infection and the state of infection in the natural course of EBV infection, whereas subsequent loss of LMP1 expression may affect the site of persistent latent infection.

Animals↗
PubMed1999

B cell response after MMTV infection: extrafollicular plasmablasts represent the main infected population and can transmit viral infection.

The immune response to mouse mammary tumor virus (MMTV) relies on the presentation of an MMTV-encoded superantigen by infected B cells to superantigen-specific T cells. The initial extrafollicular B cell differentiation involved the generation of B cells expressing low levels of B220. These B220low B cells corresponded to plasmablasts that expressed high levels of CD43 and syndecan-1 and were CD62 ligand- and IgD-. Viral DNA was detected nearly exclusively in these B220low B cells by PCR, and retroviral type-A particles were observed in their cytoplasm by electron microscopy. An MMTV transmission to the offspring was also achieved after transfer of B220low CD62 ligand- CD43+ plasmablasts into noninfected females. These data suggest that B220low plasmablasts, representing the bulk of infected B cells, are capable of sustaining viral replication and may be involved in the transmission of MMTV.

Animals↗
PubMed1996

The production of immunoregulatory cytokines is localized to the extrafollicular area of human tonsils.

The localization and production at the single cell level of 19 different human cytokines, IL-1 alpha, IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF alpha, TNF beta, IFN gamma, GM-CSF, G-CSF, and TGF beta 1-3, were studied in cryopreserved tonsillar tissue using immunohistochemical staining. The cytokine producing cells, with the exception of IL-1 expressing cells, had a characteristic morphology due to the accumulation of cytokine onto the Golgi organelle. The production of each cytokine was localized to specific compartments in tonsillar tissue sections from children with tonsillar hypertrophy or recurrent tonsillitis in the resting state. Immunoregulatory cytokines such as IL-2, IL-3, IL-4, G-CSF, GM-CSF and TGF beta were produced in the extrafollicular area and entrapped on the cell membranes as well as in pudels in the extracellular matrix surrounding the producer cells. The dominating cytokines both in tissues from recurrent tonsillitis and tonsillar hypertrophy were GM-CSF, G-CSF, and TGF beta 1-3 which were synthezised predominantly in the reticular crypt site. IL-1 alpha, beta and IL-1ra, on the other hand, were localized to the surface and crypt epithelium and to scattered regions in the extrafollicular area. IL-2, IL-6, IFN gamma and IL-10 were found much more often in sections obtained from recurrent tonsillitis tissue compared with those from tonsillar hypertrophy. Reversely, an excessive production of IL-4 was noted in tonsillar hypertrophy compared with that in recurrent tonsillitis. Thus, concomitant production of multiple cytokines was evident with similarities but also differences in cytokine pattern between the two groups studied. The data suggest that T-cell mediated B-cell activation and differentiation take place in the extrafollicular area. Children with recurrent tonsillitis had a higher amount of B-cells and monocytes compared with children with tonsillar hypertrophy. However, the number of CD3, CD4, CD8 or cytoplasmic Ig-positive cells did not differ between the two groups.

Cell Movement↗
PubMed1997

The changing preference of T and B cells for partners as T-dependent antibody responses develop.

Recirculating virgin CD4+ T cells spend their life migrating between the T zones of secondary lymphoid tissues where they screen the surface of interdigitating dendritic cells. T-cell priming starts when processed peptides or superantigen associated with class II MHC molecules are recognised. Those primed T cells that remain within the lymphoid tissue move to the outer T zone, where they interact with B cells that have taken up and processed antigen. Cognate interaction between these cells initiates immunoglobulin (Ig) class switch-recombination and proliferation of both B and T cells; much of this growth occurs outside the T zones B cells migrate to follicles, where they form germinal centres, and to extrafollicular sites of B-cell growth, where they differentiate into mainly short-lived plasma cells. T cells do not move to the extrafollicular foci, but to the follicles; there they proliferate and are subsequently involved in the selection of B cells that have mutated their Ig variable-region genes. During primary antibody responses T-cell proliferation in follicles produces many times the peak number of T cells found in that site: a substantial proportion of the CD4+ memory T-cell pool may originate from growth in follicles.

Animals↗
PubMed2006

Mantle cell lymphoma with plasma cell differentiation.

The differentiation of B lymphocytes into plasma cells (PCs) is an antigen-mediated process that largely depends on the interaction between B cells and regulatory factors in their microenvironment. Long-lived PCs are derived from activated B cells in the germinal center (GC), whereas PC differentiation from naive B cells occurs in the extrafollicular areas and the PCs are short-lived. Consequently, lymphomas arising from post-GC B cells often exhibit plasmacytic differentiation, whereas lymphomas arising from naive B cells less commonly show plasmacytic differentiation. Herein, we report 2 cases of mantle cell lymphoma (MCL) with clonal PC differentiation. Both cases presented with the typical cytologic features of MCL and were characterized by a nodular and mantle-zone growth pattern. Clusters of clonal PCs with monotypic kappa light chain expression were identified in the centers of the tumor nodules and within reactive GCs. FICTION (Fluorescence immunophenotyping and Interphase Cytogenetics as a Tool for the Investigation Of Neoplasms) analysis demonstrated the characteristic t(11;14)(q13;q32) in both the MCL cells and clonal PCs, indicating that both cell types were derived from the same B-cell clone. These findings indicate that the clonal PC differentiation may occur within GCs in some cases of MCL.

Diagnosis, Differential↗
PubMedDate not supplied

[Correlations between the functional activity and proliferation of the thyroid parenchyma. The proliferative forms of the parenchyma of the thyroid].

Multiple thyroid adenomas formed by straight or coiled epithelial cords developed in experiments on adult male rats as a result of prolonged intermittent 6-MTU administration. Such epithelial cords could be sometimes observed in thyroid parenchyma regeneration after partial thyroidectomy. These cords originated from thyrocytes of the follicle epithelium. In the proliferating thyroid parenchyma DNA replication mainly terminated in endomitoses (previously reported data) which in thyrocytes of prismatic form resulted in their separation from proximal and distal daughter cells. Proximal daughter cells kept contact with the follicle lumen but distal ones lost it, hence their iodine uptake and origination weakened. Therefore, the biosynthesis of thyroglobulin decreased in cytoplasm of distal daughter cells but the formation of thyroalbumin increased. In consequence the distal daughter cells with this shift in protein biosynthesis underwent hypertrophy and further originated the proliferation of extra follicular epithelial cords. The formation of new follicles mainly took place with the differentiation of interfollicular islets separated from proliferating extrafollicular epithelial cords. Thyrotropin, the principal stimulator of hormonopoietic thyrocyte activity, did not necessarily influence the activation of thyroid parenchyma proliferative processes.

Animals↗
PubMed1993

Immunohistochemical detection of co-localizing cytokine and antibody producing cells in the extrafollicular area of human palatine tonsils.

In vitro experiments have documented the role of cytokines in the regulation of the human humoral immune response. Which cytokines are operative in vivo and in which lymphoid compartment interactions between cytokine-producing T cells and antibody-forming B cells occur is still unclear. For that reason we studied human tonsils using immunohistochemical techniques. In tissue sections from tonsils in a resting stage after recurrent tonsillitis we observed cells producing IL-1 alpha and tumour necrosis factor-alpha (TNF-alpha) which were exclusively localized in the mantle zone of the follicle and in the extrafollicular area. Furthermore, a high frequency of interferon-gamma (IFN-gamma)-producing cells was detected in the extrafollicular area, but not inside the follicles. Occasional IL-2- and IL-4-producing cells were found in the extrafollicular area. Immunohistochemical detection of antibody isotypes revealed that B cells, IgM-membrane-positive, were localized inside the follicles and mantle zones, whereas IgD-membrane-positive cells were mainly found in the mantle zones of secondary follicles. In contrast, plasma cells producing IgG1-4 and IgA1-2 were found in the extrafollicular area. No IgD and IgE antibody-forming cells were detected in tonsils, whereas IgM antibody-forming cells were detected in the extrafollicular area. The co-localization of cytokine-producing cells and antibody-forming cells in human tonsil suggests that T-B cell interactions, required for B cell differentiation and isotype switching, take place in the extrafollicular area.

Antibody-Producing Cells↗
PubMed2026

Multimodal computational framework resolves B cell maturation in autoimmunity and ageing.

Identification of the origin of pathogenic immune cells is crucial for therapeutic interventions and diagnosis but pseudotime methods struggle to trace immune cells accurately. Current trajectory inference methods for B cell development and response in health and disease either ignore or underutilize antigen receptor sequence information, limiting their ability to resolve developmental pathways, particularly for pathogenic populations. Widely used methods such as Monocle 3 reconstruct developmental paths from transcriptomic similarity alone, discarding the features from immune receptors. Dandelion has combined the immune receptor features with transcriptomics but it struggles to simulate the trajectory path of B cells. Here we present ClonoTrace, a computational framework that integrates BCR sequence features with transcriptomic trajectory inference through gated fusion of multimodal embeddings. In fetal B cell development and germinal centre development, ClonoTrace demonstrates closer concordance with the canonical reference ordering than Monocle 3 and Dandelion. Applied to systemic lupus erythematosus, ClonoTrace indicates a memory B cell extrafollicular maturation route alongside the naïve B cell route, accompanied by induction of ZEB2 with a concomitant decline of BACH2 along the trajectory, as a candidate alternative route to pathogenic double negative 2 B cells (DN2) in systemic lupus erythematosus (SLE) patients. In healthy ageing, ClonoTrace resolved three candidate age-related B cell maturation routes, from naïve, IgM+ memory and switched-memory B cells, each passing through a DN2-associated transcriptional state that is ordered before age-associated B cells along the inferred trajectory. ClonoTrace's fate probability algorithm indicated that IgM+ memory B cell to ABC transition as the leading candidate age-associated transition, which may be distinct from SLE DN2 maturation. ClonoTrace provides a generalizable framework for receptor-informed trajectory inference, describing candidate developmental routes of pathogenic B cell populations in autoimmunity and ageing.

Humans↗
PubMed1995

Immunohistochemical comparative investigations of lymphatic tissue in reactive processes, myasthenic thymuses and Hodgkin's disease.

In this study coexpression of cytokeratin and desmin, and occasionally also Ki-1 antigen, was displayed in extrafollicular reticulum cells of reactive lymph nodes. The absence or expression of trace amounts of these proteins in normal lymphoid tissue suggests that activation of T cell regions is correlated with the increased frequency of cytokeratin, desmin and Ki-1 expressing cells, and therefore may be a transient phenomenon. S-100-positive interdigitating reticular cells were found occasionally in extrafollicular T cell region of normal lymph nodes. They were, however, more numerous in reactive lymphatic tissue. In the myasthenic thymuses cells forming Hassall's corpuscles displayed coexpression of cytokeratin, desmin and Ki-1 antigen. Medullary epithelial cells were also cytokeratin-positive and, additionally, Ki-1 antigen was expressed on some cells dispersed in whole thymic tissue. S-100-positive interdigitating reticular cells were especially numerous in the thymic medulla and some of them found inside the Hassall's corpuscles. In Hodgkin's disease deficiency of cytokeratin and desmin in extrafollicular reticulum cells is a constant phenomenon in spite of a classic inflammatory background. However, Ki-1 antigen displayed Reed-Sternberg cells which, similar as some thymic cell elements, appear to originate from stromal perivascular mesenchyme. This fact suggests that Reed-Sternberg cells in Hodgkin's disease are pathologic counterparts of extrafollicular reticulum cells which represent a cellular differentiation defect to produce desmin and cytokeratin but with a possibility of Ki-1 antigen expression. The consequence of this may be the disregulation of immune system and the observed immunologic abnormalities. Further studies are needed to elucidate the role of Epstein-Barr viruses in this process. S-100-positive interdigitating reticular cells were in close contact with Reed-Sternberg cells and they were especially large and with numerous cells processes in the mixed cellularity (MC) subtype. The occurrence of interdigitating reticulum cells with S-100 protein expression, especially numerous in the T cell region activated of peripheral lymphatic tissue, as well as their close contact with Reed-Sternberg cells and with cells forming Hassall's corpuscles suggest their eventual possible role in the function of the immune system.

Adolescent↗
PubMed1981

Immunohistochemical evaluation of J-chain expression by intra- and extra-follicular immunoglobulin-producing human tonsillar cells.

Cytoplasmic J-chain expression by Ig-producing cells was characterized immunohistochemically in normal specimens of palatine and nasopharyngeal tonsils (adenoids). Altogether follicular immunocytes, which were mainly of ther IgG and IgM isotypes, showed a much higher percentage of J-chain positivity than the extrafollicular ones, in agreement with the idea that this polypeptide is principally a marker of differentiating or newly differentiated Ig-producing cells. Thus, in concurrence with the predominating IgG isotype, J-chain expression was almost 50% in the germinal centres of lymphoid follicles but only about 2% in the extrafollicular compartment. By contrast, a substantial number of J-chain-positive IgA immunocytes were found in the latter compartment. Since it is believed that extrafollicular Ig-producing cells are mainly derived from follicular centre cells, this result indicated that significant isotype switching is involved in tonsillar B-cell differentiation. Most tonsillar IgD immunocytes were J-chain-positive, in accordance with the notion that IgD expression is a feature of relatively early clonal development. It is postulated that J-chain-positive B-cell blasts may leave the tonsils and, through isotype switching, contribute to the dimer-producing IgA-cell populations normally found in the exocrine glands of the upper aero-digestive tract.

B-Lymphocytes↗
PubMed1981

Tridimensional study of the deep cortex of the rat lymph node. IV. Differential labelling of the deep cortex units with 3H-uridine.

Using tridimensional reconstruction, it was recently found that the deep cortex of rat lymph nodes comprises one to several basic "units." Each unit is a semi-rounded structure contiguous to the peripheral cortex and bulging into the medulla of a node. Other investigators reported that transfused lymphocytes, heavily labelled in vitro by 3H-uridine, became concentrated in an ill-defined region of nodes, referred to as the mid and deep cortex. This suggested to us that the in vivo labelling of nodes with 3H-uridine might allow to further characterize the units on a physiological basis. Therefore, rats were injected intravenously with a dose of 1--20 muCi of 3H-uridine/gm body weight and sacrificed 1 hour to 3 days later. The radioautographs of their nodes were exposed up to 535 days. The observations revealed that a large dose of 3H-uridine combined with a long exposure of the radioautographs yielded a differential labelling of the cell population of the units, characterized by a much more intense reaction than that of the surrounding structures. This demonstrated that the physiology of the lymphocyte population of the deep cortex units differs from the morphologically similar lymphocyte population of the extrafollicular zone of the peripheral cortex. The possible reason(s) for the differential labelling of the units is discussed.

Animals↗
PubMed1995

[In vitro differenciation and functions of dendritic cells obtained from CD34+ hematopoietic progenitors].

Dendritic Cells (DC) are professional antigen presenting cells, necessary during the initiation of immune responses. The study of the role of DC in the establishment of this response has long been tempered by the difficulties to purify DC in sufficient numbers. In vitro generation of DC, from CD34+ hematopoietic progenitors in human and mice, should permit to clarify the relationships between the different DC types isolated in vivo and their roles. GM-CSF has been described to play a key role in the propagation of DC. In human, in association with TNF alpha, it allows the generation of DC from CD34+ progenitors. Those in vitro generated DC are capable of receptor mediated endocytosis and can present soluble antigen to specific T cell clones and activate naive T cells. During activation of naive T cells CD86 (on DC)--CD28 (on T lymphocyte) interaction seems to play a critical role. Interestingly, DC express a functional CD40, which triggering upregulates expression of CD80 and CD86 and induces cytokine production, indicating a reciprocal talk between DC and T cells during the course of antigen presentation. Finally, in vitro generated DC interact directly with B cells, activated through their CD40 antigen, leading to enhanced growth, differentiation (IgM production) and preferential isotype switch towards IgA. Thus, in the extrafollicular area of secondary lymphoid organs, in addition to prime naive T cells, DC might also directly provide costimulatory signals involved during the initiation of primary B cell responses.

Animals↗
PubMed2002

CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells.

B cell terminal differentiation is associated with the onset of high-level antibody secretion and cell cycle arrest. Here the cyclin-dependent kinase (CDK) inhibitor p18(INK4c) is shown to be required within B cells for both terminating cell proliferation and differentiation of functional plasma cells. In its absence, B cells hyperproliferate in germinal centers and extrafollicular foci in response to T-dependent antigens but serum antibody titers are severely reduced, despite unimpaired germinal center formation, class switch recombination, variable region-directed hypermutation, and differentiation to antibody-containing plasmacytoid cells. The novel link between cell cycle control and plasma cell differentiation may, at least in part, relate to p18(INK4c) inhibition of CDK6. Cell cycle arrest mediated by p18(INK4C) is therefore requisite for the generation of functional plasma cells.

Animals↗