The Experts below are selected from a list of 74436 Experts worldwide ranked by ideXlab platform
Per Brandtzaeg - One of the best experts on this subject based on the ideXlab platform.
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novel monoclonal antibodies for studies of human and rhesus macaque secretory component and human J Chain
Monoclonal antibodies in immunodiagnosis and immunotherapy, 2016Co-Authors: Ruijun Zhang, Per Brandtzaeg, Munir S Alam, Richard M Scearce, Bradley Lockwood, Kwanki Hwang, Robert Parks, Sallie R Permar, Barton F HaynesAbstract:Immunoglobulin A (IgA) antibodies exist in monomeric, dimeric, and secretory forms. Dimerization of IgA depends on a 15-kD polypeptide termed “Joining (J) Chain,” which is also part of the binding site for an epithelial glycoprotein called “secretory component (SC),” whether this after apical cleavage on secretory epithelia is ligand bound in secretory IgA (SIgA) or in a free form. Uncleaved membrane SC, also called the “polymeric Ig receptor,” is thus crucial for transcytotic export of SIgA to mucosal surfaces, where it interacts with and modulates commensal bacteria and mediates protective immune responses against exogenous pathogens. To evaluate different forms of IgA, we have produced mouse monoclonal antibodies (MAbs) against human J-Chain and free SC. We found that J-Chain MAb 9A8 and SC MAb 9H7 identified human dimeric IgA and SIgA in enzyme-linked immunoassay and western blot analysis, as well as functioning in immunohistochemistry to identify cytoplasmic IgA of intestinal lamina propria plasmabla...
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immunobiology of the tonsils and adenoids
Mucosal Immunology (Fourth Edition), 2015Co-Authors: Per BrandtzaegAbstract:Abstract Nasopharynx-associated lymphoid tissue (NALT), constituting mainly Waldeyer's ring in humans, is a unique inductive site for T- and B-cell responses with abundant plasma cell generation. The most prominent NALT structures are the unpaired nasopharyngeal tonsil (adenoids) and the paired palatine tonsils, which appear functionally similar to the paired rodent NALT structures located dorsal to the cartilaginous soft palate. All human NALT structures show similarities with lymph nodes and participate in both systemic-type and mucosal secretory-type immunity. Primary follicles occur at 16 weeks of gestation, which is comparable to Peyer's patches but different from rodent NALT whose organogenesis begins at birth. Germinal centers arise shortly after birth in T-cell-dependent B-cell responses and are associated with somatic hypermutation of immunoglobulin (Ig) V-region. Downstream switching to various Ig isotypes also takes place, with or without concurrent expression of the J-Chain gene. The J Chain is a crucial part of dimeric IgA and pentameric IgM, making these Ig polymers able to interact with the epithelial polymeric Ig receptor. This interaction is central in the formation of secretory IgA and secretory IgM. Accumulating evidence suggests a maJor role for NALT in antibody-mediated immunity of the airways and associated glands.
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potential of nasopharynx associated lymphoid tissue for vaccine responses in the airways
American Journal of Respiratory and Critical Care Medicine, 2011Co-Authors: Per BrandtzaegAbstract:Nasopharynx-associated lymphoid tissue (NALT), constituting Waldeyer's ring in humans, is a unique inductive site for B-cell responses and plasma cell generation. This makes the nasal route of vaccine administration interesting for induction of mucosal and systemic antibodies. The unpaired nasopharyngeal tonsil (adenoids) and the paired palatine tonsils are prominent NALT structures, functionally similar to the paired rodent NALT structures located dorsal to the cartilaginous soft palate. Human NALT is more strategically located, however, because its elements are exposed to both airborne and alimentary antigens and have antigen-retaining crypts. It also shows similarities with lymph nodes and participates both in systemic- and secretory-type mucosal immunity. Primary follicles occur at 16 weeks of gestation, which is similar to Peyer's patches but different from rodent NALT whose organogenesis begins at birth. The formation of germinal centers reflecting B-cell activation does not take place until shortly after birth, and terminal differentiation of plasma cell can be seen about 2 weeks postnatally. Germinal centers arise in T cell-dependent B-cell responses and are associated with somatic hypermutation of Ig V-region genes. Downstream switching to various Ig isotypes also takes place, with or without concurrent expression of the J-Chain gene. The J Chain is a crucial part of dimeric IgA and pentameric IgM, making these Ig polymers able to interact with the epithelial polymeric Ig receptor. This interaction is central in the formation of secretory IgA and secretory IgM. Accumulating evidence suggests a maJor role for NALT in antibody immunity of the respiratory tract and associated glands.
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function of mucosa associated lymphoid tissue in antibody formation
Immunological Investigations, 2010Co-Authors: Per BrandtzaegAbstract:Abundant evidence supports the notion that human intestinal plasma cells are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists about the uptake, processing, and presentation of luminal antigens occurring in GALT to accomplish priming and sustained expansion of mucosal B cells. Also, it is unclear how the germinal center reaction so strikingly promotes class switch to IgA and expression of J Chain, although the commensal microbiota appears to contribute to both diversification and memory. B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, but the cues directing homing to secretory effector sites beyond the gut require better definition. In this respect, the role of human Waldeyer's ring (including adenoids and the palatine tonsils) as a regional mucosa-associated lymphoid tissue must be better defined, although the balance of e...
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subclass composition and J Chain expression of the compensatory gastrointestinal igg cell population in selective iga deficiency
Clinical and Experimental Immunology, 2008Co-Authors: D E Nilssen, Per Brandtzaeg, Stig S Froland, O FausaAbstract:The subclass distribution of IgG-producing immunocytes was examined by two-colour immunohistochemistry in gastrointestinal mucosa of 14 patients with selective serum IgA deficiency providing the following biopsy material: gastric (n = 1); JeJunal (n = 12); colonic (n = 1); and rectal (n = 2). All except two patients suffered from various infections, and coeliac disease was observed in six of them. Control reference data were based on biopsies from immunologically intact subJects, including histologically normal JeJunal (n = 10) and large bowel (n = 10) mucosa and stomach mucosa with slight chronic gastritis (n = 8). The total mucosal population of immunoglobulin-producing cells per 500 microns gut length unit was only slightly decreased in IgA deficiency because of an increased number of IgG (30%) and especially IgM (71%) immunocytes. The IgG1 immunocyte proportion in the proximal gut (median 87%) was higher than that in the comparable controls (gastric 69%, JeJunal 66%). A similar trend was seen in the distal gut (69%) compared with controls from the large bowel mucosa (55%). Conversely, IgG2 and IgG3 cell proportions were significantly decreased compared with the respective controls from the proximal gut. The same was true for IgG4, which also was significantly reduced in JeJunal mucosa. Paired staining for cytoplasmic J Chain and immunoglobulin isotype showed 71% positivity for JeJunal IgG-producing cells in IgA deficiency, which was somewhat reduced compared with comparable controls (89%). J Chain appeared to be preferentially expressed by IgG1 cells (75%), but was also found in IgG2 (70%), IgG3 (32%) and IgG4 cells (33%). IgM-producing cells showed a J-Chain positivity (99%) in IgA deficiency similar to normal (100%). Our results suggested that the block in mucosal B cell differentiation to IgA expression in the proximal gut is mainly located immediately upstream to the CH alpha 1 gene, giving excessive terminal maturation of J-Chain-positive IgG1 immunocytes.
Marian Elliott Koshland - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin J Chain gene from the mouse b lymphocyte differentiation dna sequence lymphocyte specific promoter elements sl mapping
2016Co-Authors: Linda Matsuuchi, Gordon M Cann, Marian Elliott KoshlandAbstract:During a primary immune response, murine B lymphocytes are induced to express the gene for the immu- noglobulin J Chain. As a first step in determining the mecha- nism of induction, genomic DNA clones encoding the murine J Chain were obtained from cell lines representative of B lym- phocytes before and after J Chain expression. Analysis of the coding regions showed that the J Chain gene has a different structure from the other immunoglobulin genes. It consists of four exons organized in a simple 7.3-kilobase transcription unit that does not require DNA rearrangement or alternative processing for expression. These structural properties indicate that transcription of the J Chain gene is initiated by changes in chromatin conformation, probably involving a J Chain-specific DNA-binding factor. Analysis of the 5' flanking sequences of the J Chain gene, on the other hand, showed that the promoter region contains two conserved elements that have been impli- cated in the lymphocyte-specific expression of the light Chain genes. The sharing of these elements suggests that, once the J Chain gene is activated, its transcription is regulated by
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b cell specific activator protein prevents two activator factors from binding to the immunoglobulin J Chain promoter until the antigen driven stages of b cell development
Journal of Biological Chemistry, 1999Co-Authors: Jeffrey J Wallin, Marian Elliott Koshland, Julie L Rinkenberger, Sulekha Rao, Edwin R Gackstetter, Patty ZwolloAbstract:Abstract The immunoglobulin J Chain gene is inducibly transcribed in mature B cells upon antigen recognition and a signal from interleukin-2 (IL-2). B cell-specific activator protein (BSAP), a transcription factor that silences J Chaintranscription, has been identified as a nuclear target of the IL-2 signal. The levels of BSAP progressively decrease in response to IL-2 and this change correlates with the differentiation of B cells into antibody secreting plasma cells. Here we report the binding of the upstream stimulatory factor (USF) to an E-box motif immediately upstream from the BSAP site on the J Chain promoter. Mutations in the USF binding motif significantly decrease J Chain promoter activity in J Chain expressing B cell lines. We also show that a functional relationship exists between USF and a second J Chain positive-regulating factor, B-MEF2, using co-immunoprecipitation assays and transfections. Finally, we provide evidence that the binding of BSAP prevents USF and B-MEF2 from interacting with the J Chain promoter during the antigen-independent stages of B cell development. It is not until the levels of BSAP decrease during the antigen-driven stages of B cell development that both USF and B-MEF2 are able to bind to their respective promoter elements and activate J Chaintranscription.
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a stage specific enhancer of immunoglobulin J Chain gene is induced by interleukin 2 in a presecretor b cell stage
Immunity, 1998Co-Authors: Changjoong Kang, Colleen Sheridan, Marian Elliott KoshlandAbstract:Interleukin-2 (IL-2)-induced transcription of the J Chain gene was used as a model for analyzing cytokine regulation during B cell development. To determine whether IL-2 signals are targeted to a J Chain gene enhancer as well as to its promoter, the sequences flanking the J Chain gene were first examined for DNase I hypersensitivity. Of six sites identified, two strong ones, 7.5 kb upstream of the J Chain gene, were found to be associated with an enhancer that is active only during the antigen-driven stages of B cell development. Further analyses of the enhancer in the IL-2-responsive presecretor BCL1 cells showed that the enhancer is activated at this stage by an IL-2 signal that functions by opening the enhancer chromatin and stimulating STAT5 to bind to a STAT5 element critical for the enhancer induction. Moreover, after this early induction stage, the enhancer was shown to be constitutively open and active in terminally differentiated plasma cells.
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an interleukin 2 signal relieves bsap pax5 mediated repression of the immunoglobulin J Chain gene
Immunity, 1996Co-Authors: Julie L Rinkenberger, Jeffrey J Wallin, Kirk W Johnson, Marian Elliott KoshlandAbstract:Abstract Cytokine regulation of B cell development was analyzed using interleukin-2 (IL-2)-induced transcription of the J Chain gene as a model system. A nuclear target of the IL-2 signal was identified as the Pax5 transcription factor, BSAP, which recognizes a negative regulatory motif in the J Chain promoter. Functional assays showed that BSAP mediates the silencing of the J Chain gene during the early stages of B cell development, but repression is relieved during the antigen-driven stages in a concentration-dependent manner by an IL-2-induced down-regulation of BSAP RNA expression. At the low levels present in J Chain–expressing plasma cells, BSAP repression could be overridden by positive-acting factors binding to downstream J Chain promoter elements. Overexpression of BSAP in these cells reversed the positive regulation and inhibited J Chain gene transcription. Thus, IL-2 regulation of BSAP concentration may provide a mechanism for controlling both repressor and activator functions of BSAP during a B cell immune response.
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polymer igm assembly and secretion in lymphoid and nonlymphoid cell lines evidence that J Chain is required for pentamer igm synthesis
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Mary Jane Niles, Linda Matsuuchi, Marian Elliott KoshlandAbstract:The requirements for IgM assembly and secretion were evaluated by introducing a constitutively expressed J-Chain cDNA into lymphoid and nonlymphoid cell lines expressing the secretory form of monomer IgM. Assays of cell lysates and supernatants showed that only secretory monomer IgM is required for the synthesis and secretion of hexamer IgM, whereas J Chain, as well as the secreted form of monomer, is required for the synthesis and secretion of pentamer IgM. Moreover, J Chain facilitates the polymerization process so that pentamer IgM is preferentially synthesized. Other components of the polymerization process were found to be shared by all the cell lines examined, whether the cells were of lymphoid or nonlymphoid origin and had a rudimentary or developed secretory apparatus. These results identify monomer IgM and J Chain as the two components that determine the B-cell-specific expression of IgM antibodies and, thus, as the appropriate targets for therapeutic regulation of IgM responses.
Finneirik Johansen - One of the best experts on this subject based on the ideXlab platform.
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secretory antibody formation conserved binding interactions between J Chain and polymeric ig receptor from humans and amphibians
Journal of Immunology, 2007Co-Authors: Ranveig Braathen, Per Brandtzaeg, Valerie S Hohman, Finneirik JohansenAbstract:Abs of the secretory Ig (SIg) system reinforce numerous innate defense mechanisms to protect the mucosal surfaces against microbial penetration. SIgs are generated by a unique cooperation between two distinct cell types: plasma cells that produce polymers of IgA or IgM (collectively called pIgs) and polymeric Ig receptor (pIgR)-expressing secretory epithelial cells that mediate export of the pIgs to the lumen. Apical delivery of SIgs occurs by cleavage of the pIgR to release its extracellular part as a pIg-bound secretory component, whereas free secretory components are derived from an unoccupied receptor. The Joining Chain (J Chain) is crucial in pIg/SIg formation because it serves to polymerize Igs and endows them with a binding site for the pIgR. In this study, we show that the J Chain from divergent tetrapods including mammals, birds, and amphibians efficiently induced polymerization of human IgA, whereas the J Chain from nurse shark (a lower vertebrate) did not. Correctly assembled polymers showed high affinity to human pIgR. Sequence analysis of the J Chain identified two regions, conserved only in tetrapods, which by mutational analysis were found essential for pIgA-pIgR complexing. Furthermore, we isolated and characterized pIgR from the amphibian Xenopus laevis and demonstrated that its pIg binding domain showed high affinity to human pIgA. These results showed that the functional site of interaction between pIgR, J Chain and Ig H Chains is conserved in these species and suggests that SIgs originated in an ancestor common to tetrapods.
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the carboxyl terminal domains of iga and igm direct isotype specific polymerization and interaction with the polymeric immunoglobulin receptor
Journal of Biological Chemistry, 2002Co-Authors: Ranveig Braathen, Per Brandtzaeg, Inger Sandlie, Vigdis Sorensen, Finneirik JohansenAbstract:Mucosal surfaces are protected by polymeric immunoglobulins that are transported across the epithelium by the polymeric immunoglobulin receptor (pIgR). Only polymeric IgA and IgM containing a small polypeptide called the "Joining" (J) Chain can bind to the pIgR. J Chain-positive IgA consists of dimers, and some larger polymers, whereas only IgM pentamers incorporate the J Chain. We made domain swap chimeras between human IgA1 and IgM and found that the COOH-terminal domains of the heavy Chains (Calpha3 and Cmu4, respectively) dictated the size of the polymers formed and also which polymers incorporated the J Chain. We also showed that chimeric IgM molecules engineered to contain Calpha3 were able to bind the rabbit pIgR. Since the rabbit pIgR normally does not bind IgM, these results suggest that the COOH-terminal domain of the polymeric immunoglobulins is primarily responsible for interaction with the pIgR. Finally, we made a novel chimeric IgA immunoglobulin, containing the terminal domain from IgM. This recombinant molecule formed J Chain-containing pentamers that could, like IgA, efficiently form covalent complexes with the human pIgR ectodomain, known as secretory component.
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the J Chain is essential for polymeric ig receptor mediated epithelial transport of iga
Journal of Immunology, 2001Co-Authors: Finneirik Johansen, Ranveig Braathen, Per BrandtzaegAbstract:Local production of secretory (S)IgA provides adaptive immunologic protection of mucosal surfaces, but SIgA is also protective when administered passively, such as in breast milk. Therefore, SIgA is a potential candidate for therapeutic administration, but its complex structure with four different polypeptide Chains produced by two distinct cell types complicates recombinant production. The J Chain is critical in the structure of SIgA because it is required for efficient polymerization of IgA and for the affinity of such polymers to the secretory component (SC)/polymeric (p)IgR. To better understand the role of the J Chain in SIgA production, we have generated various mutant forms of the human J Chain and analyzed the function of these mutants when coexpressed with IgA. We found that the C terminus of the J Chain was not required for the formation of IgA polymers, but was essential for the binding of pIgA to SC. Likewise, we found that two of the intraChain disulfide bridges (Cys(13):Cys(101) and Cys(109):Cys(134)) were also required for the binding of pIgA to SC but, interestingly, not for IgA polymerization. Conversely, the last intraChain disulfide bridge (Cys(72):Cys(92)) was not essential for either of these two J Chain functions. Finally, we demonstrated that the presence of only Cys(15) or Cys(69) was sufficient to support polymerization of IgA, but that these polymers were mostly noncovalently stabilized. Nevertheless, these polymers bound free SC with nearly the same affinity as pIgA containing wild-type J Chain, but were transcytosed by pIgR-expressing polarized epithelial cells at a reduced efficiency.
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the b cell system of human mucosae and exocrine glands
Immunological Reviews, 1999Co-Authors: Per Brandtzaeg, I. N. Farstad, Finneirik Johansen, Craig H Morton, Inger Natvig Norderhaug, Takeshi YamanakaAbstract:: The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80-90% of all immunoglobulin (Ig)-producing cells. The maJor product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J Chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J Chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional Justification for the J Chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a "spin-off" from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J Chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin alpha 4 beta 7 and MAdCAM-1) that explain the "gut-seeking" properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgG1, IgG2) production patterns shown by local immunocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.
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the b cell system of human mucosae and exocrine glands
Immunological Reviews, 1999Co-Authors: Per Brandtzaeg, I. N. Farstad, Finneirik Johansen, Craig H Morton, Inger Natvig Norderhaug, Takeshi YamanakaAbstract:Summary: The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80–90% of all immunoglobulins (Ig)-producing cells. The maJor product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J Chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J Chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional Justification for the J Chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a ‘spin-off’ from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J Chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin α4β7 and MAdCAM-1) that explain the “gut-seeking” properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgGI, IgG2) production patterns shown by local iinmttnocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.
Martin F. Flajnik - One of the best experts on this subject based on the ideXlab platform.
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putting J Chain back on the map how might its expression define plasma cell development
Journal of Immunology, 2014Co-Authors: Caitlin D Castro, Martin F. FlajnikAbstract:Joining Chain (J Chain) is a small polypeptide that regulates multimerization of secretory IgM and IgA, the only two mammalian Igs capable of forming multimers. J Chain also is required for poly-Ig receptor–mediated transport of these Ig classes across the mucosal epithelium. It is generally assumed that all plasma cells express J Chain regardless of expressed isotype, despite the documented presence of J Chain− plasma cells in mammals, specifically in all monomeric IgA-secreting cells and some IgG-secreting cells. Compared with most other immune molecules, J Chain has not been studied extensively, in part because of technical limitations. Even the reported phenotype of the J Chain–knockout mouse is often misunderstood or underappreciated. In this short review, we discuss J Chain in light of the various proposed models of its expression and regulation, with an added focus on its evolutionary significance, as well as its expression in different B cell lineages/differentiation states.
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noncoordinate expression of J Chain and blimp 1 define nurse shark plasma cell populations during ontogeny
European Journal of Immunology, 2013Co-Authors: Caitlin D Castro, Yuko Ohta, Helen Dooley, Martin F. FlajnikAbstract:B-lymphocyte-induced maturation protein 1 (Blimp-1) is the master regulator of plasma cell development, controlling genes such as those encoding J-Chain and secretory Ig heavy Chain. However, some mammalian plasma cells do not express J-Chain, and mammalian B1 cells secrete "natural" IgM antibodies without upregulating Blimp-1. While these results have been controversial in mammalian systems, here we describe subsets of normally occurring Blimp-1(-) antibody-secreting cells in nurse sharks, found in lymphoid tissues at all ontogenic stages. Sharks naturally produce large amounts of both pentameric (classically "19S") and monomeric (classically "7S") IgM, the latter an indicator of adaptive immunity. Consistent with the mammalian paradigm, shark Blimp-1 is expressed in splenic 7S IgM-secreting cells, though rarely detected in the J-Chain(+) cells producing 19S IgM. Although IgM transcript levels are lower in J-Chain(+) cells, these cells nevertheless secrete 19S IgM in the absence of Blimp-1, as demonstrated by ELISPOT and metabolic labeling. Additionally, cells in the shark BM equivalent (epigonal) are Blimp-1(-). Our data suggest that, in sharks, 19S-secreting cells and other secreting memory B cells in the epigonal are maintained for long periods without Blimp-1, but like in mammals, Blimp-1 is required for terminating the B-cell program following an adaptive immune response in the spleen.
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J Chain in the nurse shark implications for function in a lower vertebrate
Journal of Immunology, 2003Co-Authors: Valerie S Hohman, Martin F. Flajnik, Andrew S Greenberg, Lynn L Rumfelt, Sue E Stewart, D Avila, Lisa A SteinerAbstract:J Chain is a small polypeptide covalently attached to polymeric IgA and IgM. In humans and mice, it plays a role in binding Ig to the polymeric Ig receptor for transport into secretions. The putative orthologue of mammalian J Chain has been identified in the nurse shark by sequence analysis of cDNA and the polypeptide isolated from IgM. Conservation with J Chains from other species is relatively poor, especially in the carboxyl-terminal portion, and, unlike other J Chains, the shark protein is not acidic. The only highly conserved segment in all known J Chains is a block of residues surrounding an N-linked glycosylation site. Of the eight half-cystine residues that are conserved in mammalian J Chains, three are lacking in the nurse shark, including two in the carboxyl-terminal segment that have been reported to be required for binding of human J Chain-containing IgA to secretory component. Taken together with these data, the relative abundance of J Chain transcripts in the spleen and their absence in the spiral valve (intestine) suggest that J Chain in nurse sharks may not have a role in Ig secretion. Analysis of J Chain sequences in diverse species is in agreement with accepted phylogenetic relationships, with the exception of the earthworm, suggesting that the reported presence of J Chain in invertebrates should be reassessed.
Barbara A Hendrickson - One of the best experts on this subject based on the ideXlab platform.
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protection against rotavirus shedding after intranasal immunization of mice with a chimeric vp6 protein does not require intestinal iga
Virology, 2006Co-Authors: Monica M Mcneal, Barbara A Hendrickson, Susan C Stone, Mitali Basu, Judy A Bean, John D Clements, Anthony H C Choi, Richard L WardAbstract:Abstract Intranasal immunization of mice with chimeric VP6 and the adJuvant LT(R192G) consistently elicits >95% reductions in fecal rotavirus shedding following challenge. To determine the association between mucosal antibody and protection, we immunized BALB/c wt and J Chain knockout (Jch−/−) mice with VP6 and either LT(R192G) or cholera toxin (CT). Both strains developed nearly equal levels of serum rotavirus IgG, but Jch−/− mice, which cannot transport dimeric IgA across epithelial cell surfaces, developed >4-fold higher levels of serum rotavirus IgA. Stool rotavirus IgA was present in wt but undetectable in Jch−/− mice. When challenged with rotavirus strain EDIM, reductions in rotavirus shedding were nearly identical in VP6-immunized wt and Jch−/− mice (i.e., 97% and 92%, respectively; P > 0.01). Th1 CD4 T cell responses were also detected in VP6-immunized animals based on high levels of IFN-γ and IL-2 found after in vitro VP6 stimulation of spleen cells. Therefore, protection induced by intranasal immunization of mice with VP6 and adJuvant does not depend on intestinal rotavirus IgA antibody but appears to be associated with CD4 T cells.
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mechanisms of heterosubtypic immunity to lethal influenza a virus infection in fully immunocompetent t cell depleted beta2 microglobulin deficient and J Chain deficient mice
Journal of Immunology, 1997Co-Authors: Suzanne L Epstein, Barbara A Hendrickson, Julia A Misplon, C M Lawson, E E Max, Kanta SubbaraoAbstract:Immunity that is cross-protective between different influenza A virus subtypes (termed heterosubtypic immunity) can be demonstrated readily in some animals but only rarely in humans. Induction of heterosubtypic immunity in humans by vaccines would provide public health benefit, perhaps offering some protection against pandemics or other new influenza A strains. Therefore, we studied mechanisms mediating heterosubtypic immunity in mice. Immunization with either A/H1N1 or A/H3N2 virus protected mice against mortality following heterosubtypic challenge while providing modest reductions in lung virus titers. No cross-protection was seen with distantly related type B influenza virus. Depletion of CD4+ or CD8+ T cells or both around the time of challenge had no significant effect on survival, indicating that these cells are not required at the effector stage. beta2-microglobulin knockout mice could be protected readily against heterosubtypic challenge, confirming that class I-restricted T cells are not required. In beta2-microglobulin -/- mice, depletion of CD4+ T cells partially abrogated heterosubtypic immunity, showing that they play a role in these mice. Passive transfer of Abs to naive recipients protected against subsequent challenge with homologous but not heterosubtypic virus. Because a role for secretory Abs has been suggested, we studied dependence on the J Chain, which is required for polymeric Ig receptor-mediated IgA transport. J Chain knockout mice were readily protected by heterosubtypic immunity, indicating that polymeric Ig receptor-mediated transport is not required. Better understanding of heterosubtypic immunity should be valuable in analyzing new vaccines, including peptide and DNA vaccines, intended to induce broadly cross-reactive immunity.
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lack of association of secretory component with iga in J Chain deficient mice
Journal of Immunology, 1996Co-Authors: Barbara A Hendrickson, Blaise Corthesy, L Rindisbacher, D Kendall, D A Waltz, Marian R Neutra, J G SeidmanAbstract:J Chain has been proposed to play a role in the mucosal transport of polymeric Igs (pIg) by the polymeric Ig receptor (pIgR). We have previously reported the generation of J Chain-deficient mice. These mice exhibited elevated serum IgA and depleted biliary and fecal IgA levels compared with wild-type mice. We report here that, unlike the IgA levels in bile and feces, IgA levels in local mucosal and glandular secretions were not depressed in J Chain-deficient mice. Breast milk, intestinal mucosal surface, and nasal wash IgA levels in the mutant mice were similar to wild-type mice while bronchoalveolar lavage IgA levels were higher in the J Chain-deficient animals. Western blot analysis with an Ab to secretory component (SC), the portion of the pIgR that remains bound to pig in secretions, and immunoprecipitation with Abs directed against IgA showed that secreted IgA was associated with SC in wild-type but not J Chain-deficient mice. The IgA in wild-type secretions was polymeric while the secretions of J Chain-deficient mice contained IgA monomers and other nonpolymeric IgA forms. Thus, J Chain is not essential for IgA transport by intestinal, mammary, or respiratory epithelia but is necessary for the stable association of pIgA with SC. Further, we suggest that J Chain-deficient IgA is transported into secretions by a different mechanism than wild-type IgA.
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altered hepatic transport of immunoglobulin a in mice lacking the J Chain
Journal of Experimental Medicine, 1995Co-Authors: Barbara A Hendrickson, Blaise Corthesy, D Kendall, Marian R Neutra, E E Max, D A Conner, D J Ladd, J E Casanova, Christine E Seidman, J G SeidmanAbstract:We have created J Chain knockout mice to define the physiologic role of the J Chain in immunoglobulin synthesis and transport. The J Chain is covalently associated with pentameric immunoglobulin (Ig) M and dimeric IgA and is also expressed in most IgG-secreting cells. J Chain-deficient mice have normal serum IgM and IgG levels but markedly elevated serum IgA. Although polymeric IgA was present in the mutant mice, a larger proportion of their serum IgA was monomeric than was found in wild-type mouse serum. Bile and fecal IgA levels were decreased in J Chain-deficient mice compared with wild-type mice, suggesting inefficient transport of J Chain-deficient IgA by hepatic polymeric immunoglobulin receptors (pIgR). The pIgR-mediated transport of serum-derived IgA from wild-type and mutant mice was assessed in Madin-Darby canine kidney (MDCK) cells transfected with the pIgR. These studies revealed selective transport by pIgR-expressing MDCK cells of wild-type IgA but not J Chain-deficient IgA. We conclude that although the J Chain is not required for IgA dimerization, it does affect the efficiency of polymerization or have a role in maintaining IgA dimer stability. Furthermore, the J Chain is essential for efficient hepatic pIgR transport of IgA.
