RESUMO
Wild organisms are regularly exposed to a wide range of parasites, requiring the management of an effective immune response while avoiding immunopathology. Currently, our knowledge of immunoparasitology primarily derives from controlled laboratory studies, neglecting the genetic and environmental diversity that contribute to immune phenotypes observed in wild populations. To gain insight into the immunologic variability in natural settings, we examined differences in immune gene expression of two Alaskan stickleback (Gasterosteus aculeatus) populations with varying susceptibility to infection by the cestode Schistocephalus solidus. Between these two populations, we found distinct immune gene expression patterns at the population level in response to infection with fish from the high-infection population displaying signs of parasite-driven immune manipulation. Further, we found significant differences in baseline immune gene profiles between the populations, with uninfected low-infection population fish showing signatures of inflammation compared to uninfected high-infection population fish. These results shed light on divergent responses of wild populations to the same parasite, providing valuable insights into host-parasite interactions in natural ecosystems.
Assuntos
Cestoides , Infecções por Cestoides , Doenças dos Peixes , Smegmamorpha , Animais , Smegmamorpha/imunologia , Smegmamorpha/genética , Smegmamorpha/parasitologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/parasitologia , Infecções por Cestoides/veterinária , Infecções por Cestoides/imunologia , Infecções por Cestoides/parasitologia , Cestoides/imunologia , Cestoides/fisiologia , Interações Hospedeiro-Parasita/imunologia , Alaska , Imunidade Inata/genéticaRESUMO
The cestode Schistocephalus solidus is a common parasite in freshwater threespine stickleback populations, imposing strong fitness costs on their hosts. Given this, it is surprising how little is known about the timing and development of infections in natural stickleback populations. Previous work showed that young-of-year stickleback can get infected shortly after hatching. We extended this observation by comparing infection prevalence of young-of-year stickleback from 3 Alaskan populations (Walby, Cornelius and Wolf lakes) over 2 successive cohorts (2018/19 and 2019/20). We observed strong variation between sampling years (2018 vs 2019 vs 2020), stickleback age groups (young-of-year vs 1-year-old) and sampling populations.
Assuntos
Infecções por Cestoides , Doenças dos Peixes , Smegmamorpha , Alaska/epidemiologia , Animais , Infecções por Cestoides/epidemiologia , Infecções por Cestoides/veterinária , Doenças dos Peixes/epidemiologia , Doenças dos Peixes/parasitologia , Interações Hospedeiro-Parasita , Lagos/parasitologia , Smegmamorpha/parasitologiaRESUMO
Increasingly, basic science educators at medical and health science programs are faced with the challenge of delivering fundamental science content using evidence-based pedagogical approaches that build students' fund of knowledge while also supporting their development as self-regulated learners. This has led to an increased use of active learning-based pedagogies such as flipped classroom teaching. However, there are many open questions about the conditions necessary for successful flipped classroom sessions. In particular, the role of student compliance (i.e., participation, engagement, attendance) in mediating performance needs to be evaluated. This is especially important in accelerated curricula where multiple basic science disciplines are integrated together in pass-fail courses, presenting challenges to both students' time and cognitive load. Data on prematriculation performance, in-class participation, weekly quiz performance, and summative assessment performance from three cohorts of medical students (n = 146) at a new medical school were collected and analyzed. We found that historically high-performing students more readily participated in flipped classroom application sessions compared with historically lower-performing students. Correlational analysis of performance on weekly formative quizzes and the summative course exam was not related to in-class participation. However, performance on weekly formative quizzes played the most significant role in students' performance on summative exams. Efforts to understand the benefits of in-class participation beyond short-term assessment performance, such as long-term knowledge retention or development of noncognitive skills, should be undertaken to justify using such time- and human resource-intensive pedagogies.NEW & NOTEWORTHY This study explores the use of flipped classroom teaching in a voluntary and accelerated medical school course. We found that historically high-performing students attend class, whereas historically low-performing students do not attend class as readily. Formative assessment performance appears to be more important than participation in determining the final grade. Correlation of high performance (>90%) with participation may differentiate students who excel in our curriculum from those who simply pass with superficial knowledge.
Assuntos
Aprendizagem Baseada em Problemas , Estudantes de Medicina , Currículo , HumanosRESUMO
Coordinated recombination of homologous antigen receptor loci is thought to be important for allelic exclusion. Here we show that homologous immunoglobulin alleles pair in a stage-specific way that mirrors the recombination patterns of these loci. The frequency of homologous immunoglobulin pairing was much lower in the absence of the RAG-1-RAG-2 recombinase and was restored in Rag1-/- developing B cells with a transgene expressing a RAG-1 active-site mutant that supported DNA binding but not cleavage. The introduction of DNA breaks on one immunoglobulin allele induced ATM-dependent repositioning of the other allele to pericentromeric heterochromatin. ATM activated by the cleaved allele acts in trans on the uncleaved allele to prevent biallelic recombination and chromosome breaks or translocations.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Imunoglobulinas/genética , Proteínas Serina-Treonina Quinases/genética , Recombinação Genética , Proteínas Supressoras de Tumor/genética , Alelos , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Linfócitos B/metabolismo , Células Cultivadas , Quebras de DNA , Rearranjo Gênico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , VDJ Recombinases/metabolismoRESUMO
Vertebrate immunity is a complex system consisting of a mix of constitutive and inducible defences. Furthermore, host immunity is subject to selective pressure from a range of parasites and pathogens which can produce variation in these defences across populations. As populations evolve immune responses to parasites, they may adapt via a combination of (1) constitutive differences, (2) shared inducible responses, or (3) divergent inducible responses. Here, we leverage a powerful natural host-parasite model system (Gasterosteus aculeatus and Schistochephalus solidus) to tease apart the relative contributions of these three types of adaptations to among-population divergence in response to parasites. Gene expression analyses revealed limited evidence of significant divergence in constitutive expression of immune defence, and strong signatures of conserved inducible responses to the parasite. Furthermore, our results highlight a handful of immune-related genes which show divergent inducible responses which may contribute disproportionately to functional differences in infection success or failure. In addition to investigating variation in evolutionary adaptation to parasite selection, we also leverage this unique data set to improve understanding of cellular mechanisms underlying a putative resistance phenotype (fibrosis). Combined, our results provide a case study in evolutionary immunology showing that a very small number of genes may contribute to genotype differences in infection response.
Assuntos
Doenças dos Peixes , Parasitos , Smegmamorpha , Animais , Doenças dos Peixes/genética , Expressão Gênica , Interações Hospedeiro-Parasita/genética , Smegmamorpha/genéticaRESUMO
Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.
Assuntos
Mitose , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas com Domínio T/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Polaridade Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas com Domínio T/metabolismo , Linfócitos T/enzimologiaRESUMO
Parasites can be a major cause of natural selection on hosts, which consequently evolve a variety of strategies to avoid, eliminate, or tolerate infection. When ecologically similar host populations present disparate infection loads, this natural variation can reveal immunological strategies underlying adaptation to infection and population divergence. For instance, the tapeworm Schistocephalus solidus persistently infects 0-80% of threespine stickleback (Gasterosteus aculeatus) in lakes on Vancouver Island. To test whether these heterogeneous infection rates result from evolved differences in immunity, we experimentally exposed laboratory-reared fish from ecologically similar high-infection and no-infection populations to controlled doses of Schistocephalus We observed heritable between-population differences in several immune traits: Fish from the naturally uninfected population initiated a stronger granulocyte response to Schistocephalus infection, and their granulocytes constitutively generate threefold more reactive oxygen species in cell culture. Despite these immunological differences, Schistocephalus was equally successful at establishing initial infections in both host populations. However, the no-infection fish dramatically suppressed tapeworm growth relative to high-infection fish, and parasite size was intermediate in F1 hybrid hosts. Our results show that stickleback recently evolved heritable variation in their capacity to suppress helminth growth by two orders of magnitude. Data from many natural populations indicate that growth suppression is widespread but not universal and, when present, is associated with reduced infection prevalence. Host suppression of helminth somatic growth may be an important immune strategy that aids in parasite clearance or in mitigating the fitness costs of persistent infection.
Assuntos
Cestoides/crescimento & desenvolvimento , Infecções por Cestoides/parasitologia , Doenças dos Peixes/parasitologia , Smegmamorpha/parasitologia , Vertebrados/parasitologia , Animais , Cestoides/imunologia , Doenças dos Peixes/imunologia , Granulócitos/imunologia , Granulócitos/parasitologia , Interações Hospedeiro-Parasita/imunologia , Explosão Respiratória/imunologia , Smegmamorpha/imunologia , Vertebrados/imunologia , Virulência/imunologiaRESUMO
Parasite infections are a product of both ecological processes affecting host-parasite encounter rates and evolutionary dynamics affecting host susceptibility. However, few studies examine natural infection variation from both ecological and evolutionary perspectives. Here, we describe the ecological and evolutionary factors generating variation in infection rates by a tapeworm (Schistocephalus solidus) in a vertebrate host, the threespine stickleback (Gasterosteus aculeatus). To explore ecological aspects of infection, we measured tapeworm prevalence in Canadian stickleback inhabiting two distinct environments: marine and freshwater. Consistent with ecological control of infection, the tapeworm is very rare in marine environments, even though marine fish are highly susceptible. Conversely, commonly infected freshwater stickleback exhibit substantial resistance in controlled laboratory trials, suggesting that high exposure risk overwhelms their recently evolved resistance. We also tested for parasite adaptation to its host by performing transcontinental reciprocal infections, using stickleback and tapeworm populations from Europe and western Canada. More infections occurred in same-continent host-parasite combinations, indicating parasite "local" adaptation, at least on the scale of continents. However, the recently evolved immunity of freshwater hosts applies to both local and foreign parasites. The pattern of adaptation described here is not wholly compatible with either of the common models of host-parasite coevolution (i.e., matching infection or targeted recognition). Instead, we propose a hybrid, eco-evolutionary model to explain the remarkable pattern of global host resistance and local parasite infectivity.
Assuntos
Coevolução Biológica , Interações Hospedeiro-Parasita , Smegmamorpha/parasitologia , Animais , Canadá , Cestoides , Europa (Continente) , Doenças dos Peixes , ParasitosRESUMO
Coordination of V rearrangements between loci on homologous chromosomes is critical for Ig and TCR allelic exclusion. The Ataxia Telangietasia mutated (ATM) protein kinase promotes DNA repair and activates checkpoints to suppress aberrant Ig and TCR rearrangements. In response to RAG cleavage of Igκ loci, ATM inhibits RAG expression and suppresses further Vκ-to-Jκ rearrangements to enforce Igκ allelic exclusion. Because V recombination between alleles is more strictly regulated for TCRß and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCRß and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCRß or IgH loci in mice lacking ATM. A preassembled DJß complex that decreases the number of TCRß rearrangements needed for a productive TCRß gene further increased frequencies of ATM-deficient cells with biallelic TCRß expression. IgH and TCRß proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits VH transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCRß genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCRß or IgH expression while decreasing the frequency of ATM-deficient lymphocytes with aberrant V-to-DJ recombination. Our data demonstrate that core components of the DNA damage response and cell cycle machinery cooperate to help enforce IgH and TCRß allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability.
Assuntos
Ciclina D3/genética , Reparo do DNA/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proliferação de Células , Ciclina D3/antagonistas & inibidores , Dano ao DNA , Reparo do DNA/imunologia , Proteínas de Homeodomínio/biossíntese , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias J de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Cadeias delta de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Éxons VDJ/genéticaRESUMO
Studying the mechanisms underlying the genotype-phenotype association is crucial in genetics. Gene expression studies have deepened our understanding of the genotype â expression â phenotype mechanisms. However, traditional expression quantitative trait loci (eQTL) methods often overlook the critical role of gene co-expression networks in translating genotype into phenotype. This gap highlights the need for more powerful statistical methods to analyze genotype â network â phenotype mechanism. Here, we develop a network-based method, called snQTL, to map quantitative trait loci affecting gene co-expression networks. Our approach tests the association between genotypes and joint differential networks of gene co-expression via a tensor-based spectral statistics, thereby overcoming the ubiquitous multiple testing challenges in existing methods. We demonstrate the effectiveness of snQTL in the analysis of three-spined stickleback (Gasterosteus aculeatus) data. Compared to conventional methods, our method snQTL uncovers chromosomal regions affecting gene co-expression networks, including one strong candidate gene that would have been missed by traditional eQTL analyses. Our framework suggests the limitation of current approaches and offers a powerful network-based tool for functional loci discoveries.
RESUMO
When species disperse into previously unoccupied habitats, new populations encounter unfamiliar species interactions such as altered parasite loads. Theory predicts that newly founded populations should exhibit destabilized eco-evolutionary fluctuations in infection rates and immune traits. However, to understand founder effects biologists typically rely on retrospective studies of range expansions, missing early-generation infection dynamics. To remedy this, we experimentally founded whole-lake populations of threespine stickleback. Infection rates were temporally stable in native source lakes. In contrast, newly founded populations exhibit destabilized host-parasite dynamics: high starting infection rates led to increases in a heritable immune trait (peritoneal fibrosis), suppressing infection rates. The resulting temporal auto-correlation between infection and immunity suggest that newly founded populations can exhibit rapid host-parasite eco-evolutionary dynamics.
RESUMO
Eco-evolutionary experiments are typically conducted in semi-unnatural controlled settings, such as mesocosms; yet inferences about how evolution and ecology interact in the real world would surely benefit from experiments in natural uncontrolled settings. Opportunities for such experiments are rare but do arise in the context of restoration ecology-where different "types" of a given species can be introduced into different "replicate" locations. Designing such experiments requires wrestling with consequential questions. (Q1) Which specific "types" of a focal species should be introduced to the restoration location? (Q2) How many sources of each type should be used-and should they be mixed together? (Q3) Which specific source populations should be used? (Q4) Which type(s) or population(s) should be introduced into which restoration sites? We recently grappled with these questions when designing an eco-evolutionary experiment with threespine stickleback (Gasterosteus aculeatus) introduced into nine small lakes and ponds on the Kenai Peninsula in Alaska that required restoration. After considering the options at length, we decided to use benthic versus limnetic ecotypes (Q1) to create a mixed group of colonists from four source populations of each ecotype (Q2), where ecotypes were identified based on trophic morphology (Q3), and were then introduced into nine restoration lakes scaled by lake size (Q4). We hope that outlining the alternatives and resulting choices will make the rationales clear for future studies leveraging our experiment, while also proving useful for investigators considering similar experiments in the future.
RESUMO
Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the importance of this process and the precise molecular mechanisms by which it is achieved have remained enigmatic. This brief review summarizes current knowledge of the extent to which Ig and TCR loci are subject to allelic exclusion. Recent progress in studying and defining mechanistic steps and molecules that may control the monoallelic initiation and subsequent inhibition of V-to-(D)-J recombination is outlined using the mouse TCRß locus as a model with frequent comparisons to the mouse IgH and Igκ loci. Potential consequences of defects in mechanisms that control Ag receptor allelic exclusion and a reappraisal of the physiologic relevance of this immunologic process also are discussed.
Assuntos
Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Alelos , Animais , Autoimunidade/genética , Camundongos , Recombinação Genética , Tolerância a Antígenos Próprios/genéticaRESUMO
The paucity of murine memory B cell markers has been a significant impediment to the study of memory. The most commonly used marker is IgG, which is neither sensitive nor specific, because activated nonmemory cells can be IgG(+), and memory cells can be IgM(+). In this article, we show that, together, PD-L2 (CD273), CD80, and CD73 define at least five phenotypic subsets of murine memory B cells. These subsets are generated from naive cells bearing a single BCR in response to a single T-dependent Ag. This diversity is independent of class switch, because IgG(1)- and IgM-bearing memory cells are found within each compartment. Memory subsets defined by PD-L2, CD80, and CD73 are biologically distinct from one another, because they differ in ontogeny and selection. Together, these distinctions suggest that there is a spectrum of memory B cells and progressive acquisition from more naive-like to more memory-like properties.
Assuntos
Antígenos de Diferenciação/imunologia , Subpopulações de Linfócitos B/imunologia , Rearranjo Gênico do Linfócito B/imunologia , Memória Imunológica/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Antígenos de Diferenciação/genética , Rearranjo Gênico do Linfócito B/genética , Memória Imunológica/genética , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/genéticaRESUMO
Feedback inhibition of V(D)J recombination enforces Ag receptor allelic exclusion in mammalian lymphocytes. Yet, in-frame VbetaDJbeta exons can assemble on both alleles in human and mouse alphabeta T lineage cells. To elucidate mechanisms that enforce TCRbeta allelic exclusion in such cells, we analyzed Vbeta expression and rearrangement in mice containing a functional Vbeta14DJbeta1.5Cbeta1 gene (Vbeta14(NT)) and/or Vbeta8.2DJbeta1.1Cbeta1 transgene (Vbeta8(Tg)). The majority of Vbeta14(NT) and Vbeta8(Tg) alphabeta T lineage cells expressed only Vbeta14(+) or Vbeta8(+) TCRbeta-chains, respectively, and lacked Vbeta rearrangements on wild-type TCRbeta loci. However, endogenous Vbeta rearrangements and alphabeta T lineage cells expressing endogenous Vbetas from wild-type alleles alone or with the prerearranged Vbeta in cell surface TCRbeta-chains were observed in Vbeta14(NT) and Vbeta8(Tg) mice. Although nearly all Vbeta8(Tg):Vbeta14(NT) thymocytes and splenic alphabeta T cells expressed Vbeta8(+) TCRbeta-chains, only half of these lymphocytes expressed Vbeta14(+) TCRbeta-chains, even though similar steady-state levels of Vbeta14(NT) mRNA were expressed in Vbeta8(+)Vbeta14(+) and Vbeta8(+)Vbeta14(-) populations. Our data demonstrated that posttranscriptional silencing of functionally assembled endogenous VbetaDJbetaCbeta genes can enforce TCRbeta allelic exclusion and reveal another mechanism that contributes to the development of lymphocytes with monospecific Ag receptors.
Assuntos
Interferência de RNA , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/metabolismo , Alelos , Animais , Citometria de Fluxo , Rearranjo Gênico do Linfócito T , Hibridomas/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologiaRESUMO
Ag receptor allelic exclusion is thought to occur through monoallelic initiation and subsequent feedback inhibition of recombinational accessibility. However, our previous analysis of mice containing a V(D)J recombination reporter inserted into Vbeta14 (Vbeta14(Rep)) indicated that Vbeta14 chromatin accessibility is biallelic. To determine whether Vbeta14 recombinational accessibility is subject to feedback inhibition, we analyzed TCRbeta rearrangements in Vbeta14(Rep) mice containing a preassembled in-frame transgenic Vbeta8.2Dbeta1Jbeta1.1 or an endogenous Vbeta14Dbeta1Jbeta1.4 rearrangement on the homologous chromosome. Expression of either preassembled VbetaDJbetaC beta-chain accelerated thymocyte development because of enhanced cellular selection, demonstrating that the rate-limiting step in early alphabeta T cell development is the assembly of an in-frame VbetaDJbeta rearrangement. Expression of these preassembled VbetaDJbeta rearrangements inhibited endogenous Vbeta14-to-DJbeta rearrangements as expected. However, in contrast to results predicted by the accepted model of TCRbeta feedback inhibition, we found that expression of these preassembled TCR beta-chains did not downregulate recombinational accessibility of Vbeta14 chromatin. Our findings suggest that TCRbeta-mediated feedback inhibition of Vbeta14 rearrangements depends on inherent properties of Vbeta14, Dbeta, and Jbeta recombination signal sequences.
Assuntos
Diversidade de Anticorpos , Cromatina/fisiologia , Retroalimentação Fisiológica/fisiologia , Rearranjo Gênico do Linfócito T/imunologia , Região de Junção de Imunoglobulinas , Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Transdução de Sinais/imunologia , Animais , Diversidade de Anticorpos/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Genes Reporter/imunologia , Mutação em Linhagem Germinativa/imunologia , Região de Junção de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Perda de Heterozigosidade/imunologia , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transdução de Sinais/genética , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Parasites impose fitness costs on their hosts. Biologists often assume that natural selection favors infection-resistant hosts. Yet, when the immune response itself is costly, theory suggests that selection may sometimes favor loss of resistance, which may result in alternative stable states where some populations are resistant and others are tolerant. Intraspecific variation in immune costs is rarely surveyed in a manner that tests evolutionary patterns, and there are few examples of adaptive loss of resistance. Here, we show that when marine threespine stickleback colonized freshwater lakes, they gained resistance to the freshwater-associated cestode Schistocephalus solidus. Extensive peritoneal fibrosis and inflammation are a commonly observed phenotype that contributes to suppression of cestode growth and viability but also imposes a substantial cost on fecundity. Combining genetic mapping and population genomics, we find that opposing selection generates immune system differences between tolerant and resistant populations, consistent with divergent optimization.
Assuntos
Cestoides , Doenças dos Peixes , Smegmamorpha , Animais , Cestoides/genética , Doenças dos Peixes/parasitologia , Interações Hospedeiro-Parasita/genética , Imunidade , Lagos , Smegmamorpha/genéticaRESUMO
We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated.
Assuntos
Formação de Anticorpos/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/fisiologia , Linfócitos B/imunologia , Imunidade Inata/imunologia , Animais , Fator Ativador de Células B/metabolismo , Linfócitos B/citologia , Feminino , Memória Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Commensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions, as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However, few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here, we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immune genes. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated with host gene expression. These families were all tightly correlated with host expression of immune genes and processes, falling into one of three categories-those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with the abundance of these taxa, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition.IMPORTANCE Here, we document associations between host gene expression and gut microbiome composition in a nonmammalian vertebrate species. We highlight associations between expression of immune genes and both microbiome diversity and abundance of specific microbial taxa. These findings support other findings from model systems which have suggested that gut microbiome composition and host immunity are intimately linked. Furthermore, we demonstrate that these correlations are truly systemic; the gene expression detailed here was collected from an important fish immune organ (the head kidney) that is anatomically distant from the gut. This emphasizes the systemic impact of connections between gut microbiota and host immune function. Our work is a significant advancement in the understanding of immune-microbiome links in nonmodel, natural systems.
Assuntos
Bactérias/genética , Microbioma Gastrointestinal , Expressão Gênica , Interações entre Hospedeiro e Microrganismos , Smegmamorpha/genética , Smegmamorpha/imunologia , Animais , Bactérias/classificação , Bactérias/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , RNA Ribossômico 16S/genética , Smegmamorpha/microbiologia , SimbioseRESUMO
Over the past decade, the development and clinical use of immunotherapy agents has increased exponentially. As clinical experience builds with these agents so too does our understanding of the associated adverse effects. In particular, the effects of immunotherapy on the kidneys, individual nephrons, and kidney function remain less well described than the adverse effects on barrier organ systems such as the gastrointestinal tract and skin. However, phase IV post-marketing surveillance and clinical case studies together with basic research has begun to reveal mechanisms by which immunotherapy mediates renal adverse effects. This work may lead to improvements in treatment guidelines and therapy. These advances are particularly important as post-cancer survival increases leaving patients to cope with the consequences of not only the cancer, but the short- and long-term adverse effects of treatment. Here we discuss the major renal adverse effects encountered with individual immunotherapeutic agents, putative mechanisms, their current management, and how cancer survivorship programs can help patients who have been treated with immunotherapy.