RESUMO
The immune system protects the host from infection and works to heal damaged tissue after infection or injury. There is increasing evidence that the immune system and the nervous system work in concert to achieve these goals. The sensory nervous system senses injury, infection, and inflammation, which results in a direct pain signal. Direct activation of peripheral sensory nerves can drive an inflammatory response in the skin. Immune cells express receptors for numerous transmitters released from sensory and autonomic nerves, which allows the nervous system to communicate directly with the immune system. This communication is bidirectional because immune cells can also produce neurotransmitters. Both innate and adaptive immune cells respond to neuronal signaling, but T cells appear to be at the helm of neuroimmune communication.
Assuntos
Neuroimunomodulação , Linfócitos T , Humanos , Pele , Inflamação , Transdução de SinaisRESUMO
Lymph nodes and spleens are innervated by sympathetic nerve fibers that enter alongside arteries. Despite discovery of these nerve fibers nearly 40 years ago, the role of these nerves during response to infection remains poorly defined. We have found that chemical depletion of sympathetic nerve fibers compromises the ability of mice to develop protective immune memory to a Staphylococcus aureus infection. Innate control of the primary infection was not impacted by sympathectomy. Germinal center formation is also compromised in nerve-depleted animals; however, protective antibody responses are still generated. Interestingly, protective CD4+ T-cell memory fails to form in the absence of sympathetic nerves after S aureus infection.
Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Camundongos , Animais , Linfócitos T CD4-Positivos , Linfonodos , Sistema Nervoso SimpáticoRESUMO
The activation of naive CD8 T cells typically results in the formation of effector cells (TE) as well as phenotypically distinct memory cells that are retained over time. Memory CD8 T cells can be further subdivided into central memory, effector memory (TEM), and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express IL-21R, we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin α4ß7 on CD8 T cells primed in vitro and on circulating CD8 T cells in the mixed bone marrow chimeras. The requirement for IL-21 to establish CD8 TE/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection; nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in lymphopenic environments. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Movimento Celular , Memória Imunológica/imunologia , Interleucinas/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Subpopulações de Linfócitos T/citologiaRESUMO
CD8 T-cell responses are critical for protection against intracellular pathogens and tumors. The induction and properties of these responses are governed by a series of integrated processes that rely heavily on cell-cell interactions. Intercellular adhesion molecule (ICAM)-1 functions to enhance the strength of antigenic stimulation, extend the duration of contact with antigen-presenting cells, and augment cytokine signals, which are all factors that influence peripheral CD8 T-cell differentiation. Although previous studies suggest that ICAM-1 is essential for establishing memory T-cell populations following peptide immunization, the roles of ICAM-1 in antiviral cellular immunity are less well understood. Here we show that, following a prototypic acute viral infection, the formation and maintenance of memory-phenotype CD127(hi), KLRG-1(lo) CD8 T cells does not require ICAM-1. Nevertheless, ICAM-1 expression on nonlymphocytes dictates the phenotypic and functional attributes of the antiviral CD8 T-cell populations that develop and promotes the gradual attrition of residual effector-like CD127(lo), KLRG-1(hi) CD8 T cells during the memory phase of the response. Although memory T cells do emerge and are maintained if ICAM-1 expression is abolished, the secondary proliferative capacity of these T cells is severely curtailed. Collectively, these studies reveal potential dual roles for ICAM-1 in both promoting the decay of effector responses and programming the sensitivity of memory CD8 T cells to secondary stimuli.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica/fisiologia , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Doença Aguda , Animais , Molécula 1 de Adesão Intercelular/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lectinas Tipo C , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/metabolismoRESUMO
The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprising both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this review, we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation, and also highlight the potential counterbalancing role of IL-21.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-2/imunologia , Interleucinas/imunologia , Animais , Imunidade Inata , Memória Imunológica , Inflamação/imunologiaRESUMO
Stress contributes to infection and cancer susceptibility, but the mediating mechanisms are still being elucidated. CD8 T cells are critical players in antiviral and antitumor immune responses. A recent study by Globig et al., together with a growing body of literature, link norepinephrine produced during the stress response to CD8 T cell dysfunction.
Assuntos
Adrenérgicos , Neoplasias , Humanos , Infecção Persistente , Ativação Linfocitária , Linfócitos T CD8-Positivos/patologiaRESUMO
Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice does not protect against reinfection and is associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Here, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed immunoglobulin G (IgG) class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model, and a US Food and Drug Administration (FDA)-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease.
Assuntos
Proteínas de Bactérias , Toxinas Bacterianas , Clostridioides difficile , Centro Germinativo , Receptores CXCR4 , Animais , Receptores CXCR4/metabolismo , Receptores CXCR4/imunologia , Centro Germinativo/imunologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Clostridioides difficile/imunologia , Clostridioides difficile/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocina CXCL12/metabolismo , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Memória Imunológica , Feminino , Formação de Anticorpos/imunologiaRESUMO
Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4+ T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1+ T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca2+-NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25+ T regulatory cells and dysregulated PD-1+ T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Receptor de Morte Celular Programada 1/genética , Monitorização Imunológica , Linfócitos T Reguladores/patologiaRESUMO
During many chronic infections, the responding CD8 T cells become exhausted as they progressively lose their ability to elaborate key effector functions. Unlike prototypic memory CD8 cells, which rapidly synthesize IFN-gamma following activation, severely exhausted T cells fail to produce this effector molecule. Nevertheless, the ontogeny of exhausted CD8 T cells, as well as the underlying mechanisms that account for their functional inactivation, remains ill defined. We have used cytokine reporter mice, which mark the transcription of IFN-gamma mRNA by the expression of Thy1.1, to decipher how activation events during the early stages of a chronic infection dictate the development of exhaustion. We show that virus-specific CD8 T cells clearly respond during the early stages of chronic lymphocytic choriomeningitis virus infection, and that this early T cell response is more pronounced than that initially observed in acutely infected hosts. Thus, exhausted CD8 T cells appear to emerge from populations of potently activated precursors. Unlike acute infections, which result in massive expansion of the responding T cells, there is a rapid attenuation of further expansion during chronic infections. The exhausted T cells that subsequently emerge in chronically infected hosts are incapable of producing the IFN-gamma protein. Surprisingly, high levels of the IFN-gamma transcript are still present in exhausted cells, demonstrating that ablation of IFN-gamma production by exhausted cells is not due to transcriptional silencing. Thus, posttranscription regulatory mechanisms likely disable this effector module.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Inativação Gênica/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Transcrição Gênica/imunologia , Doença Aguda , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Doença Crônica , Técnicas de Introdução de Genes , Genes Reporter/imunologia , Interferon gama/biossíntese , Ativação Linfocitária/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco/imunologia , Células-Tronco/patologia , Células-Tronco/virologia , Antígenos Thy-1/biossíntese , Antígenos Thy-1/genética , Regulação para Cima/genética , Regulação para Cima/imunologia , Ativação Viral/imunologiaRESUMO
T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.
Assuntos
Linfócitos T/imunologia , Animais , Citocinas/imunologia , Humanos , Linfócitos T/virologiaRESUMO
CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of CD4 T cell help. These factors set the transcriptional landscape of the responding T cells, which in turn influences their phenotypic and functional attributes as well as ultimate fate. Under certain conditions, such as during chronic infections, the development of these usually successful responses becomes subverted. Here we discuss advances in our understanding of the cellular and molecular determinants of T cell quality, and the formation of effector, memory, and exhausted CD8 T cells, during acute and chronic infections.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções/imunologia , Doença Aguda , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Apresentação Cruzada/imunologia , Humanos , Memória Imunológica/imunologia , Transcrição Gênica/imunologiaRESUMO
Apoptosis plays an important role in eliminating UV-damaged keratinocytes, but its role in UV-induced immune suppression is not clear. Langerhans cells (LCs) may function as inducers of immune suppression. We have shown that LCs derived from mice deficient in the proapoptotic Bid (BH3-interacting death domain protein) gene (Bid KO) resist apoptosis and induce amplified immune responses. In this report, we examined responses in Bid KO mice to UVB exposure. Acute UV exposure led Bid KO mice to develop fewer apoptotic cells and retain a greater fraction of LCs in the epidermal layer of skin in comparison to wild-type mice. Bid KO mice were also markedly resistant to local and systemic UV tolerance induction to hapten sensitization and contact hypersensitivity responses. Elicitation responses and inflammation at skin sensitization sites in UV-treated Bid KO mice were equal to or greater than nonsuppressed control responses. In Bid KO mice, LCs accumulated in lymph nodes to greater numbers, demonstrated longer lifespans, and contained fewer DNA-damaged cells. These studies provide evidence that Bid activation is a critical upstream mediator in UV-induced keratinocyte and LC apoptosis and that its absence abrogates UV-induced immune tolerance.
Assuntos
Apoptose/efeitos da radiação , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/fisiologia , Terapia de Imunossupressão , Pele/citologia , Raios Ultravioleta , Animais , Proteínas Reguladoras de Apoptose , Tolerância Imunológica/efeitos da radiação , Queratinócitos/citologia , Células de Langerhans/citologia , Camundongos , Camundongos Knockout , Pele/efeitos da radiaçãoRESUMO
Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However, the role of lymphocyte-derived ACh in viral infection is unknown. Here, we show that the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production, is robustly induced in both CD4+ and CD8+ T cells during lymphocytic choriomeningitis virus (LCMV) infection in an IL-21-dependent manner. Deletion of Chat within the T cell compartment in mice ablated vasodilation in response to infection, impaired the migration of antiviral T cells into infected tissues, and ultimately compromised the control of chronic LCMV clone 13 infection. Our results reveal a genetic proof of function for ChAT in T cells during viral infection and identify a pathway of T cell migration that sustains antiviral immunity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Colina O-Acetiltransferase/imunologia , Interleucinas/imunologia , Coriomeningite Linfocítica/imunologia , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/enzimologia , Movimento Celular , Colina O-Acetiltransferase/genética , Feminino , Ativação Linfocitária , Vírus da Coriomeningite Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , VasodilataçãoRESUMO
The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies. As revealed by RNA-seq and targeted quantitative PCR (qPCR), dorsal root ganglion (DRG) sensory neurons harvested from either naïve or immunized mice lack enzymes (i.e., RAG1, RAG2, AID, or UNG) required for generating antibody diversity and, therefore, cannot make antibodies. Additionally, transgenic mice that express a reporter fluorescent protein under the control of Igγ1 constant region fail to express Ighg1 transcripts in DRG sensory neurons. Furthermore, neural sequestration of antibodies occurs in mice rendered deficient in neuronal Rag2, but antibody sequestration is not observed in DRG sensory neurons isolated from mice that lack mature B cells [e.g., Rag1 knock out (KO) or µMT mice]. Finally, adoptive transfer of Rag1-deficient bone marrow (BM) into wild-type (WT) mice or WT BM into Rag1 KO mice revealed that antibody sequestration was observed in DRG sensory neurons of chimeric mice with WT BM but not with Rag1-deficient BM. Together, these results indicate that DRG sensory neurons sequester and retain antigen-specific antibodies released by antibody-secreting plasma cells. Coupling this work with previous studies implicating DRG sensory neurons in regulating antigen trafficking during immunization raises the interesting possibility that the nervous system collaborates with the immune system to regulate antigen-mediated responses.
Assuntos
Anticorpos/metabolismo , Linfócitos B/imunologia , Gânglios Espinais/patologia , Inflamação/imunologia , Células Receptoras Sensoriais/metabolismo , Animais , Antígenos/imunologia , Células Cultivadas , Imunidade Humoral , Imunização , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimunomodulação , Células Receptoras Sensoriais/imunologiaRESUMO
The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences more than simply T cell responses, and may provide new therapeutic options for chronically infected patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , HIV-1/imunologia , Hepacivirus/imunologia , Vírus da Hepatite B/imunologia , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/imunologia , Viroses/terapia , Animais , Antígenos CD/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Terapia de Alvo Molecular , Receptores Imunológicos/metabolismo , Viroses/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4+CD44hiCD62Llo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.
Assuntos
Pressão Sanguínea/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Colina O-Acetiltransferase/metabolismo , Hemostasia/fisiologia , Animais , Células Cultivadas , Retroalimentação Fisiológica/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown. Here, we show in vivo that Mule controls murine intestinal stem and progenitor cell proliferation by modulating Wnt signaling via c-Myc. Mule also regulates protein levels of the receptor tyrosine kinase EphB3 by targeting it for proteasomal and lysosomal degradation. In the intestine, EphB/ephrinB interactions position cells along the crypt-villus axis and compartmentalize incipient colorectal tumors. Our study thus unveils an important new avenue by which Mule acts as an intestinal tumor suppressor by regulation of the intestinal stem cell niche.
Assuntos
Efrina-B3/metabolismo , Intestinos/citologia , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Nicho de Células-Tronco , Ubiquitina-Proteína Ligases/metabolismo , Via de Sinalização Wnt , Polipose Adenomatosa do Colo/patologia , Alelos , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Endocitose , Células HEK293 , Humanos , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Celulas de Paneth/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Supressoras de Tumor , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/deficiênciaRESUMO
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.