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  • Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-19
    Charlie Bridgewood; Kassem Sharif; Jonathan Sherlock; Abdulla Watad; Dennis McGonagle

    The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

    更新日期:2020-01-21
  • Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-16
    Yusuke Takeuchi; Keiji Hirota; Shimon Sakaguchi

    Mutations of the genes encoding T‐cell receptor (TCR)‐proximal signaling molecules, such as ZAP‐70, can be causative of immunological diseases ranging from T‐cell immunodeficiency to T‐cell–mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap‐70 gene, spontaneously develop T‐cell–mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap‐70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self‐peptides/MHC complexes, shifting self‐reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self‐reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self‐peptide/MHC complexes on antigen‐presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL‐6 to drive the arthritogenic T cells to differentiate into arthritogenic T‐helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte‐macrophage colony‐stimulating factor‐secreting effector Th17 cells, mediating chronic bone‐destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune‐suppressing Treg cells to treat and prevent RA.

    更新日期:2020-01-16
  • Inflammasomes contributing to inflammation in arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-16
    Lotte Spel; Fabio Martinon

    Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

    更新日期:2020-01-16
  • Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-13
    Laura C. Cappelli; Mekha A. Thomas; Clifton O. Bingham; Ami A. Shah; Erika Darrah

    The development of inflammatory arthritis in patients receiving immune checkpoint inhibitor therapy is increasingly recognized due to the growing use of these drugs for the treatment of cancer. This represents an important opportunity not only to define the mechanisms responsible for the development of this immune‐related adverse event and to ultimately predict or prevent its development, but also to provide a unique window into early events in the development of inflammatory arthritis. Knowledge gained through the study of this patient population, for which the inciting event is known, could shed light into the pathogenesis of autoimmune arthritis. This review will highlight the clinical and immunologic features of these entities to define common elements for future study.

    更新日期:2020-01-13
  • A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-13
    Michelle A. E. Brouwer; Freek R. van de Schoor; Hedwig D. Vrijmoeth; Mihai G. Netea; Leo A. B. Joosten

    Articular joints are a major target of Borrelia burgdorferi, the causative agent of Lyme arthritis. Despite antibiotic treatment, recurrent or persistent Lyme arthritis is observed in a significant number of patients. The host immune response plays a crucial role in this chronic arthritic joint complication of Borrelia infections. During the early stages of B. burgdorferi infection, a major hinder in generating a proper host immune response is the lack of induction of a strong adaptive immune response. This may lead to a delayed hyperinflammatory reaction later in the disease. Several mechanisms have been suggested that might be pivotal for the development of Lyme arthritis and will be highlighted in this review, from molecular mimicry of matrix metallopeptidases and glycosaminoglycans, to autoimmune responses to live bacteria, or remnants of Borrelia spirochetes in joints. Murine studies have suggested that the inflammatory responses are initiated by innate immune cells, but this does not exclude the involvement of the adaptive immune system in this dysregulated immune profile. Genetic predisposition, via human leukocyte antigen‐DR isotype and microRNA expression, has been associated with the development of antibiotic‐refractory Lyme arthritis. Yet the ultimate cause for (antibiotic‐refractory) Lyme arthritis remains unknown. Complex processes of different immune cells and signaling cascades are involved in the development of Lyme arthritis. When these various mechanisms are fully been unraveled, new treatment strategies can be developed to target (antibiotic‐refractory) Lyme arthritis more effectively.

    更新日期:2020-01-13
  • Innate immunity to malaria—The role of monocytes
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-16
    Katherine R. Dobbs; Juliet N. Crabtree; Arlene E. Dent

    Monocytes are innate immune cells essential for host protection against malaria. Upon activation, monocytes function to help reduce parasite burden through phagocytosis, cytokine production, and antigen presentation. However, monocytes have also been implicated in the pathogenesis of severe disease through production of damaging inflammatory cytokines, resulting in systemic inflammation and vascular dysfunction. Understanding the molecular pathways influencing the balance between protection and pathology is critical. In this review, we discuss recent data regarding the role of monocytes in human malaria, including studies of innate sensing of the parasite, immunometabolism, and innate immune training. Knowledge gained from these studies may guide rational development of novel antimalarial therapies and inform vaccine development.

    更新日期:2020-01-06
  • Differentiation and adaptation of natural killer cells for anti‐malarial immunity
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-24
    Martin R. Goodier; Asia‐Sophia Wolf; Eleanor M. Riley

    Natural killer cells employ a diverse arsenal of effector mechanisms to target intracellular pathogens. Differentiation of natural killer (NK) cell activation pathways occurs along a continuum from reliance on innate pro‐inflammatory cytokines and stress‐induced host ligands through to interaction with signals derived from acquired immune responses. Importantly, the degree of functional differentiation of the NK cell lineage influences the magnitude and specificity of interactions with host cells infected with viruses, bacteria, fungi, and parasites. Individual humans possess a vast diversity of distinct NK cell clones, each with the capacity to vary along this functional differentiation pathway, which ‐ when combined ‐ results in unique individual responses to different infections. Here we summarize these NK cell differentiation events, review evidence for direct interaction of malaria‐infected host cells with NK cells and assess how innate inflammatory signals induced by malaria parasite‐associated molecular patterns influence the indirect activation and function of NK cells. Finally, we discuss evidence that anti‐malarial immunity develops in parallel with advancing NK differentiation, coincident with a loss of reliance on inflammatory signals, and a refined capacity of NK cells to target malaria parasites more precisely, particularly through antibody‐dependent mechanisms.

    更新日期:2020-01-06
  • Complement in malaria immunity and vaccines
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-26
    Liriye Kurtovic; Michelle J. Boyle; D. Herbert Opi; Alexander T. Kennedy; Wai‐Hong Tham; Linda Reiling; Jo‐Anne Chan; James G. Beeson

    Developing efficacious vaccines for human malaria caused by Plasmodium falciparum is a major global health priority, although this has proven to be immensely challenging over the decades. One major hindrance is the incomplete understanding of specific immune responses that confer protection against disease and/or infection. While antibodies to play a crucial role in malaria immunity, the functional mechanisms of these antibodies remain unclear as most research has primarily focused on the direct inhibitory or neutralizing activity of antibodies. Recently, there is a growing body of evidence that antibodies can also mediate effector functions through activating the complement system against multiple developmental stages of the parasite life cycle. These antibody‐complement interactions can have detrimental consequences to parasite function and viability, and have been significantly associated with protection against clinical malaria in naturally acquired immunity, and emerging findings suggest these mechanisms could contribute to vaccine‐induced immunity. In order to develop highly efficacious vaccines, strategies are needed that prioritize the induction of antibodies with enhanced functional activity, including the ability to activate complement. Here we review the role of complement in acquired immunity to malaria, and provide insights into how this knowledge could be used to harness complement in malaria vaccine development.

    更新日期:2020-01-06
  • B‐cell memory in malaria: Myths and realities
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-16
    Damián Pérez‐Mazliah; Francis M. Ndungu; Racheal Aye; Jean Langhorne

    B‐cell and antibody responses to Plasmodium spp., the parasite that causes malaria, are critical for control of parasitemia and associated immunopathology. Antibodies also provide protection to reinfection. Long‐lasting B‐cell memory has been shown to occur in response to Plasmodium spp. in experimental model infections, and in human malaria. However, there are reports that antibody responses to several malaria antigens in young children living with malaria are not similarly long‐lived, suggesting a dysfunction in the maintenance of circulating antibodies. Some studies attribute this to the expansion of atypical memory B cells (AMB), which express multiple inhibitory receptors and activation markers, and are hyporesponsive to B‐cell receptor (BCR) restimulation in vitro. AMB are also expanded in other chronic infections such as tuberculosis, hepatitis B and C, and HIV, as well as in autoimmunity and old age, highlighting the importance of understanding their role in immunity. Whether AMB are dysfunctional remains controversial, as there are also studies in other infections showing that AMB can produce isotype‐switched antibodies and in mouse can contribute to protection against infection. In light of these controversies, we review the most recent literature on either side of the debate and challenge some of the currently held views regarding B‐cell responses to Plasmodium infections.

    更新日期:2020-01-06
  • The regulation of CD4+ T cells during malaria
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-01
    Rajiv Kumar; Jessica R. Loughland; Susanna S. Ng; Michelle J. Boyle; Christian R. Engwerda

    Malaria is a major global health problem. Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria‐endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug‐resistant parasites. Immune responses generated against Plasmodium parasites that cause malaria are generally not sufficient to prevent the establishment of infection and can even contribute to the development of disease, unless individuals have survived multiple infections. Research conducted in experimental models, controlled human malaria infection studies, and with malaria patients from disease‐endemic areas indicate the rapid development of immunoregulatory pathways in response to Plasmodium infection. These “imprinted” immune responses limit inflammation, and likely prevent progression to severe disease manifestations. However, they also cause slow acquisition of immunity and possibly hamper the development of vaccine‐mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4+ T cells that play critical roles in priming phagocytic cells to capture and kill malaria parasites, as well as helping B cells produce functional anti‐parasitic antibodies. In this review, we describe mechanisms of CD4+ T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti‐parasitic and pathological functions. We also offer some ideas about how host‐directed approaches might be applied to modulate CD4+ T cell functions to improve vaccine responses and enhance development of natural immunity.

    更新日期:2020-01-06
  • Using two phases of the CD4 T cell response to blood‐stage murine malaria to understand regulation of systemic immunity and placental pathology in Plasmodium falciparum infection
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-06
    Komi Gbedande; Victor H. Carpio; Robin Stephens

    Plasmodium falciparum infection and malaria remain a risk for millions of children and pregnant women. Here, we seek to integrate knowledge of mouse and human T helper cell (Th) responses to blood‐stage Plasmodium infection to understand their contribution to protection and pathology. Although there is no complete Th subset differentiation, the adaptive response occurs in two phases in non‐lethal rodent Plasmodium infection, coordinated by Th cells. In short, cellular immune responses limit the peak of parasitemia during the first phase; in the second phase, humoral immunity from T cell–dependent germinal centers is critical for complete clearance of rapidly changing parasite. A strong IFN‐γ response kills parasite, but an excess of TNF compared with regulatory cytokines (IL‐10, TGF‐β) can cause immunopathology. This common pathway for pathology is associated with anemia, cerebral malaria, and placental malaria. These two phases can be used to both understand how the host responds to rapidly growing parasite and how it attempts to control immunopathology and variation. This dual nature of T cell immunity to Plasmodium is discussed, with particular reference to the protective nature of the continuous generation of effector T cells, and the unique contribution of effector memory T cells.

    更新日期:2020-01-06
  • Deciphering host immunity to malaria using systems immunology
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-14
    Claire Loiseau; Martha M. Cooper; Denise L. Doolan

    A century of conceptual and technological advances in infectious disease research has changed the face of medicine. However, there remains a lack of effective interventions and a poor understanding of host immunity to the most significant and complex pathogens, including malaria. The development of successful interventions against such intractable diseases requires a comprehensive understanding of host‐pathogen immune responses. A major advance of the past decade has been a paradigm switch in thinking from the contemporary reductionist (gene‐by‐gene or protein‐by‐protein) view to a more holistic (whole organism) view. Also, a recognition that host‐pathogen immunity is composed of complex, dynamic interactions of cellular and molecular components and networks that cannot be represented by any individual component in isolation. Systems immunology integrates the field of immunology with omics technologies and computational sciences to comprehensively interrogate the immune response at a systems level. Herein, we describe the system immunology toolkit and report recent studies deploying systems‐level approaches in the context of natural exposure to malaria or controlled human malaria infection. We contribute our perspective on the potential of systems immunity for the rational design and development of effective interventions to improve global public health.

    更新日期:2020-01-06
  • Decoding the complexities of human malaria through systems immunology
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-03
    Tuan M. Tran; Peter D. Crompton

    The complexity of the Plasmodium parasite and its life cycle poses a challenge to our understanding of the host immune response against malaria. Studying human immune responses during natural and experimental Plasmodium infections can enhance our understanding of malaria‐protective immunity and inform the design of disease‐modifying adjunctive therapies and next‐generation malaria vaccines. Systems immunology can complement conventional approaches to facilitate our understanding of the complex immune response to the highly dynamic malaria parasite. In this review, recent studies that used systems‐based approaches to evaluate human immune responses during natural and experimental Plasmodium falciparum and Plasmodium vivax infections as well as during immunization with candidate malaria vaccines are summarized and related to each other. The potential for next‐generation technologies to address the current limitations of systems‐based studies of human malaria are discussed.

    更新日期:2020-01-06
  • The immunology of Plasmodium vivax malaria
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-23
    Lis R. Antonelli; Caroline Junqueira; Joseph M Vinetz; Douglas T. Golenbock; Marcelo U. Ferreira; Ricardo T. Gazzinelli

    Plasmodium vivax infection, the predominant cause of malaria in Asia and Latin America, affects ~14 million individuals annually, with considerable adverse effects on wellbeing and socioeconomic development. A clinical hallmark of Plasmodium infection, the paroxysm, is driven by pyrogenic cytokines produced during the immune response. Here, we review studies on the role of specific immune cell types, cognate innate immune receptors, and inflammatory cytokines on parasite control and disease symptoms. This review also summarizes studies on recurrent infections in individuals living in endemic regions as well as asymptomatic infections, a serious barrier to eliminating this disease. We propose potential mechanisms behind these repeated and subclinical infections, such as poor induction of immunological memory cells and inefficient T effector cells. We address the role of antibody‐mediated resistance to P. vivax infection and discuss current progress in vaccine development. Finally, we review immunoregulatory mechanisms, such as inhibitory receptors, T regulatory cells, and the anti‐inflammatory cytokine, IL‐10, that antagonizes both innate and acquired immune responses, interfering with the development of protective immunity and parasite clearance. These studies provide new insights for the clinical management of symptomatic as well as asymptomatic individuals and the development of an efficacious vaccine for vivax malaria.

    更新日期:2020-01-06
  • Immunity against sexual stage Plasmodium falciparum and Plasmodium vivax parasites
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-16
    Roos M. de Jong; Surafel K. Tebeje; Lisette Meerstein‐Kessel; Fitsum G. Tadesse; Matthijs M. Jore; Will Stone; Teun Bousema

    The efficient spread of malaria from infected humans to mosquitoes is a major challenge for malaria elimination initiatives. Gametocytes are the only Plasmodium life stage infectious to mosquitoes. Here, we summarize evidence for naturally acquired anti‐gametocyte immunity and the current state of transmission blocking vaccines (TBV). Although gametocytes are intra‐erythrocytic when present in infected humans, developing Plasmodium falciparum gametocytes may express proteins on the surface of red blood cells that elicit immune responses in naturally exposed individuals. This immune response may reduce the burden of circulating gametocytes. For both P. falciparum and Plasmodium vivax, there is a solid evidence that antibodies against antigens present on the gametocyte surface, when co‐ingested with gametocytes, can influence transmission to mosquitoes. Transmission reducing immunity, reducing the burden of infection in mosquitoes, is a well‐acknowledged but poorly quantified phenomenon that forms the basis for the development of TBV. Transmission enhancing immunity, increasing the likelihood or intensity of transmission to mosquitoes, is more speculative in nature but is convincingly demonstrated for P. vivax. With the increased interest in malaria elimination, TBV and monoclonal antibodies have moved to the center stage of malaria vaccine development. Methodologies to prioritize and evaluate products are urgently needed.

    更新日期:2020-01-06
  • The immune response to malaria in utero
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-25
    Margaret E. Feeney

    Malaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malaria‐specific T‐ and B‐cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strategies.

    更新日期:2020-01-06
  • Cerebral Plasmodium falciparum malaria: The role of PfEMP1 in its pathogenesis and immunity, and PfEMP1‐based vaccines to prevent it
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-27
    Anja Ramstedt Jensen; Yvonne Adams; Lars Hviid

    Malaria, a mosquito‐borne infectious disease caused by parasites of the genus Plasmodium continues to be a major health problem worldwide. The unicellular Plasmodium‐parasites have the unique capacity to infect and replicate within host erythrocytes. By expressing variant surface antigens Plasmodium falciparum has evolved to avoid protective immune responses; as a result in endemic areas anti‐malaria immunity develops gradually over many years of multiple and repeated infections. We are studying the role of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed by asexual stages of P. falciparum responsible for the pathogenicity of severe malaria. The immunopathology of falciparum malaria has been linked to cyto‐adhesion of infected erythrocytes to specific host receptors. A greater appreciation of the PfEMP1 molecules important for the development of protective immunity and immunopathology is a prerequisite for the rational discovery and development of a safe and protective anti‐disease malaria vaccine. Here we review the role of ICAM‐1 and EPCR receptor adhering falciparum‐parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of developing a vaccine targeted specifically to prevent this disease.

    更新日期:2020-01-06
  • Fast and fierce versus slow and smooth: Heterogeneity in immune responses to Plasmodium in the controlled human malaria infection model
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-12
    Xi Zen Yap; Matthew B. B. McCall; Robert W. Sauerwein

    Controlled human malaria infection (CHMI) is an established model in clinical malaria research. Upon exposure to Plasmodium falciparum parasites, malaria‐naive volunteers differ in dynamics and composition of their immune profiles and subsequent capacity to generate protective immunity. CHMI volunteers are either inflammatory responders who have prominent cellular IFN‐γ production primarily driven by adaptive T cells, or tempered responders who skew toward antibody‐mediated humoral immunity. When exposed to consecutive CHMIs under antimalarial chemoprophylaxis, individuals who can control parasitemia after a single immunization (fast responders) are more likely to be protected against a subsequent challenge infection. Fast responders tend to be inflammatory responders who can rapidly induce long‐lived IFN‐γ+ T cell responses. Slow responders or even non‐responders can also be protected, but via a more diverse range of responses that take a longer time to reach full protective efficacy, in part due to their tempered phenotype. The latter group can be identified at baseline before CHMI by higher expression of inhibitory ligands CTLA‐4 and TIM‐3 on CD4+ T cells. Delineating heterogeneity in human immune responses to P. falciparum will facilitate rational design and strategy towards effective malaria vaccines.

    更新日期:2020-01-06
  • Whole parasite vaccines for the asexual blood stages of Plasmodium
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-10
    Michael F. Good; Danielle I. Stanisic

    After many decades of research, an effective vaccine for malaria is still not available. Most research efforts have focused on identifying a key target antigen and then using powerful adjuvants to generate specific antibodies that can block parasites from entering host cells (hepatocytes, red blood cells). However, the inability to generate sufficiently potent antibody responses has led to significant disappointment with current vaccine programs. An additional challenge for sub‐unit vaccines is that key vaccine antigens are highly polymorphic. These challenges have spurred radically different approaches to malaria vaccine development. Many of these involve the use of “whole parasites”—either extracted from mosquitoes or cultured. With these, every parasite molecule for that particular strain is included in the vaccine. This strategy is showing great promise following several clinical trials with irradiated sporozoites. However, a whole‐parasite approach to a blood stage vaccine has not advanced as quickly. This article outlines the history, the different approaches that are being taken and the challenges associated with whole parasite blood stage vaccines and discusses recent exciting developments as these vaccines now move into the clinic.

    更新日期:2020-01-06
  • Role of lymph node stroma and microenvironment in T cell tolerance
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-19
    Vikas Saxena; Lushen Li; Christina Paluskievicz; Vivek Kasinath; Asher Bean; Reza Abdi; Christopher M. Jewell; Jonathan S. Bromberg

    Lymph nodes (LNs) are at the cross roads of immunity and tolerance. These tissues are compartmentalized into specialized niche areas by lymph node stromal cells (LN SCs). LN SCs shape the LN microenvironment and guide immunological cells into different zones through establishment of a CCL19 and CCL21 gradient. Following local immunological cues, LN SCs modulate activity to support immune cell priming, activation, and fate. This review will present our current understanding of LN SC subsets roles in regulating T cell tolerance. Three major types of LN SC subsets, namely fibroblastic reticular cells, lymphatic endothelial cells, and blood endothelial cells, are discussed. These subsets serve as scaffolds to support and regulate T cell homeostasis. They contribute to tolerance by presenting peripheral tissue antigens to both CD4 and CD8 T cells. The role of LN SCs in regulating T cell migration and tolerance induction is discussed. Looking forward, recent advances in bioengineered materials and approaches to leverage LN SCs to induce T cell tolerance are highlighted, as are current clinical practices that allow for manipulation of the LN microenvironment to induce tolerance. Increased understanding of LN architecture, how different LN SCs integrate immunological cues and shape immune responses, and approaches to induce T cell tolerance will help further combat autoimmune diseases and graft rejection.

    更新日期:2019-12-29
  • Minding the gap: The impact of B‐cell tolerance on the microbial antibody repertoire
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-27
    Joel Finney; Akiko Watanabe; Garnett Kelsoe; Masayuki Kuraoka

    B lymphocytes must respond to vast numbers of foreign antigens, including those of microbial pathogens. To do so, developing B cells use combinatorial joining of V‐, D‐, and J‐gene segments to generate an extraordinarily diverse repertoire of B‐cell antigen receptors (BCRs). Unsurprisingly, a large fraction of this initial BCR repertoire reacts to self‐antigens, and these “forbidden” B cells are culled by immunological tolerance from mature B‐cell populations. While culling of autoreactive BCRs mitigates the risk of autoimmunity, it also opens gaps in the BCR repertoire, which are exploited by pathogens that mimic the forbidden self‐epitopes. Consequently, immunological tolerance, necessary for averting autoimmune disease, also acts to limit effective microbial immunity. In this brief review, we recount the evidence for the linkage of tolerance and impaired microbial immunity, consider the implications of this linkage for vaccine development, and discuss modulating tolerance as a potential strategy for strengthening humoral immune responses.

    更新日期:2019-12-29
  • Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-20
    Corey Tan; Mark Noviski; John Huizar; Julie Zikherman

    Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self‐reactive B cell receptors (BCRs) from populating the periphery. Despite this, modest self‐reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77‐eGFP, expression of which scales with the degree of self‐reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self‐reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance.

    更新日期:2019-12-29
  • Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-26
    Deborah L. Burnett; Joanne H. Reed; Daniel Christ; Christopher C. Goodnow

    The adaptive immune system is tasked with producing antibodies that recognize a wide scope of potential pathogens, including those never before encountered, and concurrently avoiding formation of antibodies binding host tissues. The diverse repertoire of antibodies produced by V(D)J recombination inevitably includes autoantibodies that bind to self‐antigens, estimated to be as much as 70% of nascent antibodies on immature B cells. Early theoretical models of tolerance hypothesized that such self‐reactive clones could not possibly be allowed to survive and mature. However from the first direct view of the fate of nascent B cells carrying a self‐binding antibody it was clear that many “forbidden clones” circulate to secondary lymphoid tissues, where they adopt an IgMlow IgD+ cell surface phenotype and are prevented from secreting autoantibodies by a series of tolerance checkpoints referred to as “clonal anergy.” Since anergic B cells can be reactivated to secrete pathogenic autoantibodies in certain settings, the advantage of controlling self‐reactive antibodies by clonal anergy has until recently remained enigmatic. Here we review this topic and recent advances showing that anergic B cells are recruited into the germinal center to mutate away from self‐reactivity, undergoing “clonal redemption” into cells making antibodies with exquisite specificity for foreign immunogens.

    更新日期:2019-12-29
  • Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-22
    Kevin S. Cashman; Scott A. Jenks; Matthew C. Woodruff; Deepak Tomar; Christopher M. Tipton; Christopher D. Scharer; F. Eun‐Hyung Lee; Jeremy M. Boss; Iñaki Sanz

    The maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B‐cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess. Functional autoreactive, flow cytometric, and single‐cell cloning assays have proven to be critical in deciphering breaks in B‐cell tolerance within autoimmunity; however, newer approaches to assess human B‐cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.

    更新日期:2019-12-29
  • Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-12
    Eric Meffre; Kevin C. O'Connor

    A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti‐CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B‐cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B‐cell tolerance defects are primary to autoimmune diseases and may result from altered B‐cell receptor signaling and dysregulated T‐cell/regulatory T‐cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self‐antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27−CD21−/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self‐antigens.

    更新日期:2019-12-29
  • BAFF inhibition in SLE—Is tolerance restored?
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-28
    Shaun W Jackson; Anne Davidson

    The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF‐like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low‐affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM‐ and IgG‐producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

    更新日期:2019-12-29
  • Autoreactive B cells in SLE, villains or innocent bystanders?
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-21
    Jennie A. Hamilton; Hui‐Chen Hsu; John D. Mountz

    The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B‐cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B‐cells encounter T‐follicular helper cells (Tfh) that produce interleukin (IL)‐21, IL‐4 and pathogenic cytokines, IL‐17 and IFN gamma (IFNɣ). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B‐cell stage as a major juncture where transient autocrine IFNβ expression by developing B‐cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody‐producing plasmablasts. Recent studies highlight transitional B‐cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B‐cell responsiveness to cytokines and other environment factors.

    更新日期:2019-12-29
  • T‐cell exhaustion in HIV infection
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-27
    Craig Fenwick; Victor Joo; Patricia Jacquier; Alessandra Noto; Riddhima Banga; Matthieu Perreau; Giuseppe Pantaleo

    The T‐cell response is central in the adaptive immune‐mediated elimination of pathogen‐infected and/or cancer cells. This activated T‐cell response can inflict an overwhelming degree of damage to the targeted cells, which in most instances leads to the control and elimination of foreign invaders. However, in conditions of chronic infection, persistent exposure of T cells to high levels of antigen results in a severe T‐cell dysfunctional state called exhaustion. T‐cell exhaustion leads to a suboptimal immune‐mediated control of multiple viral infections including the human immunodeficiency virus (HIV). In this review, we will discuss the role of T‐cell exhaustion in HIV disease progression, the long‐term defect of T‐cell function even in aviremic patients on antiretroviral therapy (ART), the role of exhaustion‐specific markers in maintaining a reservoir of latently infected cells, and exploiting these markers in HIV cure strategies.

    更新日期:2019-12-29
  • Exhaustion may not be in the human B cell vocabulary, at least not in malaria
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-25
    Prasida Holla; Abhijit Ambegaonkar; Haewon Sohn; Susan K. Pierce

    T cells exposed to persistent antigen in the inflammatory environment of chronic infections often show progressive loss of effector functions, high expression of inhibitory receptors and distinct transcriptional programs. T cells in this functional state are termed “exhausted” and T cell exhaustion is associated with inefficient control of infections. A remarkably similar scenario has been described for B cells during chronic infections in humans, including malaria, in which case a subpopulation of atypical memory B cells (MBCs) greatly expands and these MBCs show attenuation of B cell receptor signaling, loss of the B cell effector functions of antibody and cytokine production, high expression of inhibitory receptors and distinct transcriptional profiles. The expansion of these MBCs is also associated with inefficient control of infections. Despite the similarities with exhausted T cells we speculate that at least in malaria, atypical MBCs may not be exhausted but rather may be functional, possibly even beneficial. Our recent results suggest that we simply may not have known how to ask an atypical MBC to function. Thus, exhaustion may not be in the human B cell's vocabulary, at least not in malaria.

    更新日期:2019-12-29
  • Regulatory B cells: Development, phenotypes, functions, and role in transplantation
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-27
    Rowa Y. Alhabbab; Estefanía Nova-Lamperti; Octavio Aravena; Hannah M. Burton; Robert I. Lechler; Anthony Dorling; Giovanna Lombardi

    The interest in regulatory B cells (Bregs) began in the 1970s with the evidence that B cells could downregulate the immune system by the production of “inhibitory” antibodies. Subsequently, a series of results from different studies have emphasized that B cells have antibody‐independent immunoregulatory functions. Since then, different subsets of B cells with regulatory functions and their development and mechanisms of action have been identified both in human and in animal models of inflammation, transplantation, and autoimmunity. The present review outlines the suggested pathways by which Bregs develop, describes the different subsets of Bregs with their phenotypes and function as well as their role in transplantation, highlighting the differences between human and animal studies throughout.

    更新日期:2019-12-29
  • The five dimensions of B cell tolerance
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-14
    Jeffrey L. Platt; Mayara Garcia de Mattos Barbosa; Marilia Cascalho

    B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto‐toxicity. As useful as this understanding has proved, it fails to fully explain the existence of auto‐reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells and antigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto‐reactive and absence of these auto‐reactive B cells is associated with disease. We suggest that auto‐reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease.

    更新日期:2019-12-29
  • The emerging role of regulatory T cells following lung transplantation
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-19
    Jason M. Gauthier; M. Shea Harrison; Alexander S. Krupnick; Andrew E. Gelman; Daniel Kreisel

    Regulatory T cells (Treg) have proven to be a powerful immunologic force in nearly every organ system and hold therapeutic potential for a wide range of diseases. Insights gained from non‐transplant pathologies, such as infection, cancer, and autoimmunity, are now being translated to the field of solid organ transplantation, particularly for livers and kidneys. Recent insights from animal models of lung transplantation have established that Tregs play a vital role in suppressing rejection and facilitating tolerance of lung allografts, and such discoveries are being validated in human studies and preclinical trials. Given that long‐term outcomes following lung transplantation remain profoundly limited by chronic rejection, Treg therapy holds the potential to significantly improve patient outcomes and should be aggressively investigated.

    更新日期:2019-12-29
  • Future prospects for CD8+ regulatory T cells in immune tolerance
    Immunol. Rev. (IF 11.292) Pub Date : 2019-10-08
    Léa Flippe; Séverine Bézie; Ignacio Anegon; Carole Guillonneau

    CD8+ Tregs have been long described and significant progresses have been made about their phenotype, their functional mechanisms, and their suppressive ability compared to conventional CD4+ Tregs. They are now at the dawn of their clinical use. In this review, we will summarize their phenotypic characteristics, their mechanisms of action, the similarities, differences and synergies between CD8+ and CD4+ Tregs, and we will discuss the biology, development and induction of CD8+ Tregs, their manufacturing for clinical use, considering open questions/uncertainties and future technically accessible improvements notably through genetic modifications.

    更新日期:2019-12-29
  • Memory T‐cell exhaustion and tolerance in transplantation
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-05
    Christina R. Hartigan; He Sun; Mandy L. Ford

    One of the biggest barriers to achieving allograft tolerance is the presence of immunological memory within the recipient, which confers a faster, more robust immune response that is in most cases more resistant to pharmacologic immunosuppression. This review will identify the mechanisms by which alloreactive T cells arise within hosts prior to transplantation, and explore the properties of immunological memory that contribute to allograft rejection. In doing so we will also illuminate how targeting pathways that induce memory T cell exhaustion can promote allograft tolerance. Recent studies demonstrating the impact of the allograft microenvironment on memory cell survival and activation, as well as new therapeutic strategies that are being explored to mitigate memory driven allograft rejection, will also be reviewed.

    更新日期:2019-12-29
  • Impact of infection on transplantation tolerance
    Immunol. Rev. (IF 11.292) Pub Date : 2019-09-19
    Shuangjin Yu; Chang Su; Xunrong Luo

    Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection‐tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti‐pathogen immunity in clinically relevant scenarios.

    更新日期:2019-12-29
  • Insights into the study and origin of the citrullinome in rheumatoid arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-25
    Justyna Fert‐Bober; Erika Darrah; Felipe Andrade

    The presence of autoantibodies and autoreactive T cells to citrullinated proteins and citrullinating enzymes in patients with rheumatoid arthritis (RA), together with the accumulation of citrullinated proteins in rheumatoid joints, provides substantial evidence that dysregulated citrullination is a hallmark feature of RA. However, understanding mechanisms that dysregulate citrullination in RA has important challenges. Citrullination is a normal process in immune and non‐immune cells, which is likely activated by different conditions (eg, inflammation) with no pathogenic consequences. In a complex inflammatory environment such as the RA joint, unique strategies are therefore required to dissect specific mechanisms involved in the abnormal production of citrullinated proteins. Here, we will review current models of citrullination in RA and discuss critical components that, in our view, are relevant to understanding the accumulation of citrullinated proteins in the RA joint, collectively referred to as the RA citrullinome. In particular, we will focus on potential caveats in the study of citrullination in RA and will highlight methods to precisely detect citrullinated proteins in complex biological samples, which is a confirmatory approach to mechanistically link the RA citrullinome with unique pathogenic pathways in RA.

    更新日期:2019-12-27
  • Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-19
    Georgiana Cabău; Tania O. Crișan; Viola Klück; Radu A. Popp; Leo A. B. Joosten

    Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage‐associated molecules leading to an enhanced non‐specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low‐grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long‐term systemic inflammation seen in gout. We revisit existing evidence for urate‐induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.

    更新日期:2019-12-19
  • Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-16
    Mikhail Volkov; Karin Anna van Schie; Diane van der Woude

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

    更新日期:2019-12-18
  • Microbial orchestra in juvenile idiopathic arthritis: Sounds of disarray?
    Immunol. Rev. (IF 11.292) Pub Date : 2019-12-13
    Miika Arvonen; Petri Vänni; Aditya Narayan Sarangi; Mysore V Tejesvi; Paula Vähäsalo; Amita Aggarwal; Matthew L Stoll

    The role of the microbiota in multiple autoimmune diseases, including juvenile idiopathic arthritis (JIA) has earned substantial attention in the last 10 years. Increasing evidence suggests that the microbiota's link to JIA begins in early childhood, as early life events that influence the nature of the microbiota also appear to influence disease risk. In this review, we discuss these early life events including mode of delivery, infant feeding practice, antibiotics exposure, and other events and their impacts on the microbiota and on disease risk; reported abnormalities of the microbiota in children with JIA; mechanisms by which an altered microbiota at birth and later on in childhood may influence disease risk; and the prospects for therapeutic alteration of the microbiota in children with JIA.

    更新日期:2019-12-13
  • Advances in genetics toward identifying pathogenic cell states of rheumatoid arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-28
    Tiffany Amariuta, Yang Luo, Rachel Knevel, Yukinori Okada, Soumya Raychaudhuri

    Rheumatoid arthritis (RA) risk has a large genetic component (~60%) that is still not fully understood. This has hampered the design of effective treatments that could promise lifelong remission. RA is a polygenic disease with 106 known genome‐wide significant associated loci and thousands of small effect causal variants. Our current understanding of RA risk has suggested cell‐type‐specific contexts for causal variants, implicating CD4 + effector memory T cells, as well as monocytes, B cells and stromal fibroblasts. While these cellular states and categories are still mechanistically broad, future studies may identify causal cell subpopulations. These efforts are propelled by advances in single cell profiling. Identification of causal cell subpopulations may accelerate therapeutic intervention to achieve lifelong remission.

    更新日期:2019-11-30
  • Pathogenic Th1 responses in CHIKV‐induced inflammation and their modulation upon Plasmodium parasites co‐infection
    Immunol. Rev. (IF 11.292) Pub Date : 2019-11-26
    Anthony Torres‐Ruesta, Teck‐Hui Teo, Yi‐Hao Chan, Laurent Rénia, Lisa F. P. Ng

    The induction of polyarthritis and polyarthralgia is a hallmark of arthritogenic alphavirus infections, with an exceptionally higher morbidity observed with chikungunya virus (CHIKV). While the mechanisms underlying these incapacitating acute symptoms remain partially understood, the progression to chronic conditions in some cases remains unanswered. The highly pro‐inflammatory nature of alphavirus disease has suggested the involvement of virus‐specific, joint‐infiltrating Th1 cells as one of the main pathogenic mediators of CHIKV‐induced joint pathologies. This review summarizes the role of cell‐mediated immune responses in CHIKV pathogenesis, with a specific focus on pro‐inflammatory Th1 responses in the development of CHIKV joint inflammation. Furthermore, due to the explosive nature of arthritogenic alphavirus outbreaks and their recent expansion across the world, co‐infections with other highly prevalent pathogens such as malaria are likely to occur but the pathological outcomes of such interactions in humans are unknown. This review will also discuss the potential impact of malaria co‐infections on CHIKV pathogenesis and their relevance in alphavirus control programs in endemic areas.

    更新日期:2019-11-28
  • Regulation of NK cell responsiveness to achieve self-tolerance and maximal responses to diseased target cells.
    Immunol. Rev. (IF 11.292) Pub Date : 2008-09-02
    Nathalie T Joncker,David H Raulet

    Inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules govern the capacity of natural killer (NK) cells to attack class I-deficient cells ('missing-self recognition'). These receptors are expressed stochastically, such that the panel of expressed receptors varies between NK cells. This review addresses how the activity of NK cells is coordinated in the face of this variation to achieve a repertoire that is self-tolerant and optimally reactive with diseased cells. Recent studies show that NK cells arise in normal animals or humans that lack any known inhibitory receptors specific for self-MHC class I. These NK cells exhibit self-tolerance and exhibit functional hyporesponsiveness to stimulation through various activating receptors. Evidence suggests that hyporesponsiveness is induced because these NK cells cannot engage inhibitory MHC class I molecules and are therefore persistently over-stimulated by normal cells in the environment. Finally, we discuss evidence that hyporesponsiveness is a quantitative trait that varies depending on the balance of signals encountered by developing NK cells. Thus, a tuning process determines the functional set-point of NK cells, providing a basis for discriminating self from missing-self, and at the same time endowing each NK cell with the highest inherent responsiveness compatible with self-tolerance.

    更新日期:2019-11-01
  • 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes.
    Immunol. Rev. (IF 11.292) Pub Date : 2001-08-22
    K S Boles,S E Stepp,M Bennett,V Kumar,P A Mathew

    2B4 is a member of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer (NK) cells and other leukocytes. It is the high affinity ligand for CD48. Engagement of 2B4 on NK-cell surfaces with specific antibodies or CD48 can trigger cell-mediated cytotoxicity, interferon-gamma secretion, phosphoinositol turnover and NK-cell invasiveness. The function of 2B4 in CD8+ T cells and myeloid cells remains unknown. The cytoplasmic domain of 2B4 contains unique tyrosine motifs (TxYxxV/I) that associate with src homology 2 domain-containing protein or signaling lymphocyte activation molecule (SLAM)-associated protein, whose mutation is the underlying genetic defect in the X-linked lymphoproliferative disease (XLPD). Impaired signaling via 2B4 and SLAM is implicated in the immunopathogenesis of XLPD. CS1 is a novel member of the CD2 subset that contains two of the unique tyrosine motifs present in 2B4 and SLAM. Signaling through 2B4, CS1 and other members of the CD2 subset may play a major role in the regulation of NK cells and other leukocyte functions.

    更新日期:2019-11-01
  • Challenges in the pursuit of immune tolerance.
    Immunol. Rev. (IF 11.292) Pub Date : 2011-04-15
    Gerald T Nepom,E William St Clair,Laurence A Turka

    Strategies for inducing immune tolerance are fundamentally similar across a spectrum of immune-mediated disorders, including allergic disease, autoimmunity, and rejection of allografts. In each case, the objective of establishing an immunoregulatory balance is challenged by variable upswings in effector cell populations and proinflammatory mediators of immunity, requiring careful, and innovative therapeutic intervention to restore stability. The Immune Tolerance Network, an international consortium sponsored by the National Institutes of Health, seeks to advance both the scientific understanding and the clinical success of immune therapies for these disorders, through an innovative and collaborative effort involving clinical trials and mechanistic studies. Over the last decade, scientists have evaluated cell-based ablation and deviation strategies in trials using lymphocyte-specific targeting, induction of host-donor hematopoietic chimerism, induction of antigen-specific immune regulation, and a variety of antigen desensitization approaches. In this article, we review some of the highlights of this experience and discuss the potential for progress, utilizing new insights into regulatory mechanisms and biomarker signatures of tolerance.

    更新日期:2019-11-01
  • The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse.
    Immunol. Rev. (IF 11.292) Pub Date : 2013-10-15
    Kathryn Lagrue,Alex Carisey,Anna Oszmiana,Philippa R Kennedy,David J Williamson,Adam Cartwright,Charlotte Barthen,Daniel M Davis

    Natural killer (NK) cells discriminate between healthy and unhealthy target cells through a balance of activating and inhibitory signals at direct intercellular contacts called immune synapses. Rearrangements in the cellular cytoskeleton have long been known to be critical in assembly of immune synapses. Here, through bringing together the vast literature on this subject, the number of different ways in which the cytoskeleton is important becomes evident. The dynamics of filamentous actin are critical in (i) creating the nanometer-scale organization of NK cell receptors, (ii) establishing cellular polarity, (iii) coordinating immune receptor and integrin-mediated signaling, and (iv) directing secretion of lytic granules and cytokines. The microtubule network also is important in the delivery of lytic granules and vesicles containing cytokines to the immune synapse. Together, these data establish that the cytoskeleton acts as a central regulator of this complex and dynamic process - and an enormous amount of NK cell biology is controlled through the cytoskeleton.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Apoptotic cell recognition receptors and scavenger receptors.
    Immunol. Rev. (IF 11.292) Pub Date : 2015-12-20
    Kristen K Penberthy,Kodi S Ravichandran

    Phosphatidylserine recognition receptors are a highly diverse set of receptors grouped by their ability to recognize the 'eat-me' signal phosphatidylserine on apoptotic cells. Most of the phosphatidylserine recognition receptors dampen inflammation by inducing the production of anti-inflammatory mediators during the phagocytosis of apoptotic corpses. However, many phosphatidylserine receptors are also capable of recognizing other ligands, with some receptors being categorized as scavenger receptors. It is now appreciated that these receptors can elicit different downstream events for particular ligands. Therefore, how phosphatidylserine recognition receptors mediate specific signals during recognition of apoptotic cells versus other ligands, and how this might help regulate the inflammatory state of a tissue is an important question that is not fully understood. Here, we revisit the work on signaling downstream of the phosphatidylserine recognition receptor BAI1, and evaluate how these and other signaling modules mediate signaling downstream from other receptors, including Stabilin-2, MerTK, and αvβ5. We also propose the concept that phosphatidylserine recognition receptors could be viewed as a subset of scavenger receptors that are capable of eliciting anti-inflammatory responses to apoptotic cells.

    更新日期:2019-11-01
  • Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.
    Immunol. Rev. (IF 11.292) Pub Date : 2017-06-29
    Paul S Foster,Steven Maltby,Helene F Rosenberg,Hock L Tay,Simon P Hogan,Adam M Collison,Ming Yang,Gerard E Kaiko,Philip M Hansbro,Rakesh K Kumar,Joerg Mattes

    In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+ T-helper type-2 lymphocytes (TH 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.

    更新日期:2019-11-01
  • HIV antibodies for treatment of HIV infection.
    Immunol. Rev. (IF 11.292) Pub Date : 2017-01-31
    David M Margolis,Richard A Koup,Guido Ferrari

    The bar is high to improve on current combination antiretroviral therapy (ART), now highly effective, safe, and simple. However, antibodies that bind the HIV envelope are able to uniquely target the virus as it seeks to enter new target cells, or as it is expressed from previously infected cells. Furthermore, the use of antibodies against HIV as a therapeutic may offer advantages. Antibodies can have long half-lives, and are being considered as partners for long-acting antiretrovirals for use in therapy or prevention of HIV infection. Early studies in animal models and in clinical trials suggest that such antibodies can have antiviral activity but, as with small-molecule antiretrovirals, the issues of viral escape and resistance will have to be addressed. Most promising, however, are the unique properties of anti-HIV antibodies: the potential ability to opsonize viral particles, to direct antibody-dependent cellular cytotoxicity (ADCC) against actively infected cells, and ultimately the ability to direct the clearance of HIV-infected cells by effector cells of the immune system. These distinctive activities suggest that HIV antibodies and their derivatives may play an important role in the next frontier of HIV therapeutics, the effort to develop treatments that could lead to an HIV cure.

    更新日期:2019-11-01
  • B-cell responses to HIV infection.
    Immunol. Rev. (IF 11.292) Pub Date : 2017-01-31
    Susan Moir,Anthony S Fauci

    The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV.

    更新日期:2019-11-01
  • The "ins and outs" of complement-driven immune responses.
    Immunol. Rev. (IF 11.292) Pub Date : 2016-10-27
    Simon Freeley,Claudia Kemper,Gaëlle Le Friec

    The complement system represents an evolutionary old and critical component of innate immunity where it forms the first line of defense against invading pathogens. Originally described as a heat-labile fraction of the serum responsible for the opsonization and subsequent lytic killing of bacteria, work over the last century firmly established complement as a key mediator of the general inflammatory response but also as an acknowledged vital bridge between innate and adaptive immunity. However, recent studies particularly spanning the last decade have provided new insights into the novel modes and locations of complement activation and highlighted unexpected additional biological functions for this ancient system, for example, in regulating basic processes of the cell. In this review, we will cover the current knowledge about complement's established and novel roles in innate and adaptive immunity with a focus on the functional differences between serum circulating and intracellularly active complement and will describe and discuss the newly discovered cross-talks of complement with other cell effector systems particularly during T-cell induction and contraction.

    更新日期:2019-11-01
  • Immunogenicity of therapeutic recombinant immunotoxins.
    Immunol. Rev. (IF 11.292) Pub Date : 2016-02-13
    Ronit Mazor,Masanori Onda,Ira Pastan

    Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have normal immune systems, but much less immunogenic in patients with hematologic malignancies where the immune system is suppressed. RITs have shown efficacy in refractory hairy cell leukemia and in some children with acute lymphoblastic leukemia, but have been much less effective in solid tumors, because neutralizing antibodies develop and prevent additional treatment cycles. In this paper we will (i) review data from clinical trials describing the immunogenicity of PE38 in different patient populations; (ii) review results from clinical trials using different immunosuppressive drugs; and (iii) describe our efforts to make new less-immunogenic RITs by identifying and removing T- and B-cell epitopes to hide the RIT from the immune system.

    更新日期:2019-11-01
  • Structure and dynamics of IgE-receptor interactions: FcεRI and CD23/FcεRII.
    Immunol. Rev. (IF 11.292) Pub Date : 2015-10-27
    Brian J Sutton,Anna M Davies

    Immunoglobulin E (IgE) is well known for its role in allergic disease, the manifestations of which are mediated through its two Fc receptors, FcεRI and CD23 (FcεRII). IgE and its interactions with these receptors are therefore potential targets for therapeutic intervention, and exciting progress has been made in this direction. Furthermore, recent structural studies of IgE-Fc, the two receptors, and of their complexes, have revealed a remarkable degree of plasticity at the IgE-CD23 interface and an even more remarkable degree of dynamic flexibility within the IgE molecule. Indeed, there is allosteric communication between the two receptor-binding sites, which we now know are located at some distance from each other in IgE-Fc (at opposite ends of the Cε3 domain). The conformational changes associated with FcεRI and CD23 binding to IgE-Fc ensure that their interactions are mutually incompatible, and it may be that this functional imperative has driven IgE to evolve such a dynamic structure. Appreciation of these new structural data has revised our view of IgE structure, shed light on the co-evolution of antibodies and their receptors, and may open up new therapeutic opportunities.

    更新日期:2019-11-01
  • NK cells: tuned by peptide?
    Immunol. Rev. (IF 11.292) Pub Date : 2015-08-19
    Jayajit Das,Salim I Khakoo

    Natural killer cells express multiple receptors for major histocompatibility complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG2 family of receptors parallels the conservation of MHC-E, the ligand for CD94:NKG2A/C/E. Binding of both CD94:NKG2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA-E binding non-inhibitory peptides augment inhibition at CD94:NKG2A, while HLA-C binding non-inhibitory peptides antagonize inhibition at KIR2DL2/3, implying that KIRs are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIRs, such as KIR2DL3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD94:NKGA. Conversely, NKG2A-positive NK cells sense MHC class I downregulation more efficiently than KIRs. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.

    更新日期:2019-11-01
  • Surveillance of cell and tissue perturbation by receptors in the LRC.
    Immunol. Rev. (IF 11.292) Pub Date : 2015-08-19
    John Trowsdale,Des C Jones,Alexander D Barrow,James A Traherne

    The human leukocyte receptor complex (LRC) encompasses several sets of genes with a common evolutionary origin and which form a branch of the immunoglobulin superfamily (IgSF). Comparisons of LRC genes both within and between species calls for a high degree of plasticity. The drive for this unprecedented level of variation is not known, but it relates in part to interaction of several LRC products with polymorphic human leukocyte antigen (HLA) class I molecules. However, the range of other proposed ligands for LRC products indicates a dynamic set of receptors that have adapted to detect target molecules relating to numerous cellular pathways. Several receptors in the complex bind a molecular signature in collagenous ligands. Others detect a variety of motifs relating to pathogens in addition to cellular stress, attesting to the opportunistic versatility of LRC receptors.

    更新日期:2019-11-01
  • The nucleic acid-sensing inflammasomes.
    Immunol. Rev. (IF 11.292) Pub Date : 2015-04-17
    Tsan Sam Xiao

    Inflammasomes are oligomeric signaling complexes that promote caspase activation and maturation of proinflammatory cytokines. Structural and biophysical studies have shed light on the mechanisms of nucleic acid recognition and signaling complex assembly involving the AIM2 (absent in myeloma 2) and IFI16 (γ-interferon-inducible protein 16) inflammasomes. However, our understanding of the mechanisms of the NLRP3 (nucleotide-binding oligomerization-like receptor family, pyrin domain-containing protein 3) activation, either by nucleic acids or by other reported stimuli, has remained elusive. Exciting recent progress on the filament formation by the ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) pyrin domain and the IFI16-double stranded DNA complex has established that the formation of higher order polymers is one of the general mechanisms for signaling platform assembly in innate immune system. The paradigm-changing discovery of the extracellular function of the NLRP3-ASC inflammasome has opened the door for therapeutic targeting the inflammasome filament formation for various clinical conditions. Future characterization of the canonical and non-canonical inflammasome complexes will undoubtedly reveal more surprises on their structure and function and enrich our understanding of the molecular mechanisms of ligand recognition, activation, and regulation.

    更新日期:2019-11-01
  • Cytokine and lipid mediator networks in tuberculosis.
    Immunol. Rev. (IF 11.292) Pub Date : 2015-02-24
    Katrin D Mayer-Barber,Alan Sher

    A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections.

    更新日期:2019-11-01
  • Protein ubiquitination in lymphoid malignancies.
    Immunol. Rev. (IF 11.292) Pub Date : 2014-12-17
    Yibin Yang,Louis M Staudt

    Human lymphoid malignancies inherit gene expression networks from their normal B-cell counterpart and co-opt them for their own oncogenic purpose, which is usually governed by transcription factors and signaling pathways. These transcription factors and signaling pathways are precisely regulated at multiple steps, including ubiquitin modification. Protein ubiqutination plays a role in almost all cellular events and in many human diseases. In the past few years, multiple studies have expanded the role of ubiquitination in the genesis of diverse lymphoid malignancies. Here, we discuss our current understanding of both proteolytic and non-proteolytic functions of the protein ubiquitination system and describe how it is involved in the pathogenesis of human lymphoid cancers. Lymphoid-restricted ubiquitination mechanisms, including ubiquitin E3 ligases and deubiquitinating enzymes, provide great opportunities for the development of targeted therapies for lymphoid cancers.

    更新日期:2019-11-01
  • Macrophage proliferation, provenance, and plasticity in macroparasite infection.
    Immunol. Rev. (IF 11.292) Pub Date : 2014-10-17
    Dominik Rückerl,Judith E Allen

    Macrophages have long been center stage in the host response to microbial infection, but only in the past 10-15 years has there been a growing appreciation for their role in helminth infection and the associated type 2 response. Through the actions of the IL-4 receptor α (IL-4Rα), type 2 cytokines result in the accumulation of macrophages with a distinctive activation phenotype. Although our knowledge of IL-4Rα-induced genes is growing rapidly, the specific functions of these macrophages have yet to be established in most disease settings. Understanding the interplay between IL-4Rα-activated macrophages and the other cellular players is confounded by the enormous transcriptional heterogeneity within the macrophage population and by their highly plastic nature. Another level of complexity is added by the new knowledge that tissue macrophages can be derived either from a resident prenatal population or from blood monocyte recruitment and that IL-4 can increase macrophage numbers through proliferative expansion. Here, we review current knowledge on the contribution of macrophages to helminth killing and wound repair, with specific attention paid to distinct cellular origins and plasticity potential.

    更新日期:2019-11-01
  • Transcriptomic analysis of mononuclear phagocyte differentiation and activation.
    Immunol. Rev. (IF 11.292) Pub Date : 2014-10-17
    David A Hume,Tom C Freeman

    Monocytes and macrophages differentiate from progenitor cells under the influence of colony-stimulating factors. Genome-scale data have enabled the identification of the sets of genes that are associated with specific functions and the mechanisms by which thousands of genes are regulated in response to pathogen challenge. In large datasets, it is possible to identify large sets of genes that are coregulated with the transcription factors that regulate them. They include macrophage-specific genes, interferon-responsive genes, early inflammatory genes, and those associated with endocytosis. Such analyses can also extract macrophage-associated signatures from large cancer tissue datasets. However, cluster analysis provides no support for a signature that distinguishes macrophages from antigen-presenting dendritic cells, nor the classification of macrophage activation states as classical versus alternative, or M1 versus M2. Although there has been a focus on a small subset of lineage-enriched transcription factors, such as PU.1, more than half of the transcription factors in the genome can be expressed in macrophage lineage cells under some state of activation, and they interact in a complex network. The network architecture is conserved across species, but many of the target genes evolve rapidly and differ between mouse and human. The data and publication deluge related to macrophage biology require the development of new analytical tools and ways of presenting information in an accessible form.

    更新日期:2019-11-01
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