Advances In Immunology[JOURNAL]
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200 papers
Complement as a powerful "influencer" in the brain during development, adulthood and neurological disorders.
Petrisko TJ, Gomez-Arboledas A, Tenner AJ
Adv Immunol · 2021 · PMID 34844709 · Publisher ↗
The complement system was long considered as only a powerful effector arm of the immune system that, while critically protective, could lead to inflammation and cell death if overactivated, even in the central nervous sy...
The complement system was long considered as only a powerful effector arm of the immune system that, while critically protective, could lead to inflammation and cell death if overactivated, even in the central nervous system (CNS). However, in the past decade it has been recognized as playing critical roles in key physiological processes in the CNS, including neurogenesis and synaptic remodeling in the developing and adult brain. Inherent in these processes are the interactions with cells in the brain, and the cascade of interactions and functional consequences that ensue. As a result, investigations of therapeutic approaches for both suppressing excessive complement driven neurotoxicity and aberrant sculpting of neuronal circuits, require broad (and deep) knowledge of the functional activities of multiple components of this highly evolved and regulated system to avoid unintended negative consequences in the clinic. Advances in basic science are beginning to provide a roadmap for translation to therapeutics, with both small molecule and biologics. Here, we present examples of the critical roles of proper complement function in the development and sculpting of the nervous system, and in enabling rapid protection from infection and clearance of dying cells. Microglia are highlighted as important command centers that integrate signals from the complement system and other innate sensors that are programed to provide support and protection, but that direct detrimental responses to aberrant activation and/or regulation of the system. Finally, we present promising research areas that may lead to effective and precision strategies for complement targeted interventions to promote neurological health.
Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics.
Freiwald T, Afzali B
Adv Immunol · 2021 · PMID 34844708 · Full text
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunit...
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
Antibody dependent enhancement: Unavoidable problems in vaccine development.
Xu L, Ma Z, Li Y … +2 more , Pang Z, Xiao S
Adv Immunol · 2021 · PMID 34656289 · Full text
In some cases, antibodies can enhance virus entry and replication in cells. This phenomenon is called antibody-dependent infection enhancement (ADE). ADE not only promotes the virus to be recognized by the target cell an...
In some cases, antibodies can enhance virus entry and replication in cells. This phenomenon is called antibody-dependent infection enhancement (ADE). ADE not only promotes the virus to be recognized by the target cell and enters the target cell, but also affects the signal transmission in the target cell. Early formalin-inactivated virus vaccines such as aluminum adjuvants (RSV and measles) have been shown to induce ADE. Although there is no direct evidence that there is ADE in COVID-19, this potential risk is a huge challenge for prevention and vaccine development. This article focuses on the virus-induced ADE phenomenon and its molecular mechanism. It also summarizes various attempts in vaccine research and development to eliminate the ADE phenomenon, and proposes to avoid ADE in vaccine development from the perspective of antigens and adjuvants.
Immunology of SARS-CoV-2 infections and vaccines.
Schenten D, Bhattacharya D
Adv Immunol · 2021 · PMID 34656288 · Full text
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections trigger viral RNA sensors such as TLR7 and RIG-I, thereby leading to production of type I interferon (IFN) and other inflammatory mediators. Express...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections trigger viral RNA sensors such as TLR7 and RIG-I, thereby leading to production of type I interferon (IFN) and other inflammatory mediators. Expression of viral proteins in the context of this inflammation leads to stereotypical antigen-specific antibody and T cell responses that clear the virus. Immunity is then maintained through long-lived antibody-secreting plasma cells and by memory B and T cells that can initiate anamnestic responses. Each of these steps is consistent with prior knowledge of acute RNA virus infections. Yet there are certain concepts, while not entirely new, that have been resurrected by the biology of severe SARS-CoV-2 infections and deserve further attention. These include production of anti-IFN autoantibodies, early inflammatory processes that slow adaptive humoral immunity, immunodominance of antibody responses, and original antigenic sin. Moreover, multiple different vaccine platforms allow for comparisons of pathways that promote robust and durable adaptive immunity.
The development and physiological and pathophysiological functions of resident macrophages and glial cells.
Blank N, Mayer M, Mass E
Adv Immunol · 2021 · PMID 34656287 · Publisher ↗
In the past, brain function and the onset and progression of neurological diseases have been studied in a neuron-centric manner. However, in recent years the focus of many neuroscientists has shifted to other cell types...
In the past, brain function and the onset and progression of neurological diseases have been studied in a neuron-centric manner. However, in recent years the focus of many neuroscientists has shifted to other cell types that promote neurodevelopment and contribute to the functionality of neuronal networks in health and disease. Particularly microglia and astrocytes have been implicated in actively contributing to and controlling neuronal development, neuroinflammation, and neurodegeneration. Here, we summarize the development of brain-resident macrophages and astrocytes and their core functions in the developing brain. We discuss their contribution and intercellular crosstalk during tissue homeostasis and pathophysiology. We argue that in-depth knowledge of non-neuronal cells in the brain could provide novel therapeutic targets to reverse or contain neurological diseases.
Follicular lymphoma dynamics.
Milpied P, Gandhi AK, Cartron G … +4 more , Pasqualucci L, Tarte K, Nadel B, Roulland S
Adv Immunol · 2021 · PMID 34176559 · Publisher ↗
Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis...
Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis. For the vast majority of those who initially respond, relapses will repeatedly occur with increasing refractoriness to available treatments. Addressing the clinical challenges in FL warrants deep understanding of the nature of treatment-resistant FL cells seeding relapses, and of the biological basis of early disease progression. Great progress has been made in the last decade in the description and interrogation of the (epi)genomic landscape of FL cells, of their major dependency to the tumor microenvironment (TME), and of the stepwise lymphomagenesis process, from healthy to subclinical disease and to overt FL. A new picture is emerging, in which an ever-evolving tumor-TME duo sparks a complex and multilayered clonal and functional heterogeneity, blurring the discovery of prognostic biomarkers, patient stratification and reliable designs of risk-adapted treatments. Novel technological approaches allowing to decipher both tumor and TME heterogeneity at the single-cell level are beginning to unravel unsuspected cell dynamics and plasticity of FL cells. The upcoming drawing of a comprehensive functional picture of FL within its ecosystem holds great promise to address the unmet medical needs of this complex lymphoma.
The multi-faceted roles of TGF-β in regulation of immunity to infection.
Maizels RM
Adv Immunol · 2021 · PMID 34176558 · Publisher ↗
Transforming Growth Factor-β is a potent regulator of the immune system, acting at every stage from thymic differentiation, population of the periphery, control of responsiveness, tissue repair and generation of memory....
Transforming Growth Factor-β is a potent regulator of the immune system, acting at every stage from thymic differentiation, population of the periphery, control of responsiveness, tissue repair and generation of memory. It is therefore a central player in the immune response to infectious pathogens, but its contribution is often clouded by multiple roles acting on different cells in time and space. Hence, context is all-important in understanding when TGF-β is beneficial or detrimental to the outcome of infection. In this review, a full range of infectious agents from viruses to helminth parasites are explored within this framework, drawing contrasts and general conclusions about the importance of TGF-β in these diseases.
Panorama of stepwise involvement of the IgH 3' regulatory region in murine B cells.
Bruzeau C, Moreau J, Le Noir S … +1 more , Pinaud E
Adv Immunol · 2021 · PMID 33993921 · Publisher ↗
Among the multiple events leading to immunoglobulin (Ig) expression in B cells, stepwise activation of the Ig heavy chain locus (IgH) is of critical importance. Transcription regulation of the complex IgH locus has alway...
Among the multiple events leading to immunoglobulin (Ig) expression in B cells, stepwise activation of the Ig heavy chain locus (IgH) is of critical importance. Transcription regulation of the complex IgH locus has always been an interesting viewpoint to unravel the multiple and complex events required for IgH expression. First, regulatory germline transcripts (GLT) assist DNA remodeling events such as VDJ recombination, class switch recombination (CSR) and somatic hypermutation (SHM). Second, productive spliced transcripts restrict heavy chain protein expression associated either with the surface receptor of developing B cells or secreted in large amounts in plasma cells. One main transcriptional regulator for IgH lies at its 3' extremity and includes both a set of enhancers grouped in a large 3' regulatory region (3'RR) and a cluster of 3'CTCF-binding elements (3'CBEs). In this focused review, we will preferentially refer to evidence reported for the murine endogenous IgH locus, whether it is wt or carries deletions or insertions within the IgH 3' boundary and associated regulatory region.
The transcription factors GFI1 and GFI1B as modulators of the innate and acquired immune response.
Fraszczak J, Möröy T
Adv Immunol · 2021 · PMID 33993920 · Publisher ↗
GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal CH zinc finger motifs that are almost identical in sequenc...
GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal CH zinc finger motifs that are almost identical in sequence and bind to very similar, specific DNA sites. The second is an N-terminal 20 amino acid SNAG domain that can bind to the pocket of the histone demethylase KDM1A (LSD1) near its active site. When bound to DNA, both proteins act as bridging factors that bring LSD1 and associated proteins into the vicinity of methylated substrates, in particular histone H3 or TP53. GFI1 can also bring methyl transferases such as PRMT1 together with its substrates that include the DNA repair proteins MRE11 and 53BP1, thereby enabling their methylation and activation. While GFI1B is expressed almost exclusively in the erythroid and megakaryocytic lineage, GFI1 has clear biological roles in the development and differentiation of lymphoid and myeloid immune cells. GFI1 is required for lymphoid/myeloid and monocyte/granulocyte lineage decision as well as the correct nuclear interpretation of a number of important immune-signaling pathways that are initiated by NOTCH1, interleukins such as IL2, IL4, IL5 or IL7, by the pre TCR or -BCR receptors during early lymphoid differentiation or by T and B cell receptors during activation of lymphoid cells. Myeloid cells also depend on GFI1 at both stages of early differentiation as well as later stages in the process of activation of macrophages through Toll-like receptors in response to pathogen-associated molecular patterns. The knowledge gathered on these factors over the last decades puts GFI1 and GFI1B at the center of many biological processes that are critical for both the innate and acquired immune system.
Modeling a complex disease: Multiple sclerosis-Update 2020.
Regen T, Waisman A
Adv Immunol · 2021 · PMID 33993919 · Publisher ↗
Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) with an unknown etiology. Thereby, MS is not a uniform disease but rather represents a spectrum of disorders, where each aspec...
Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) with an unknown etiology. Thereby, MS is not a uniform disease but rather represents a spectrum of disorders, where each aspect needs to be modeled with specific requirements-for a systematic overview see our previous issue of this review (Kurschus, Wortge, & Waisman, 2011). However, there is broad consensus about the critical involvement of the immune system in the disease pathogenesis. To better understand how the immune system contributes to CNS autoimmunity, the model of experimental autoimmune encephalomyelitis (EAE) was developed. EAE can be induced in susceptible animals in many different ways, with the most popular protocol involving the activation of self-reactive T cells by a peptide based on the myelin oligodendrocyte glycoprotein sequence. In the last 10 years this model has led to major advances in our understanding of the immune system, especially the nature of IL-17-producing T cells (Th17 cells), host-microbiome interactions, the gut-brain axis and how the immune system can cause damage in different regions of the brain and the spinal cord. This update summarizes some of the main achievements in the field in the last 10 years.
Thymoproteasome optimizes positive selection of CD8 T cells without contribution of negative selection.
Ohigashi I, Takahama Y
Adv Immunol · 2021 · PMID 33993918 · Full text
Functionally competent and self-tolerant T cell repertoire is shaped through positive and negative selection in the cortical and medullary microenvironments of the thymus. The thymoproteasome specifically expressed in th...
Functionally competent and self-tolerant T cell repertoire is shaped through positive and negative selection in the cortical and medullary microenvironments of the thymus. The thymoproteasome specifically expressed in the cortical thymic epithelium is essential for the optimal generation of CD8 T cells. Although how the thymoproteasome governs the generation of CD8 T cells is not fully understood, accumulating evidence suggests that the thymoproteasome optimizes CD8 T cell production through the processing of self-peptides associated with MHC class I molecules expressed by cortical thymic epithelial cells. In this review, we describe recent advances in the mechanism of thymoproteasome-dependent generation of CD8 T cells, focusing on the process of cortical positive selection independent of apoptosis-mediated negative selection.
IgE and mast cells: The endogenous adjuvant.
El Ansari YS, Kanagaratham C, Lewis OL … +1 more , Oettgen HC
Adv Immunol · 2020 · PMID 33190734 · Publisher ↗
Mast cells and IgE are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive...
Mast cells and IgE are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. In 2015 we reviewed the evidence for the adjuvant functions of mast cells. This update includes the original text, incorporates some important developments in the field over the past five years and discusses how interventions targeting these pathways might have promise in the development of strategies to treat allergic disease.
Unexplored horizons of cDC1 in immunity and tolerance.
Balan S, Radford KJ, Bhardwaj N
Adv Immunol · 2020 · PMID 33190733 · Publisher ↗
Dendritic cells are a specialized subset of hematopoietic cells essential for mounting immunity against tumors and infectious disease as well as inducing tolerance for maintenance of homeostasis. DCs are equipped with nu...
Dendritic cells are a specialized subset of hematopoietic cells essential for mounting immunity against tumors and infectious disease as well as inducing tolerance for maintenance of homeostasis. DCs are equipped with number of immunoregulatory or stimulatory molecules that interact with other leukocytes to modulate their functions. Recent advances in DC biology identified a specific role for the conventional dendritic cell type 1 (cDC1) in eliciting cytotoxic CD8+ T cells essential for clearance of tumors and infected cells. The critical role of this subset in eliciting immune responses or inducing tolerance has largely been defined in mice whereas the biology of human cDC1 is poorly characterized owing to their extremely low frequency in tissues. A detailed characterization of the functions of many immunoregulatory and stimulatory molecules expressed by human cDC1 is critical for understanding their biology to exploit this subset for designing novel therapeutic modalities against cancer, infectious disease and autoimmune disorders.
Preserving immune homeostasis with A20.
Razani B, Malynn BA, Ma A
Adv Immunol · 2020 · PMID 33190732 · Publisher ↗
A20/TNFAIP3 is a TNF induced gene that plays a profound role in preserving cellular and organismal homeostasis (Lee, et al., 2000; Opipari etal., 1990). This protein has been linked to multiple human diseases via genetic...
A20/TNFAIP3 is a TNF induced gene that plays a profound role in preserving cellular and organismal homeostasis (Lee, et al., 2000; Opipari etal., 1990). This protein has been linked to multiple human diseases via genetic, epigenetic, and an emerging series of patients with mono-allelic coding mutations. Diverse cellular functions of this pleiotropically expressed protein include immune-suppressive, anti-inflammatory, and cell protective functions. The A20 protein regulates ubiquitin dependent cell signals; however, the biochemical mechanisms by which it performs these functions is surprisingly complex. Deciphering these cellular and biochemical facets of A20 dependent biology should greatly improve our understanding of murine and human disease pathophysiology as well as unveil new mechanisms of cell and tissue biology.
Mechanism and regulation of class switch recombination by IgH transcriptional control elements.
Oudinet C, Braikia FZ, Dauba A … +1 more , Khamlichi AA
Adv Immunol · 2020 · PMID 32981636 · Publisher ↗
Class switch recombination (CSR) plays an important role in humoral immunity by generating antibodies with different effector functions. CSR to a particular antibody isotype is induced by external stimuli, and occurs bet...
Class switch recombination (CSR) plays an important role in humoral immunity by generating antibodies with different effector functions. CSR to a particular antibody isotype is induced by external stimuli, and occurs between highly repetitive switch (S) sequences. CSR requires transcription across S regions, which generates long non-coding RNAs and secondary structures that promote accessibility of S sequences to activation-induced cytidine deaminase (AID). AID initiates DNA double-strand breaks (DSBs) intermediates that are repaired by general DNA repair pathways. Switch transcription is controlled by various regulatory elements, including enhancers and insulators. The current paradigm posits that transcriptional control of CSR involves long-range chromatin interactions between regulatory elements and chromatin loops-stabilizing factors, which promote alignment of partner S regions in a CSR centre (CSRC) and initiation of CSR. In this review, we focus on the role of IgH transcriptional control elements in CSR and the chromatin-based mechanisms underlying this control.
The role of NK cell as central communicators in cancer immunity.
Bald T, Pedde AM, Corvino D … +1 more , Böttcher JP
Adv Immunol · 2020 · PMID 32981635 · Publisher ↗
Natural killer (NK) cells are innate immune cells critically involved in the control of cancer. Their important role in cancer immunity reflects the ability of NK cells to recognize malignant cells through an array of ge...
Natural killer (NK) cells are innate immune cells critically involved in the control of cancer. Their important role in cancer immunity reflects the ability of NK cells to recognize malignant cells through an array of germline-encoded receptors expressed on their surface, enabling NK cells to detect and rapidly kill tumor cells through targeted cytotoxicity. In addition to their cytotoxic activity, NK cells fulfill a fundamental and often underappreciated role in the local orchestration of cancer immunity through their ability to communicate with innate and adaptive immune cells within the tumor microenvironment (TME), which is achieved through the secretion of multiple chemokines, cytokines, and growth factors. Within tumor tissue, NK cells regulate the recruitment, survival and functional activity of various immune cells including monocytes, granulocytes, dendritic cells and T cells, thereby shaping intratumoral immune cell composition and functionality. Emerging evidence further suggest a role of NK cells in the regulation of stromal cells within the TME. Here, we discuss key aspects of NK cell communication with other intratumoral cell types and its role for cancer immunity. Strategies aimed at boosting anti-cancer immunity by enhancing NK cell communication and functionality within tumor tissue provide attractive new ways for treatment of cancer patients.
Histone deacetylases as targets in autoimmune and autoinflammatory diseases.
Hamminger P, Rica R, Ellmeier W
Adv Immunol · 2020 · PMID 32981634 · Publisher ↗
Reversible lysine acetylation of histones is a key epigenetic regulatory process controlling gene expression. Reversible histone acetylation is mediated by two opposing enzyme families: histone acetyltransferases (HATs)...
Reversible lysine acetylation of histones is a key epigenetic regulatory process controlling gene expression. Reversible histone acetylation is mediated by two opposing enzyme families: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Moreover, many non-histone targets of HATs and HDACs are known, suggesting a crucial role for lysine acetylation as a posttranslational modification on the cellular proteome and protein function far beyond chromatin-mediated gene regulation. The HDAC family consists of 18 members and pan-HDAC inhibitors (HDACi) are clinically used for the treatment of certain types of cancer. HDACi or individual HDAC member-deficient (cell lineage-specific) mice have also been tested in a large number of preclinical mouse models for several autoimmune and autoinflammatory diseases and in most cases HDACi treatment results in an attenuation of clinical disease severity. A reduction of disease severity has also been observed in mice lacking certain HDAC members. This indicates a high therapeutic potential of isoform-selective HDACi for immune-mediated diseases. Isoform-selective HDACi and thus targeted inactivation of HDAC isoforms might also overcome the adverse effects of current clinically approved pan-HDACi. This review provides a brief overview about the fundamental function of HDACs as epigenetic regulators, highlights the roles of HDACs beyond chromatin-mediated control of gene expression and summarizes the studies showing the impact of HDAC inhibitors and genetic deficiencies of HDAC members for the outcome of autoimmune and autoinflammatory diseases with a focus on rheumatoid arthritis, inflammatory bowel disease and experimental autoimmune encephalomyelitis (EAE) as an animal model of multiple sclerosis.
Unraveling the mysteries of plasma cells.
Schuh W, Mielenz D, Jäck HM
Adv Immunol · 2020 · PMID 32327153 · Publisher ↗
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is gu...
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is guided and controlled by a complex transcriptional network accompanied by a fascinating morphological metamorphosis, governed by the combined action of Blimp-1, Xbp-1 and IRF-4. The survival of plasma cells requires the intimate interaction with a specific microenvironment, consisting of stromal cells and cells of hematopoietic origin. Cell-cell contacts, cytokines and availability of metabolites such as glucose and amino acids modulate the survival abilities of plasma cells in their niches. Moreover, plasma cells have been shown to regulate immune responses by releasing cytokines. Furthermore, plasma cells are central players in autoimmune diseases and malignant transformation of plasma cells can result in the generation of multiple myeloma. Hence, the development of sophisticated strategies to deplete autoreactive plasma cells and myeloma cells represents a challenge for current and future research.
Friend or foe? Lactobacillus in the context of autoimmune disease.
Fine RL, Mubiru DL, Kriegel MA
Adv Immunol · 2020 · PMID 32327152 · Publisher ↗
Over the last decade, the interplay between the gut microbiota, the consortium of intestinal microbes that colonizes intestinal mucosal barriers, and its host immune system has been increasingly better understood. Disrup...
Over the last decade, the interplay between the gut microbiota, the consortium of intestinal microbes that colonizes intestinal mucosal barriers, and its host immune system has been increasingly better understood. Disruption of the delicate balance between beneficial and pathogenic commensals, known as dysbiosis, contributes to a variety of chronic immunologic and metabolic diseases. Complicating this paradigm are bacterial strains that can operate paradoxically both as instigators and attenuators of inflammatory responses, depending on host background. Here, we review the role of several strains in the genus Lactobacillus within the context of autoimmune and other chronic disorders with a predominant focus on L. reuteri. While strains within this species have been shown to provide immune health benefits, they have also been demonstrated to act as a pathobiont in autoimmune-prone hosts. Beneficial functions in healthy hosts include competing with pathogenic microbes, promoting regulatory T cell development, and protecting the integrity of the gut barrier. On the other hand, certain strains can also break through a dysfunctional gut barrier, colonize internal tissues such as the spleen or liver and promote inflammatory responses in host tissues that lead to autoimmune disease. This review summarizes the manifold roles that these commensals play in the context of health and disease.
Homeostatic and pathogenic roles of PI3Kδ in the human immune system.
Sogkas G, Adriawan IR, Dubrowinskaja N … +2 more , Atschekzei F, Schmidt RE
Adv Immunol · 2020 · PMID 32327151 · Publisher ↗
Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine recepto...
Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.
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