Summary
The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting ...lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self‐regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self‐antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory response. In the first part of this review, we ...discuss the NF-κB inducers, signaling pathways, and regulators involved in immune homeostasis as well as detail the importance of post-translational regulation by ubiquitination in NF-κB function. We also indicate the stages of central and peripheral tolerance where NF-κB plays a fundamental role. With respect to central tolerance, we detail how NF-κB regulates medullary thymic epithelial cell (mTEC) development, homeostasis, and function. Moreover, we elaborate on its role in the migration of double-positive (DP) thymocytes from the thymic cortex to the medulla. With respect to peripheral tolerance, we outline how NF-κB contributes to the inactivation and destruction of autoreactive T and B lymphocytes as well as the differentiation of CD4
-T cell subsets that are implicated in immune tolerance. In the latter half of the review, we describe the contribution of NF-κB to the pathogenesis of autoimmunity and autoinflammation. The recent discovery of mutations involving components of the pathway has both deepened our understanding of autoimmune disease and informed new therapeutic approaches to treat these illnesses.
Summary
Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or ...neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long‐term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long‐term follow‐up and monitoring in dedicated transition programs to improve outcome at the adult age.
Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of ...50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte ...associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs.
The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with ...COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.
The RAS-RAF-MEK-ERK signaling pathway is vital for different cellular mechanisms including cell proliferation, differentiation and apoptosis. This importance is highlighted by the high prevalence of ...mutations in RAS or related proteins of the pathway in cancers. More recently, development abnormalities have been linked to various germline mutations in this pathway and called RASopathies. Interestingly, rare disorders such as RAS-associated leukoproliferative diseases and histiocytosis have also been recently linked to multiple mutations in the same pathway, sometimes with the same mutation. This review will focus on germline RASopathies and rare somatic RASopathies and focus on how gain-of-function mutations in the same pathway can lead to various diseases.
We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and ...vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes STING-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.
Autoimmunity by haploinsufficiency Rieux-Laucat, Frédéric; Casanova, Jean-Laurent
Science (American Association for the Advancement of Science),
09/2014, Letnik:
345, Številka:
6204
Journal Article
Recenzirano
Autoimmunity arises from self-reactive T and/or B lymphocytes, and underlies a wide range of conditions, from endocrine disorders to blood cytopenias. Genetic epidemiological studies have long ...suggested that many autoimmune conditions have an inherited component. Autoimmunity is often described as having polygenic or complex inheritance. However, both descriptions are too general to adequately describe the considerable heterogeneity in patients and conditions. Spectacular progress in the genetic dissection of autoimmunity has come from Mendelian studies of young patients with rare, distinctive conditions. Less has been learned from population-based, genome-wide association studies of more common, clinically less homogeneous conditions. The three best-characterized monogenic autoimmune disorders are autoimmune polyendocrinopathy syndrome type 1, X-linked immunoproliferative enteropathy, and autoimmune lymphoprolierative syndrome (1). On page 1623 of this issue, Kuehn et al. (2) add to this list. Patients with only one functional copy of the gene encoding cytotoxic T lymphocyte antigen 4 (CTLA4) suffer from severe autoimmunity. These heterozygous mutations result in a new phenotype, with infiltration of nonlymphoid organs, such as the intestine, lungs, and brain, by hyperactive T cells and B cells, along with more classic signs of autoimmunity.
Background
Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation ...remain unclear.
Methods
We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes.
Results
We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67,
p
= 0.028 and AUC = 0.74,
p
= 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified
ITG2AB
,
GP1BB
,
PPBP
and
SELPLG
to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for
SELPLG
and
PPBP
(AUC = 0.8,
p
= 0.046 for both). An optimal cutoff value for
PBPP
was predictive of intubation with 100% NPV and 45% PPV, and for
SELPLG
with 100% NPV and 50% PPV.
Conclusion
We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified
PPBP/CXCL7
and
SELPLG
as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.
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