Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic ...triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.
Abstract Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, ...observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
Exposure to illicit cocaine and its frequent adulterant, levamisole, is associated with ANCAs targeting neutrophil elastase (NE), neutropenia and vasculitic/thrombotic skin purpura. The mechanisms of ...cocaine/levamisole-associated autoimmunity (CLAA) are unknown. The aim of this study was to assess the ability of cocaine and levamisole to induce the release of neutrophil extracellular traps (NETs), a potential source of autoantigen and tissue injury.
We performed quantitative and qualitative assessment of NET formation in neutrophils from healthy donors exposed to either drug in vitro . In addition, IgG from sera of individuals with CLAA (CLAA-IgG) was assessed for its ability to enhance formation of, and to bind to, drug-induced NETs.
Both cocaine and levamisole could induce formation of NETs enriched in NE and, potentially, inflammatory mitochondrial DNA. Both drugs could also augment simultaneous release of B cell-activating factor belonging to the TNF family (BAFF). CLAA-IgG, but not IgG from healthy individuals, could potentiate drug-induced NETosis. Furthermore, CLAA-IgG, but not ANCA + control IgG, bound to drug-induced NETs in a pattern consistent with NE targeting.
Both cocaine and levamisole may contribute to the development of ANCAs by inducing release of potentially inflammatory NETs in association with NE autoantigen and BAFF. Enhancement of drug-induced NET release by CLAA-IgG provides a potential mechanism linking vasculitis/pupuric skin disease to acute drug exposure in patients with CLAA. Further study of this under-recognized form of autoimmunity will be likely to provide mechanistic insight into ANCA-associated vasculitis and other diseases associated with NETosis.
Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by ...sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4(+) T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health--a newly announced directive of the NIH.
Objective
To evaluate independent risk factors for readmission and to determine the major reasons for readmission in a nationally representative sample of patients with systemic lupus erythematosus ...(SLE).
Methods
We used the Nationwide Readmissions Database to identify adults with SLE who were discharged from hospital to home during January–November of 2016 and 2017. Thirty‐day all‐cause readmissions were identified. A multivariable adjusted survey‐specific logistic regression model was used to identify factors associated with readmission.
Results
A total of 132,400 hospitalized adults with SLE were discharged home during the study period; 88.3% were female, with a median age of 51.0 years (interquartile range 38.7–61.9 years). Of these, 18,973 individuals (14.3%) were readmitted within 30 days of discharge from their index hospitalization. In multivariable analyses, the factors associated with the highest odds for readmission were autoimmune hemolytic anemia (odds ratio OR 1.86 95% confidence interval (95% CI) 1.51–2.29), glomerular disease (OR 1.27 95% CI 1.19–1.36), pericarditis (OR 1.35 95% CI 1.14–1.60), heart failure (OR 1.34 95% CI 1.24–1.44), age 18–30 years (OR 1.28 95% CI 1.17–1.41 versus age ≥65 years), and Medicare (OR 1.20 95% CI 1.13–1.28) and Medicaid insurance (OR 1.26 95% CI 1.18–1.34). Sepsis (7.6%), SLE (7.4%), heart failure (3.5%), and pneumonia (3.2%) were among the most common causes for readmission.
Conclusion
In this nationally representative study of SLE readmissions, the strongest risk factors for 30‐day readmission were younger age, SLE‐related manifestations, and public insurance. These results identify patient groups with SLE that would benefit from postdischarge interventions designed to reduce hospitalizations and improve health outcomes.
IgG4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease frequently associated with allergy. The pathogenesis of IgG4-RD is poorly understood, and effective therapies are limited. ...However, IgG4-RD appears to involve some of the same pathogenic mechanisms observed in allergic disease, such as T helper 2 (Th2) and regulatory T cell (Treg) activation, IgG4 and IgE hypersecretion, and blood/tissue eosinophilia. In addition, IgG4-RD tissue fibrosis appears to involve activation of basophils and mast cells and their release of alarmins and cytokines. In this article, we review allergy-like features of IgG4-RD and highlight targeted therapies for allergy that have potential in treating patients with IgG4-RD.
The intracellular progesterone receptor links the reproductive and immune systems via regulation of CD4+ T cells.
Pg has distinct immunomodulatory properties involved in poorly understood immune ...phenomena, including maternal tolerance of the fetus, increased risk of certain infections during pregnancy or after Pg birth control, and pregnancy‐associated remission of autoimmune disease. Several potential mechanisms have been identified, including alteration of Th1 and Treg activity, but the precise cellular and molecular targets of Pg immunomodulation in vivo remain obscure, partly because Pg can signal through several different receptor types. One such receptor, the iPR, encoded by the pgr gene, is essential for reproduction in female mice and is expressed in the thymus and CD4+ T cells. We hypothesized that iPR regulates CD4+ T cell activity and adaptive immune responses in vivo. With the use of iPR KO mice, we demonstrate that iPR specifically suppresses TD antibody responses, primarily by dampening CD4+ Teff activity, likely via transcriptional repression of the IFN‐γ gene and modulation of other programs regulating CD4+ T cells. Our results highlight a novel mechanism linking the endocrine and immune systems, and they offer insight into important but poorly understood phenomena in womenˈs health and autoimmunity.
Objectives
This study generates a series of narrow‐sense heritability estimates for crown morphology of the deciduous and permanent dentition with two overarching aims. The first is to test the ...hypothesis that deciduous teeth provide a more faithful reflection of genetic information than their permanent successors. The second is to use quantitative genetic methods to evaluate assumptions underlying common data collection and analysis practices in biodistance research.
Materials and Methods
Dental morphology data were collected from longitudinal dental casts representing Australian twins and families using Arizona State Dental Anthropology System standards. Polygenic models and estimates of narrow‐sense heritability were generated using SOLAR v.8.1.1. Each model considered age, sex, and age/sex interaction as covariates.
Results
Heritability estimates significantly differed from zero for the majority of morphological crown characters. Most estimates fell within the 0.4–0.8 range typically observed for crown morphology. Mean heritability was stable across the dental complex, but for paired homologues, permanent traits often yielded higher estimates than their deciduous counterparts. Results indicate directional asymmetry in environmental influence for crown morphology and inform biodistance “best practices” related to data collection and treatment.
Conclusions
Overall, results for this sample support the use of crown morphology as a proxy for genetic variation in evolutionary research. This includes the deciduous dentition, which justifies the expansion of efforts to incorporate subadults into reconstructions of past microevolutionary processes. Results do not indicate that deciduous phenotypes more closely approximate underlying genotype, at least for deciduous/permanent homologues.
The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of ...toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterogeneous. This review describes the various immunologic pathways that may lead to irAEs along with the diverse clinical manifestations seen in clinical practice. Treatment based on the severity and specific organ involvement will also be discussed, along with an overview of current guidelines and potential challenges that arise with immunosuppressive medications.
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