A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome.

Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE). Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments.

Immune-related adverse events in checkpoint blockade: Observations from human tissue and therapeutic considerations.

Checkpoint inhibitors (CPIs) are monoclonal antibodies which, by disrupting interactions of immune checkpoint molecules with their ligands, block regulatory immune signals otherwise exploited by cancers. Despite revolutionary clinical benefits, CPI use is associated with an array of immune-related adverse events (irAEs) that mirror spontaneous autoreactivity. Severe irAEs necessitate pausing or stopping of CPI therapy and use of corticosteroids and/or other immunomodulatory interventions. Despite increasingly widespread CPI use, irAE pathobiology remains poorly understood; its elucidation may point to targeted mitigation strategies and uncover predictive biomarkers for irAE onset in patients, whilst casting new light on mechanisms of spontaneous immune-mediated disease. This review focuses on common CPI-induced irAEs of the gut, skin and synovial joints, and how these compare to immune-mediated diseases such as ulcerative colitis, vitiligo and inflammatory arthritis. We review current understanding of the immunological changes reported following CPI therapy at the level of peripheral blood and tissue. Many studies highlight dysregulation of cytokines in irAE-affected tissue, particularly IFNγ and TNF. IrAE-affected tissues are also predominantly infiltrated by T-cells, with low B-cell infiltration. Whilst there is variability between studies, patients treated with anti-programmed cell death-1 (PD-1)/PDL-1 therapies seem to exhibit CD8+ T-cell dominance, with CD4+ T-cells dominating in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. Interestingly, CD8+CXCR3+ T-cells have been reported to be elevated in gastrointestinal, dermatological and musculoskeletal -irAE affected tissues. These findings may highlight potential opportunities for therapeutic development or re-deployment of existing therapies to prevent and/or improve the outcome of irAEs.

Patients with indolent lymphomas are at high risk of infections: experience from a German outpatient clinic.

BACKGROUND: Patients with indolent B-cell non-Hodgkin lymphomas (B-NHLs) have an increased risk of infections which is caused by pathomechanisms of the diseases itself but also as a result of anti-tumor therapy. Especially the effects of anti-CD20 antibodies are well understood as these lead to decreased antibody production. Most studies regarding immunodeficiency in B-NHLs were conducted with multiple myeloma and chronic lymphocytic leukemia patients. As these studies not always represent the general population we collected and analyzed real world data from patients with indolent lymphomas and a control group (CG). RESULTS: Patients with B-NHLs undergoing therapy or who were regularly monitored in a watch and wait approach had, over the time of one year, an increased rate of infections compared to the CG of 145 healthy volunteers (mean: 11.66 vs. 7.13 infections per 1000 days). Consistent with this finding B-NHL patients received more antibiotic treatment (mean: 11.17 vs. 6.27 days) and were more often hospitalized than persons from the CG (mean: 5.19 vs. 0.99 days per 1000 days). Lymphoma patients without immunodeficiency had a lower infection rate than patients with non-symptomatic and symptomatic immunodeficiency (mean: 10.91 vs. 12.07 and 12.36 per 1000 days). The number of infections differed statistically significant for the subgroups and CG (7.13 per 1000 days). Patients with symptomatic immunodeficiency were mostly treated with regular immunoglobulin substitutions and infection rates were comparable to those of patients with asymptomatic immunodeficiency. CONCLUSIONS: Our data suggest the use of an approach with regular immune monitoring including the measurement of immunoglobulin levels and regular appointments for clinical assessment of all indolent lymphoma patients in order to identify patients with increased risk of infections. It also raises the question if patients with immunodeficiency should be treated more often with regular immunoglobulin substitution, but so far more studies are necessary to answer this question.

IL-6-Driven pSTAT1 Response Is Linked to T Cell Features Implicated in Early Immune Dysregulation.

Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4+ and CD8+ T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4+ naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4+ T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease.

SARS-CoV2 Infection During Pregnancy Causes Persistent Immune Abnormalities in Women Without Affecting the Newborns.

SARS-CoV2 infection in pregnancy and exposed newborns is poorly known. We performed a longitudinal analysis of immune system and determined soluble cytokine levels in pregnant women infected with SARS-CoV2 and in their newborns. Women with confirmed SARS-CoV2 infection and their exposed uninfected newborns were recruited from Hospital General Universitario Gregorio Marañón. Peripheral blood mononuclear cells (PBMCs), cord cells and plasma were collected at birth and 6 months later. Immunophenotyping of natural killer (NK), monocytes and CD4/CD8 T-cells were studied in cryopreserved PBMCs and cord cells by multiparametric flow cytometry. Up to 4 soluble pro/anti-inflammatory cytokines were assessed in plasma/cord plasma by ELISA assay. SARS-CoV2-infected mothers and their newborns were compared to matched healthy non-SARS-CoV2-infected mothers and their newborns. The TNFα and IL-10 levels of infected mothers were higher at baseline than those of healthy controls. Infected mothers showed increased NK cells activation and reduced expression of maturation markers that reverted after 6 months. They also had high levels of Central Memory and low Effector Memory CD4-T cell subsets. Additionally, the increased CD4- and CD8-T cell activation (CD154 and CD38) and exhaustion (TIM3/TIGIT) levels at baseline compared to controls remained elevated after 6 months. Regarding Treg cells, the levels were lower at infected mothers at baseline but reverted after 6 months. No newborn was infected at birth. The lower levels of monocytes, NK and CD4-T cells observed at SARS-CoV2-exposed newborns compared to unexposed controls significantly increased 6 months later. In conclusion, SARS-CoV2 infection during pregnancy shows differences in immunological components that could lead newborns to future clinical implications after birth. However, SARS-CoV2 exposed 6-months-old newborns showed no immune misbalance, whereas the infected mothers maintain increased activation and exhaustion levels in T-cells after 6 months.

Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

PSTPIP1-LYP phosphatase interaction: structural basis and implications for autoinflammatory disorders.

Mutations in the adaptor protein PSTPIP1 cause a spectrum of autoinflammatory diseases, including PAPA and PAMI; however, the mechanism underlying these diseases remains unknown. Most of these mutations lie in PSTPIP1 F-BAR domain, which binds to LYP, a protein tyrosine phosphatase associated with arthritis and lupus. To shed light on the mechanism by which these mutations generate autoinflammatory disorders, we solved the structure of the F-BAR domain of PSTPIP1 alone and bound to the C-terminal homology segment of LYP, revealing a novel mechanism of recognition of Pro-rich motifs by proteins in which a single LYP molecule binds to the PSTPIP1 F-BAR dimer. The residues R228, D246, E250, and E257 of PSTPIP1 that are mutated in immunological diseases directly interact with LYP. These findings link the disruption of the PSTPIP1/LYP interaction to these diseases, and support a critical role for LYP phosphatase in their pathogenesis.

Immune-related adverse events in the treatment of non-Hodgkin lymphoma with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0-407) with a median resolution time of 16 days (range 0-98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients' disease conditions need to be carefully evaluated to decide the optimal management.

Genome-wide methylation and expression analyses reveal the epigenetic landscape of immune-related diseases for tobacco smoking.

BACKGROUND: Smoking is a major causal risk factor for lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and is the main preventable cause of deaths in the world. The components of cigarette smoke are involved in immune and inflammatory processes, which may increase the prevalence of cigarette smoke-related diseases. However, the underlying molecular mechanisms linking smoking and diseases have not been well explored. This study was aimed to depict a global map of DNA methylation and gene expression changes induced by tobacco smoking and to explore the molecular mechanisms between smoking and human diseases through whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq). RESULTS: We performed WGBS on 72 samples (36 smokers and 36 nonsmokers) and RNA-seq on 75 samples (38 smokers and 37 nonsmokers), and cytokine immunoassay on plasma from 22 males (9 smokers and 13 nonsmokers) who were recruited from the city of Jincheng in China. By comparing the data of the two groups, we discovered a genome-wide methylation landscape of differentially methylated regions (DMRs) associated with smoking. Functional enrichment analyses revealed that both smoking-related hyper-DMR genes (DMGs) and hypo-DMGs were related to synapse-related pathways, whereas the hypo-DMGs were specifically related to cancer and addiction. The differentially expressed genes (DEGs) revealed by RNA-seq analysis were significantly enriched in the "immunosuppression" pathway. Correlation analysis of DMRs with their corresponding gene expression showed that genes affected by tobacco smoking were mostly related to immune system diseases. Finally, by comparing cytokine concentrations between smokers and nonsmokers, we found that vascular endothelial growth factor (VEGF) was significantly upregulated in smokers. CONCLUSIONS: In sum, we found that smoking-induced DMRs have different distribution patterns in hypermethylated and hypomethylated areas between smokers and nonsmokers. We further identified and verified smoking-related DMGs and DEGs through multi-omics integration analysis of DNA methylome and transcriptome data. These findings provide us a comprehensive genomic map of the molecular changes induced by smoking which would enhance our understanding of the harms of smoking and its relationship with diseases.

A functional spleen contributes to afucosylated IgG in humans.

As a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography-mass spectrometry (LC-MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems.

Toll-like receptors (TLRs) are a class of proteins playing a key role in innate and adaptive immune responses. TLRs are involved in the development and progression of neuroimmune diseases via initiating inflammatory responses. Thus, targeting TLRs signaling pathway may be considered as a potential therapy for neuroimmune diseases. However, the role of TLRs is elusive and complex in neuroimmune diseases. In addition to the inadequate immune response of TLRs inhibitors in the experiments, the recent studies also demonstrated that partial activation of TLRs is conducive to the production of anti-inflammatory factors and nervous system repair. Exploring the mechanism of TLRs in neuroimmune diseases and combining with developing the emerging drug may conquer neuroimmune diseases in the future. Herein, we provide an overview of the role of TLRs in several neuroimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barré syndrome and myasthenia gravis. Emerging difficulties and potential solutions in clinical application of TLRs inhibitors will also be discussed.

Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases.

PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein-protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions.

Clinical outcomes and temporal trends of immunological and non-immunological rare diseases in adult kidney transplant.

BACKGROUND: Rare diseases (RDs) encompass many difficult-to-treat conditions with different characteristics often associated with end-stage renal disease (ESRD). However, data about transplant outcomes in adult patients are still lacking and limited to case reports/case series without differentiation between immunological/non-immunological RDs. METHODS: Retrospective analysis among all adult kidney transplanted patients (KTs) with RDs (RDsKT group) performed in our high-volume transplantation center between 2005 and 2016. RDs were classified according to the Orphanet code system differentiating between immunological and non-immunological diseases, also comparing clinical outcomes and temporal trends to a control population without RDs (nRDsKT). RESULTS: Among 1381 KTs, 350 patients (25.3%) were affected by RDs (RDsKTs). During a f/up > 5 years [median 7.9 years (4.8-11.1)], kidney function and graft/patient survival did not differ from nRDsKTs. Considering all post-transplant complications, RDsKTs (including, by definition, patients with primary glomerulopathy except on IgA nephropathy) have more recurrent and de-novo glomerulonephritis (14.6% vs. 9.6% in nRDsKTs; p = 0.05), similar rates of de-novo cancers, post-transplant diabetes, dysmetabolism, hematologic disorders, urologic/vascular problems, and lower infectious episodes than nRDsKTs (63.7% vs 72.7%; p = 0.013). Additional stratification for immunological and non-immunological RDsKTs or transplantation periods (before/after 2010) showed no differences or temporal trends between groups. CONCLUSIONS: Kidney transplant centers are deeply involved in RDs management. Despite their high-complex profile, both immunological and non-immunological RDsKTs experienced favorable patients' and graft survival.

Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity.

Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.

Inborn errors of IKAROS and AIOLOS.

IKAROS is a pioneer protein of the IKZF family of transcription factors that plays an essential role in lymphocyte development. Recently, inborn errors of IKAROS have been identified in patients with B cell deficiency and hypogammaglobulinemia, and these patients often present with recurrent sinopulmonary infection. Autoimmunity and hematologic malignancies are other characteristic complications seen in the patients with IKAROS deficiency. Missense mutation involving asparagine at the 159th position results in combined immunodeficiency, often presenting with Pneumocystis jirovecii pneumonia. Inborn errors of AIOLOS, HELIOS, and PEGASUS have also been reported in patients with B cell deficiency, Evans syndrome, and hereditary thrombocytopenia, respectively. Here, we briefly review the phenotype and genotype of IKZF mutations, especially IKAROS.

Iatrogenic immune-mediated neuropathies: diagnostic, epidemiological and mechanistic uncertainties for causality and implications for clinical practice.

Acute and chronic immune-mediated neuropathies have been widely reported with medical intervention. Although causal relationship may be uncertain in many cases, a variety of drugs, several vaccination types, surgical procedures and bone marrow transplants have been reported as possible cause or trigger of a putative immune-mediated response resulting in acute and chronic neuropathies. We conducted a systematic review of the literature from 1966 to 2020 on reported cases of possible iatrogenic immune-mediated neuropathies. We determined in each case the likelihood of causality based on frequency of the association, focusing primarily on clinical presentation and disease course as well as available ancillary investigations (electrophysiology, blood and cerebrospinal fluid and neuropathology). The response to immunotherapy and issue of re-exposure were also evaluated. We also considered hypothesised mechanisms of onset of immune-mediated neuropathy in the specific iatrogenic context. We believe that a likely causal relationship exists for only few drugs, mainly antitumour necrosis factor alpha agents and immune checkpoint inhibitors, but remains largely unsubstantiated for most other suggested iatrogenic causes. Unfortunately, given the lack of an accurate diagnostic biomarker for most immune-mediated neuropathies, clinical assessment will often override ancillary investigations, resulting in lower levels of certainty that may continue to cast serious doubts on reliability of their diagnosis. Consequently, future reports of suspected cases should collect and exhaustively assess all relevant data. At the current time, besides lack of evidence for causality, the practical implications on management of suspected cases is extremely limited and therapeutic decisions appear likely no different to those made in non-iatrogenic cases.

Roles of BTLA in Immunity and Immune Disorders.

B and T lymphocyte attenuator (BTLA) is one of the most important cosignaling molecules. It belongs to the CD28 superfamily and is similar to programmed cell death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) in terms of its structure and function. BTLA can be detected in most lymphocytes and induces immunosuppression by inhibiting B and T cell activation and proliferation. The BTLA ligand, herpesvirus entry mediator (HVEM), does not belong to the classic B7 family. Instead, it is a member of the tumor necrosis factor receptor (TNFR) superfamily. The association of BTLA with HVEM directly bridges the CD28 and TNFR families and mediates broad and powerful immune effects. Recently, a large number of studies have found that BTLA participates in numerous physiopathological processes, such as tumor, inflammatory diseases, autoimmune diseases, infectious diseases, and transplantation rejection. Therefore, the present work aimed to review the existing knowledge about BTLA in immunity and summarize the diverse functions of BTLA in various immune disorders.

Dynamic Interactions Between the Immune System and the Neuroendocrine System in Health and Disease.

The immune system and the neuroendocrine system share many common features. Both consist of diverse components consisting of receptors and networks that are widely distributed throughout the body, and both sense and react to external stimuli which, on the one hand control mechanisms of immunity, and on the other hand control and regulate growth, development, and metabolism. It is thus not surprising, therefore, that the immune system and the neuroendocrine system communicate extensively. This article will focus on bi-directional immune-endocrine interactions with particular emphasis on the hormones of the hypothalamus-pituitary-thyroid (HPT) axis. New findings will be discussed demonstrating the direct process through which the immune system-derived thyroid stimulating hormone (TSH) controls thyroid hormone synthesis and bone metamorphosis, particularly in the context of a novel splice variant of TSHß made by peripheral blood leukocytes (PBL). Also presented are the ways whereby the TSHß splice variant may be a contributing factor in the development and/or perpetuation of autoimmune thyroid disease (AIT), and how systemic infection may elicit immune-endocrine responses. The relationship between non-HPT hormones, in particular adipose hormones, and immunity is discussed.