Immunodysregulation in immunodeficiency.

The primary immunodeficiency diseases are often accompanied by autoimmunity, autoinflammatory, or aberrant lymphoproliferation. The paradoxical nature of this association can be explained by the multiple cells and molecules involved in immune networks that interact with each other in synergistic, redundant, antagonistic, and parallel arrangements. Because progressively more immunodeficiencies are found to have a genetic etiology, in many cases, a monogenic pathology, an understanding of why immunodeficiency is really an immune dysfunction becomes evident. Understanding the role of specific genes allows us to better understand the complete nature of the inborn error of immunity (IEI); the latter is a term generally used when a clear genetic etiology can be discerned. Autoimmune cytopenias, inflammatory bowel disease, autoimmune thyroiditis, and autoimmune liver diseases as well as lymphomas and cancers frequently accompany primary immunodeficiencies, and it is important that the practitioner be aware of this association and to expect that this is more common than not. The treatment of autoimmune or immunodysregulation in primary immunodeficiencies often involves further immunosuppression, which places the patient at even greater risk of infection. Mitigating measures to prevent such an infection should be considered as part of the treatment regimen. Treatment of immunodysregulation should be mechanism based, as much as we understand the pathways that lead to the dysfunction. Focusing on abnormalities in specific cells or molecules, e.g., cytokines, will become increasingly used to provide a targeted approach to therapy, a prelude to the success of personalized medicine in the treatment of IEIs.

Mechanisms underlying sex differences in autoimmunity.

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.

Type 2 hypersensitivity disorders, including systemic lupus erythematosus, Sjögren's syndrome, Graves' disease, myasthenia gravis, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and graft-versus-host disease, are THαß-dominant autoimmune diseases.

The THαß host immunological pathway contributes to the response to infectious particles (viruses and prions). Furthermore, there is increasing evidence for associations between autoimmune diseases, and particularly type 2 hypersensitivity disorders, and the THαß immune response. For example, patients with systemic lupus erythematosus often produce anti-double stranded DNA antibodies and anti-nuclear antibodies and show elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 throughout the disease course. These cytokines and antibody isotypes are associated with the THαß host immunological pathway. Similarly, the type 2 hypersensitivity disorders myasthenia gravis, Graves' disease, graft-versus-host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjögren's syndrome have also been linked to the THαß pathway. Considering the potential associations between these diseases and dysregulated THαß immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferon α/ß could be explored for effective management.

The effects of Staphylococcus aureus protein a (SpA) on the expression of inflammatory cytokines in autoimmune patients and their probable immune response modulation mechanisms.

The recombinant Staphylococcal protein A (SpA) is widely used in biotechnology to purify polyclonal and monoclonal IgG antibodies. At very low concentrations, the highly-purified form of the protein A can down-regulate the activation of human B-lymphocytes and macrophages which are the key cells in determining autoimmune diseases. In the present study, the efficiency of three different forms of protein A, including native full-length SpA, the recombinant full-length SpA, and a recombinant truncated form of SpA on the reduction of 4 inflammatory cytokines, including IL-8, IL-1ß, TNF-α, and IL-6 by peripheral blood mononuclear cell (PBMCs) were studied and compared to an anti-rheumatoid arthritis commercial drug, Enbrel. The recombinant proteins were expressed in E. coli and the native form of SpA was commercially provided. PBMCs were obtained from adult patients with active rheumatoid arthritis (RA) and healthy control donors. Then, the effect of different doses of the three pure forms of SpA in comparison with Enbrel was investigated by analyzing the expression of selected cytokines using ELISA. The results showed that the truncated form of recombinant SpA significantly reduced the expression of cytokines more effectively than the other full-length formulations as well as the commercial drug Enbrel. In silico analysis shows that in the truncated protein, as the radius of gyration increases, the structure of IgG-binding domains become more open and more exposed to IgG. To summarize, our findings indicate that the truncated form of protein A is the most efficient form of SpA as it significantly decreases the secretion of evaluated cytokines from PBMCs in vitro.

The critical roles of IGFs in immune modulation and inflammation.

Insulin-like growth factors (IGFs) are crucial for embryonic and postnatal growth and development, influencing cell survival, metabolism, myogenesis, and cancer progression. Many studies have demonstrated that IGFs also play prominent roles in the modulation of both innate and adaptive immune systems during inflammation. Strikingly, IGFs dictate the phenotype and functional properties of macrophages and T cells. Furthermore, the interplay between IGFs and inflammatory cytokines may generate tissue-protective properties during inflammation. Herein, we review the recent advances on the dialogue between immune cells and IGFs, especially zooming in on the significance of immunomodulatory properties in inflammatory conditions, cancer and autoimmune diseases. The investigation of IGFs may have broad clinical implications.

Environment and systemic autoimmune rheumatic diseases: an overview and future directions.

Introduction: Despite progress in our understanding of disease pathogenesis for systemic autoimmune rheumatic diseases (SARD), these diseases are still associated with high morbidity, disability, and mortality. Much of the strongest evidence to date implicating environmental factors in the development of autoimmunity has been based on well-established, large, longitudinal prospective cohort studies. Methods: Herein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research. Results: The risk attributable to any particular environmental factor ranges from 10-200%, but exposures are likely synergistic in altering the immune system in a complex interplay of epigenetics, hormonal factors, and the microbiome leading to systemic inflammation and eventual organ damage. To reduce or forestall the progression of autoimmunity, a better understanding of disease pathogenesis is still needed. Conclusion: Owing to the complexity and multifactorial nature of autoimmune disease, machine learning, a type of artificial intelligence, is increasingly utilized as an approach to analyzing large datasets. Future studies that identify patients who are at high risk of developing autoimmune diseases for prevention trials are needed.

cGAS activation in classical dendritic cells causes autoimmunity in TREX1-deficient mice.

Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.

Immunodeficiency: Overview of primary immune regulatory disorders (PIRDs).

Primary immune regulatory disorders (PIRD) comprise a heterogeneous group of monogenic disorders that impact homeostatic control of inflammation and immune tolerance. Patients with a PIRD typically present to medical care with symptoms of autoimmunity or hyperinflammation as the dominant clinical feature, symptoms that include fever, rash, lymphadenopathy, organomegaly, arthritis, and colitis are commonplace. Notably, PIRDs are a distinct entity from primary immune deficiency disorders (PIDD), which are primarily defined by a qualitative or quantitative defect in immunity, which manifests as a susceptibility to recurrent infections. PIDDs and PIRDs can be challenging to differentiate because the clinical presentations can be similar. Red flags for PIRDs include multiple autoimmune diagnoses in the same patient, chronic lymphadenopathy, hepatomegaly, and/or splenomegaly, chronic colitis, hemophagocytic lymphohistiocytosis (HLH), Epstein Barr virus (EBV) susceptibility, recurrent or persistent fever, vasculitis, and sterile inflammation. For simplicity in this brief review, we limit our discussion of PIRDs to the following categories multiple autoimmune diseases, immune dysregulation with colitis, disorders with HLH and/or EBV susceptibility, autoinflammatory syndromes, type 1 interferonopathies, and disorders of sterile inflammation. Diagnosing a PIRD requires a broad immune evaluation for both immune system deficiencies and inflammation, along with genetic testing. Given the complex nature of these diseases, treatment often requires a team of subspecialists. Treatment, depending on the specific diagnosis, may be somewhat empiric with nonspecific immune modulators, symptom-directed therapies, and, in severe cases, hematopoietic stem cell transplantation; however, with the increasing number of biologics available, we are often able to use targeted immune therapy or even gene therapy.

Exploring the molecular landscape of lymphocyte activation gene-3: A literature review.

Molecular structure and cellular distribution of lymphocyte activation gene-3 (LAG-3) have been studied extensively since 1990. However, several unresolved questions remain. It is well-established that LAG-3 plays a significant role in maintaining immune homeostasis. The presence of deficiencies in LAG-3 has been observed to be linked with autoimmune disorders, whereas the excessive expression of LAG-3 within the tumor microenvironment hinders immune responses, particularly those mediated by lymphocytes, thereby facilitating immune evasion. Consequently, investigations into these 2 aspects have become a prominent focus in both fundamental and clinical research. The objective of this review is to examine the functions and molecular characteristics of LAG-3, as well as its current clinical applications in the context of tumor immune escape and autoimmune disease. The ultimate aim is to explore and propose novel immune therapy approach.

Post-Coronavirus Disease Autoimmunity-associated Morvan's Syndrome.

A lot of autoimmune conditions have been found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are multiple cases of autoimmune and autoinflammatory diseases reported after the coronavirus disease 2019 (COVID-19) pandemic. Autoimmune neurological presentations have also been reported but are very rare. Morvan's syndrome is a life-threatening autoimmune disease and is very rare. Morvan's syndrome is classically characterized by neuromyotonia, dysautonomia, insomnia, and neuropsychiatric symptoms. Leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein 2 (CASPR2) autoimmunity has also been associated with Morvan's syndrome. We hereby report an interesting case of a male patient in his 40s, who had a history of COVID-19 infection, following which he had bilateral lower-limb weakness and pain, with profuse sweating, and was later diagnosed as a case of SARS-CoV-2-associated Morvan's syndrome.

Transcription factor EGR2 alleviates autoimmune uveitis via activation of GDF15 to modulate the retinal microglial phenotype.

Uveitis is a vision-threatening disease primarily driven by a dysregulated immune response, with retinal microglia playing a pivotal role in its progression. Although the transcription factor EGR2 is known to be closely associated with uveitis, including Vogt-Koyanagi-Harada disease and Behcet's disease, and is essential for maintaining the dynamic homeostasis of autoimmunity, its exact role in uveitis remains unclear. In this study, diminished EGR2 expression was observed in both retinal microglia from experimental autoimmune uveitis (EAU) mice and inflammation-induced human microglia cell line (HMC3). We constructed a mice model with conditional knockout of EGR2 in microglia and found that EGR2 deficiency resulted in increased intraocular inflammation. Meanwhile, EGR2 overexpression downregulated the expression of inflammatory cytokines as well as cell migration and proliferation in HMC3 cells. Next, RNA sequencing and ChIP-PCR results indicated that EGR2 directly bound to its downstream target growth differentiation factor 15 (GDF15) and further regulated GDF15 transcription. Furthermore, intravitreal injection of GDF15 recombinant protein was shown to ameliorate EAU progression in vivo. Meanwhile, knockdown of GDF15 reversed the phenotype of EGR2 overexpression-induced microglial inflammation in vitro. In summary, this study highlighted the protective role of the transcription factor EGR2 in AU by modulating the microglial phenotype. GFD15 was identified as a downstream target of EGR2, providing a unique target for uveitis treatment.

IL-17 family cytokines in inflammatory or autoimmune skin diseases.

As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.

Development of a novel nomogram for predicting prognosis of North Chinese with autoimmune cerebellar ataxia.

PURPOSE: The aim of this study was to develop a prognostic nomogram which could predict the prognosis of north Chinese patients with autoimmune cerebellar ataxia (ACA) after immunotherapy. METHODS: Patients with an initial diagnosis of ACA who accepted first-line immunotherapy at our hospital from March 2018 to May 2023 were retrospectively reviewed. Modified Rankin Scale (mRS) was used to evaluate neurological outcomes. According to the mRS scores after immunotherapy, patients with ACA were divided into good prognosis group (mRS 0-2) and poor prognosis group (mRS 3-6). The nomogram for poor prognosis of ACA patients were built based on logistic regression analysis. The validation of the prognostic model was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). RESULTS: A total of 86 patients with ACA who received immunotherapy at our hospital were included in this study. They were randomly divided into a training cohort (n = 60) and a validation cohort (n = 26) at a ratio of 7:3. Multivariate analyses revealed that that prognostic variables significantly related to the poor prognosis of ACA were age, elevated cerebrospinal fluid (CSF) albumin (ALB) and abnormal magnetic resonance imaging (MRI). The nomogram was constructed based on above 3 factors. The C-index of the nomogram was 0.935 (95% CI: 0.884-0.991) in the training set and 0.933 (95% CI: 0.763-0.994) in the validation set. The calibration plots for the nomogram showed that predictions of risk of poor prognosis were almost consistent with actual observations. The DCAs showed great clinical usefulness of the nomograms. CONCLUSION: We successfully developed a nomogram to predict poor prognosis for ACA patients using risk factors of age, elevated CSF-ALB and abnormal MRI.

A simplified model to understand the targeted disease-modifying anti-inflammatory drugs.

This review presents a simplified model to understand better how disease-modifying anti-inflammatory drugs (DMAIDs) work in immune-mediated inflammatory diseases (IMIDs) with a focus on rheumatology, dermatology, and gastroenterology. In this model, IMIDs are listed on a spectrum from autoinflammatory to autoimmune characterised by the involvement of either mostly the innate or the adaptive immune system. DMAIDs specifically target these immune components and have shown efficacy in distinct IMIDs. DMAID classes include TNF blockers, IL-1 blockers, IL-6 receptor blockers, IL-17 blockers, IL-23 blockers, and janus kinase inhibitors.

The anti-inflammatory and tolerogenic potential of small spleen peptides.

Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.

Autoantibodies in COVID-19 and Other Viral Diseases: Molecular, Cellular, and Clinical Perspectives.

Autoantibodies are immune system-produced antibodies that wrongly target the body's cells and tissues for attack. The COVID-19 pandemic has made it possible to link autoantibodies to both the severity of pathogenic infection and the emergence of several autoimmune diseases after recovery from the infection. An overview of autoimmune disorders and the function of autoantibodies in COVID-19 and other infectious diseases are discussed in this review article. We also investigated the different categories of autoantibodies found in COVID-19 and other infectious diseases including the potential pathways by which they contribute to the severity of the illness. Additionally, it also highlights the probable connection between vaccine-induced autoantibodies and their adverse outcomes. The review also discusses the therapeutic perspectives of autoantibodies. This paper advances our knowledge about the intricate interaction between autoantibodies and COVID-19 by thoroughly assessing the most recent findings.

Sequence variants influencing the regulation of serum IgG subclass levels.

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Off-the-shelf CAR-T cells could prove paradigm shifting for autoimmune diseases.

Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.

Robust detection of infectious disease, autoimmunity, and cancer from the paratope networks of adaptive immune receptors.

Liquid biopsies based on peripheral blood offer a minimally invasive alternative to solid tissue biopsies for the detection of diseases, primarily cancers. However, such tests currently consider only the serum component of blood, overlooking a potentially rich source of biomarkers: adaptive immune receptors (AIRs) expressed on circulating B and T cells. Machine learning-based classifiers trained on AIRs have been reported to accurately identify not only cancers but also autoimmune and infectious diseases as well. However, when using the conventional "clonotype cluster" representation of AIRs, individuals within a disease or healthy cohort exhibit vastly different features, limiting the generalizability of these classifiers. This study aimed to address the challenge of classifying specific diseases from circulating B or T cells by developing a novel representation of AIRs based on similarity networks constructed from their antigen-binding regions (paratopes). Features based on this novel representation, paratope cluster occupancies (PCOs), significantly improved disease classification performance for infectious disease, autoimmune disease, and cancer. Under identical methodological conditions, classifiers trained on PCOs achieved a mean AUC of 0.893 when applied to new individuals, outperforming clonotype cluster-based classifiers (AUC 0.714) and the best-performing published classifier (AUC 0.777). Surprisingly, for cancer patients, we observed that "healthy-biased" AIRs were predicted to target known cancer-associated antigens at dramatically higher rates than healthy AIRs as a whole (Z scores >75), suggesting an overlooked reservoir of cancer-targeting immune cells that could be identified by PCOs.

Autoimmune gastritis studies and gastric cancer: True renaissance or bibliometric illusion.

A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.