Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune demyelinating neuropathy that is most commonly characterized clinically by progressive proximal and distal weakness affecting the upper and lower extremities, sensory loss, and reduced or absent reflexes. These symptoms evolve over the time course of 8 weeks or more. While the majority of CIDP demonstrates this clinical phenotype, there are CIDP variants as well. The milieu of the underlying pathophysiology and immunologic factors involved is complex and involves components of both the innate and adaptive immune systems. As more is understood about the underlying pathophysiology, novel targets and patterns have emerged guiding further classification and management. This is most notable in the discovery of antibodies targeting paranodal and nodal regions related to anti-neurofascin-155 and anti-contactin-1 antibody-mediated disease resulting in a reclassification as demyelinating nodo-paranodopathies. Triggering antigens and correlative antibodies for CIDP are otherwise undiscovered. While first-line therapies for CIDP currently are broad and non-targeted, a shift in approach has been to develop specific targeted treatments guided by what is understood about the underlying pathophysiology. Some of these targets include specific types of B-cell depletion, complement inhibition, immunoglobulin G (IgG) reduction via inhibition of the neonatal Fc receptor (FcRn) recycling of IgGs, treatments related to T-cell dysfunction, and macrophage inhibition.

Multifocal motor neuropathy (MMN) is an acquired autoimmune polyneuropathy that affects almost exclusively the motor nerve fibers. Typically seen in middle-aged adults, its predominant clinical feature is a chronically progressive asymmetric weakness that affects the distal upper extremities most significantly. Minor sensory symptoms, sensory examination findings or abnormal sensory nerve conduction studies can be seen in the lower extremities in a minority of patients. Electrodiagnostic studies reveal motor conduction blocks at noncompressible sites, and minor findings of other demyelinating features such as conduction slowing or temporal dispersion. Anti-GM1 antibody titers are elevated in less than half of MMN patients, and more recent studies suggest mechanisms including antibody-induced complement attack at the node of Ranvier with resulting ion channel dysfunction. Peripheral nerve magnetic resonance imaging and neuromuscular ultrasound often reveal non-uniform enlargement of the nerve roots, plexuses, or peripheral nerve segments, thus being useful in assisting diagnosis. The differential diagnosis of MMN mainly includes motor neuron disease or demyelinating sensorimotor polyneuropathies. Immunoglobulin therapy is the first-line and mainstay of treatment, being effective in maintaining or restoring muscle strength in the majority of patients. However, motor strength often slowly declines over the long term, even with maintenance immunoglobulin treatment. More effective immunotherapy is needed to halt the slow progression of MMN, and complement inhibition appears to be a promising option in the near future.

Although using Rituximab (RTX) and intravenous immunoglobulin (IVIg) alone or sequentially is a well-established treatment for several autoimmune diseases, the combination of these two forms of therapy is still rare, and its use is poorly studied.

To perform a systematic review on the use of RTX associated with IVIG in autoimmune conditions.

PubMed/MEDLINE, EMBASE, and Scielo databases were screened for articles on RTX plus IVIg in autoimmune diseases until May 2024.

The review encompassed 21 studies evaluating RTX and IVIg for autoimmune diseases. Ten studies focused on pemphigus, involving 85 patients with diverse subtypes (47 pemphigus vulgaris, 27 pemphigoids, and 11 other variants). Most were case reports or series, with one retrospective study including controls. Positive outcomes were reported across all but one case of paraneoplastic pemphigus. Infections, such as P. jirovecii pneumonia, were noted in three studies, highlighting a potential risk. The other 11 studies involved 24 patients with conditions like polyneuropathies, lupus with CNS involvement, and neuromyelitis optica. While most reported favorable outcomes, one trial on IVIg-dependent polyneuropathies found RTX ineffective in reducing IVIg needs. Adverse events included pneumonia, venous thrombosis with pulmonary embolism, and infusion reactions, demonstrating the need for careful monitoring.

RTX plus IVIg seems to be an alternative option for the treatment of refractory autoimmune diseases. However, more studies with a larger number of participants and in different autoimmune diseases are desired.

Immunoglobulin G (IgG) antibodies are an essential component of humoral immunity protecting the host from recurrent infections. Among all antibody isotypes, IgG antibodies have a uniquely long half-life, can basically reach any tissue in the body, and have the ability to kill opsonized target cells, which has made them the molecule of choice for therapeutic interventions in cancer and autoimmunity. Moreover, IgG antibodies in the form of pooled serum IgG preparations from healthy donors are used to treat chronic inflammatory and autoimmune diseases, providing evidence that serum IgG antibodies can have an active immunomodulatory activity. Research over the last two decades has established that the single sugar moiety attached to each IgG heavy chain plays a very important role in modulating the pro- and anti-inflammatory activities of IgG. Moreover, specific sugar moieties such as sialic acid and galactose residues can serve as highly specific biomarkers for ongoing inflammatory processes. This chapter will summarize how different sugar residues in the IgG sugar moiety change upon inflammation and how such changes may translate to altered IgG function and hence maybe useful for optimizing or modulating the function of therapeutic antibodies.

The WHO has given a permissive recommendation for an off-label one-dose human papillomavirus (HPV) vaccine schedule to prevent cervical cancer, based on evidence of comparable protection to two or three doses of vaccine. While neutralizing antibodies are thought to be the primary mechanism of protection, the persistence of immunity and whether other antibody-mediated mechanisms of protection are involved is unclear. Using systems serology, we investigated HPV antibody responses in serum from Fijian girls who were unvaccinated or received one, two or three doses of quadrivalent HPV vaccine six years earlier. We also evaluated their HPV antibody responses 28 days following a dose of bivalent HPV vaccine. After six years, one dose induced lower antibody concentrations but similar antibody profiles and phagocytic function as two or three doses. Following bivalent vaccine, antibody concentrations, particularly IgG1/IgG3, antibody profiles and phagocytic function were similar between previously vaccinated girls, indicating immune memory after one dose. Cross-reactive antibody responses against non-vaccine genotypes (HPV31/33/45/52/58) were lower following one dose than two or three doses. These findings provide novel insights into serological immunity and recall responses following one-dose HPV vaccination.

Inflammation is a complex biological response that can be both induced and actively suppressed by IgG-Fc gamma receptor (FcγR) interactions. This review explores the role of IgG sialylation in reducing or blocking inflammatory responses. We first revisit foundational studies that established the anti-inflammatory properties of sialylated IgG1 Fc. These early investigations revealed that the sialylated fraction is crucial for intravenous immunoglobulin's (IVIg's) ability to reduce inflammation in many autoinflammatory diseases and defined a paracrine signaling mechanism underlying this activity. Next, we discuss a recently identified mechanism whereby sialylated IgG directly induces RE1-Silencing Transcription Factor (REST) which functions as a transcriptional repressor of NF-κB1. This mechanism suggests a very broad role for sialylated IgG signaling in inflammation control since NF-κB is a central mediator of responses downstream of diverse activating receptors on both adaptive and innate immune cells. Finally, we review a set of soluble factors that are suppressed by sialylated IgG signaling in the murine airway and in purified human macrophages, providing additional insight into mechanisms by which sialylated IgG contributes to broad inflammatory control.

Glycosylation of humanized antibody at Fc-Asn297 significantly affects the Fc-mediated killing of target cells through effector functions, especially antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent vaccinal effect (ADVE). Previous studies showed that therapeutic immunoglobulin G (IgG) antibodies with α2,6-sialyl complex type (SCT) glycan attached to Fc-Asn297 exhibited optimal binding to the Fc receptors on effector cells associated with ADCC, ADCP, and ADVE. However, the production of antibodies with homogeneous Fc-SCT glycan requires multiple in vitro enzymatic and purification steps. In this study, we report two cell-based methods to produce Fc-GlcNAc antibody and Fc-SCT-enriched antibodies with improved effector functions. First, we expressed endoglycosidase S2 in Expi293F GnT1- cells to trim all N-glycans to Fc-GlcNAc antibody for in vitro transglycosylation to generate homogeneous antibodies with well-defined Fc glycan. Second, we engineered the glycosylation pathway of HEK293T cells through knock-out of undesired glycosyltransferases and knock-in of desired glycosyltransferases to produce Fc-SCT-enriched antibodies and evaluated their binding to Fc receptors, and we found that the Fc-SCT-enriched antibody is like or better than the homogeneous Fc-SCT antibody in binding to the Fc receptors associated with ADCC, ADCP, and ADVE.

Immune thrombocytopenia (ITP) is characterized by a reduction in platelet counts, stemming from an autoimmune-mediated process where platelets are excessively cleared by macrophages. This enhanced phagocytosis is a cardinal pathogenic mechanism in ITP. Antigen B (AgB), a principal component of the Echinococcus granulosus cyst fluid, plays a pivotal role in safeguarding the parasite from host immune defenses by modulating macrophage activation. In this study, we explored the potential of AgB to regulate macrophage activation in the context of ITP. Our observations indicated a diminished presence of M1 macrophages and a reduced phagocytic capacity in patients infected with E. granulosus sensu stricto. We isolated AgB from E. granulosus cyst fluid (EgCF) and discovered that it could suppress the polarization of M1 macrophages and weaken their phagocytic activity via Fcγ receptors, consequently alleviating thrombocytopenia in an ITP mouse model. At the molecular level, AgB was found to suppress the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) by impeding their nuclear translocation, leading to a reduction in the generation of inflammatory cytokines. Furthermore, AgB was shown to inhibit Toll-like receptor 4 (TLR4) endocytosis and the recycling of CD14. In aggregate, our findings uncover a novel immunomodulatory mechanism of AgB, which suppresses macrophage phagocytosis by regulating TLR4 endocytosis and the subsequent activation of NF-κB and IRF3 signaling pathways. These insights shed new light on the molecular intricacies of E. granulosus-induced immune evasion and suggest that AgB may serve as a promising therapeutic agent for ITP.

Antibody-dependent enhancement (ADE) of infectious disease is a phenomenon whereby host antibodies increase the severity of an infection. It is well established in viral infections but ADE also has an underappreciated role during bacterial, fungal and parasitic infections. ADE can occur during both primary infections and re-infections with the same or a related pathogen; therefore, understanding the underlying mechanisms of ADE is critical for understanding the pathogenesis and progression of many infectious diseases. Here, we review the four distinct mechanisms by which antibodies increase disease severity during an infection. We discuss the most established mechanistic explanation for ADE, where cross-reactive, disease-enhancing antibodies bound to pathogens interact with Fc receptors, thereby enhancing pathogen entry or replication, ultimately increasing the total pathogen load. Additionally, we explore how some pathogenic antibodies can shield bacteria from complement-dependent killing, thereby enhancing bacterial survival. We interrogate the molecular mechanisms by which antibodies can amplify inflammation to drive severe disease, even in the absence of increased pathogen replication. We also examine emerging roles for autoantibodies in enhancing the pathogenesis of infectious diseases. Finally, we discuss how we can leverage these insights to improve vaccine design and future treatments for infectious diseases.

Growing evidence suggests that chronic inflammation, resulting from intricate immune system interactions, significantly contributes to the onset of psychiatric disorders. Observational studies have identified a link between immunoglobulin G (IgG) N-glycosylation and various psychiatric conditions, but the causality of these associations remains unclear.

Genetic variants for IgG N-glycosylation traits and psychiatric disorders were obtained from published genome-wide association studies. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran's Q test, MR-Egger intercept test, leave-one-out analyses, and MR-PRESSO global test were used for sensitivity analyses.

In the Psychiatric Genomics Consortium (PGC) database, genetically predicted IGP7 showed a protective role in schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP), while elevated IGP34, and IGP57 increased SCZ risk. High levels of IGP21 were associated with an increased risk of post-traumatic stress disorder (PTSD), while elevated levels of IGP22 exhibited a causal association with a decreased risk of attention-deficit/hyperactivity disorder (ADHD). No causal relationship between IgG N-glycan traits and autism spectrum disorder (ASD) and no evidence of reverse causal associations was found.

Here, we demonstrate that IgG N-glycan traits have a causal relationship with psychiatric disorders, especially IGP7's protective role, offering new insights into their pathogenesis. Our findings suggest potential strategies for predicting and intervening in psychiatric disorder risk through IgG N-glycan traits.

Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.

All four subclasses of immunoglobulin G (IgG) antibodies have glycan structures attached to the protein part of the IgG molecules. Glycans linked to the Fc portion of IgG are found in all IgG antibodies, while about one-fifth of IgG antibodies in plasma also have glycans attached to the Fab portion of IgG. The IgG3 subclass is characterized by more complex glycosylation compared to other IgG subclasses. In this review, we discuss the significant influence that glycans exert on the structural and functional properties of IgG. We provide a comprehensive overview of how the composition of these glycans can affect IgG's effector functions by modulating its interactions with Fcγ receptors and other molecules such as the C1q component of complement, which in turn influence various immune responses triggered by IgG, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In addition, the importance of glycans for the efficacy of therapeutics like monoclonal antibodies and intravenous immunoglobulin (IVIg) therapy is discussed. Moreover, we offer insights into IgG glycosylation characteristics and roles derived from general population, disease-specific, and interventional studies. These studies indicate that IgG glycans are important biomarkers and functional effectors in health and disease.

Idiopathic inflammatory myopathies (IIMs) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging and new therapies are badly needed. The small number of cases with diverse presentations and different diagnostic criteria significantly affect clinical trial results. Only IVIG has been internationally approved for IIM patients. Most clinical trials of new biologic therapies have failed to meet their primary endpoints in IIM, with only one biologic drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biologic drugs, including B cell depletion therapies, abatacept, Janus kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder or eating restriction along with the abrupt onset of other co-occurring symptoms (tics, behavioral and cognitive regression, etc.). PANS is thought to be a post-infectious immunopsychiatric disorder, although as with most post-infectious disorders, it is challenging to establish a causal relationship with proposed infectious triggers. Intravenous immunoglobulin (IVIG) can modulate inflammation and support the elimination of infection and has been used for treatment of many post-infectious inflammatory disorders and autoimmune conditions. The aim of the study is to explore the pro-inflammatory state in PANS before and after administration of IVIG.

Children with moderate-to-severe PANS received six infusions of IVIG (Octagam 5%, Octapharma) every 3 weeks with post treatment follow-up. Blood samples and psychiatric measures were obtained at Visits 1 (pre-treatment), 7 and 8 (4 and 11 weeks after last infusion, respectively). Myeloid cell activation was assessed via flow cytometry.

All ten patients included in the study were male, White, with mean age 12.4 years (range 6-16). Statistically significant improvements following IVIG treatment were demonstrated in all psychometric assessments and parent questionnaires including CY-BOCS (obsessive compulsive scale), YGTSS (tic scale) and a parent PANS rating scale (for all scales p<0.001). The fraction of pro-inflammatory monocytes and dendritic cells decreased from pre-IVIG treatment levels. The proportional reductions were not compensated by increases in total white blood cells; pro-inflammatory monocytes post-IVIG were decreased as a proportion of CD14+ myeloid cells and in absolute number.

The results of this study suggest that active PANS is associated with a pro-inflammatory state. This pro-inflammatory profile and psychometric scores improved following IVIG treatment. Future work will aim to further elucidate the roles of innate and adaptive immune responses in PANS and the regulatory mechanism(s) of IVIG in PANS treatment.

Kawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.

We investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.

FCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.

FCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

To describe the short-term response, early prognostic markers, and survival after treatment of canine immune-mediated thrombocytopenia (ITP) with human intravenous immunoglobulin (hIVIG) and methylprednisolone.

Retrospective cohort study.

Private referral veterinary medical center.

Twenty-seven client-owned dogs with primary or secondary ITP.

All dogs received 2 mg/kg IV methylprednisolone once daily and a single infusion of 5% hIVIG administered over 6-12 hours.

A substantial increase in platelet count within 60 ± 12 hours post-hIVIG infusion (T60) was observed in 19 of the 27 (70%) dogs with ITP (responders). Thirty-four variables, including serum immunoglobulin (Ig) G concentration 24 ± 12 hours post-hIVIG infusion (T24IgG) and increase in serum IgG concentration 24 ± 12 hours post-hIVIG infusion (T24ΔIgG), were compared between responders and nonresponders at 5 different time points. Mortality rates of responders and nonresponders were evaluated 14 days post-hIVIG infusion. Serum T24IgG and serum T24ΔIgG were both significantly higher at T60 in responders. All responders were alive 14 days post-hIVIG infusion, and their mortality rate was significantly lower compared with nonresponders.

Responder dogs had an excellent 14-day survival rate. Serum T24IgG and serum T24ΔIgG concentrations accurately predicted response status at 60 hours post-hIVIG infusion.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

The generalized and sclerodermic form of lichen myxedematosus, known as scleromyxedema (SMX), is a chronic mucinosis that manifests cutaneously and has multiple systemic comorbidities. There are few available treatment options and no established therapeutic guidelines. We describe a 48-year-old man who had intravenous immunoglobulins (IVIg), oral corticosteroids, and methotrexate (MTX) for the treatment of SMX, monoclonal gammopathy, and arthritis. Because of its effectiveness and high level of tolerance, IVIg is the most often used first-line therapy for SMX and has been used for an increasing range of skin conditions. In our instance, better control of skin disease and extracutaneous manifestations was made possible by combining IVIg with oral prednisone and MTX. To the best of our knowledge, this is the first instance of SMX treatment that has combined therapeutic approaches with a favorable safety profile.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Scleromyxedema or generalized diffuse lichen myxoedematosus is a rare mucinosis that is associated with monoclonal gammopathy and which frequently affects multiple extracutaneous organ systems. The pathogenesis of scleromyxedema has not been fully elucidated, but includes stimulation of glycosaminoglycan synthesis. The clinical course of scleromyxedema is chronic and often progressive, leading to severe morbidity and even death. The characteristic skin findings encompass multiple waxy papules often on indurated plaques, while thickening of skin leads to conspicuous folds on glabella and dorsal aspects of finger joints. Microscopical manifestations are dermal deposits of glycosaminoglycans between collagen bundles in reticular dermis, increased numbers of fibroblasts and fibrosis as well as loss of elastic fibers. Progressive skin involvement results in decreased mobility of the mouth and joints and even contractures. Extracutaneous manifestations occur in the musculoskeletal or cardiovascular system, in the gastrointestinal or respiratory tract, in the kidneys or in the central and peripheral nervous system. There are no in-label or evidence-based treatments available for scleromyxedema, but by expert consensus high-dose immunoglobulins are considered as treatment of choice, followed in case of insufficient efficacy by systemic glucocorticosteroids and then lenalidomide or thalidomide. In severe and refractory cases, autologous hematopoietic stem cell transplantation has been performed. Long-term maintenance treatment is usually required to prevent recurrences. Close interdisciplinary follow-up is recommended.

Immune thrombocytopenia (ITP) is an autoimmune disorder that causes a significant reduction in peripheral blood platelet count. Fortunately, due to an increased understanding of ITP, there have been significant improvements in the diagnosis and treatment of these patients. Over the past decade, there have been a variety of proven therapeutic options available for ITP patients, including intravenous immunoglobulins (IVIG), Rituximab, corticosteroids, and thrombopoietin receptor agonists (TPO-RAs). Although the effectiveness of current therapies in treating more than two-thirds of patients, still some patients do not respond well to conventional therapies or fail to achieve long-term remission. Recently, a significant advancement has been made in identifying various mechanisms involved in the pathogenesis of ITP, leading to the development of novel treatments targeting these pathways. It seems that new agents that target plasma cells, Bruton tyrosine kinase, FcRn, platelet desialylation, splenic tyrosine kinase, and classical complement pathways are opening new ways to treat ITP. In this study, we reviewed the pathophysiology of ITP and summarized updates in this population's management and treatment options. We also took a closer look at the 315 ongoing trials to investigate their progress status and compare the effectiveness of interventions. May our comprehensive view of ongoing clinical trials serve as a guiding beacon, illuminating the path towards future trials of different drugs in the treatment of ITP patients.

Immunoglobulin G (IgG) antibodies in the form of high-dose intravenous immunoglobulin (IVIG) exert immunomodulatory activity and are used in this capacity to treat inflammatory and autoimmune diseases. Reductionist approaches have revealed that terminal sialylation of the single asparagine-linked (N-linked) glycan at position 297 of the IgG1 Fc bestows antiinflammatory activity, which can be recapitulated by introduction of an F241A point mutation in the IgG1 Fc (FcF241A). Here, we examined the antiinflammatory activity of CHO-K1 cell-produced FcF241A in vivo in models of autoimmune inflammation and found it to be independent of sialylation. Intriguingly, sialylation markedly improved the half-life and bioavailability of FcF241A via impaired interaction with the asialoglycoprotein receptor ASGPR. Further, FcF241A suppressed inflammation through the same molecular pathways as IVIG and sialylated IgG1 Fc and required the C-type lectin SIGN-R1 in vivo. This contrasted with FcAbdeg (efgartigimod), an engineered IgG1 Fc with enhanced neonatal Fc receptor (FcRn) binding, which reduced total serum IgG concentrations, independent of SIGN-R1. When coadministered, FcF241A and FcAbdeg exhibited combinatorial antiinflammatory activity. Together, these results demonstrated that the antiinflammatory activity of FcF241A requires SIGN-R1, similarly to that of high-dose IVIG and sialylated IgG1, and can be used in combination with other antiinflammatory therapeutics that rely on divergent pathways, including FcAbdeg.

While glycans are among the most abundant macromolecules on the cell with widespread functions, their role in immunity has historically been challenging to study. This is in part due to difficulties assimilating glycan analysis into routine approaches used to interrogate immune cell function. Despite this, recent developments have illuminated fundamental roles for glycans in host immunity. The growing field of glycoimmunology continues to leverage new tools and approaches to uncover the function of glycans and glycan-binding proteins in immunity. Here we utilize clinical vignettes to examine key roles of glycosylation in allergy, inborn errors of immunity, and autoimmunity. We will discuss the diverse functions of glycans as epitopes, as modulators of antibody function, and as regulators of immune cell function. Finally, we will highlight immune modulatory therapies that harness the critical role of glycans in the immune system.

Glycosylation of antibody plays an important role in Fc-mediated killing of tumor cells and virus-infected cells through effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody dependent cell-mediated phagocytosis (ADCP) and vaccinal effect. Previous studies showed that therapeutical humanized antibodies with α2-6 sialyl complex type (SCT) glycan attached to Fc-Asn297 exhibited optimal binding to the Fc receptors on effector cells associated with ADCC, ADCP and vaccinal effect. However, the production of antibodies with homogeneous Fc-SCT needs multiple in vitro enzymatic and purification steps. In this study, we report two different approaches to shorten the processes to produce SCT-enriched antibodies. First, we expressed a bacterial endoglycosidase in GNT1-KO EXPI293 cells to trim all N -glycans to mono-GlcNAc glycoforms for in vitro transglycosylation to generate homogeneous SCT antibody. Second, we engineered the glycosylation pathway of HEK293 cells through knockout of the undesired glycosyltransferases and expression of the desired glycosyltransferases to produce SCT enriched antibodies with similar binding affinity to Fc receptors and ADCC activity to homogenous SCT antibody.

Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder in which macrophages play a critical role. Mammalian sterile-20-like kinase 4 (MST4), a member of the germinal-center kinase STE20 family, has been demonstrated to be a regulator of inflammation. Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive. The expression and function of MST4 in macrophages of ITP patients and THP-1 cells, and of a macrophage-specific Mst4-/- (Mst4ΔM/ΔM) ITP mouse model were determined. Macrophage phagocytic assays, RNA sequencing (RNA-seq) analysis, immunofluorescence analysis, coimmunoprecipitation (co-IP), mass spectrometry (MS), bioinformatics analysis, and phosphoproteomics analysis were performed to reveal the underlying mechanisms. The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients, and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment. The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages. Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines, and impaired phagocytosis, which could be increased by overexpression of MST4. In a passive ITP mouse model, macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid, attenuated the expression of M1 cytokines, and promoted the predominance of FcγRIIb in splenic macrophages, which resulted in amelioration of thrombocytopenia. Downregulation of MST4 directly inhibited STAT1 phosphorylation, which is essential for M1 polarization of macrophages. Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing "idiotypic network theory" and "Treg cell theory" into an "anti-idiotypic Treg cell theory." Based on this hypothesis, an "active anti-idiotypic therapy" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.

Antibodies can mediate immune recruitment or clearance of immune complexes through the interaction of their Fc domain with cellular Fc receptors. Clustering of antibodies is a key step in generating sufficient avidity for efficacious receptor recognition. However, Fc receptors may be saturated with prevailing, endogenous serum immunoglobulin and this raises the threshold by which cellular receptors can be productively engaged. Here, we review the factors controlling serum IgG levels in both healthy and disease states, and discuss how the presence of endogenous IgG is encoded into the functional activation thresholds for low- and high-affinity Fc receptors. We discuss the circumstances where antibody engineering can help overcome these physiological limitations of therapeutic antibodies. Finally, we discuss how the pharmacological control of Fc receptor saturation by endogenous IgG is emerging as a feasible mechanism for the enhancement of antibody therapeutics.

The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic.

To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context.

A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered.

In the light of the current imbalance between gammaglobulins' demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process.

Thrombocytopenia, characterized by a decrease in platelet count, is commonly observed in sepsis and COVID-19. In sepsis, thrombocytopenia can result from various mechanisms, including impaired platelet production in the bone marrow, accelerated platelet destruction due to increased inflammation, sequestration of platelets in the spleen, immune-mediated platelet destruction, or dysregulated host responses. Similarly, thrombocytopenia has been reported in COVID-19 patients, but the immune-related mechanisms underlying this association remain unclear. Notably, interventions targeting thrombocytopenia have shown potential for improving outcomes in both sepsis and COVID-19 patients. Understanding these mechanisms is crucial for developing effective treatments.

Immunoglobulin (IgG) Fc glycosylation has been shown to be important for the biological activity of antibodies. Fc sialylation is important for the anti-inflammatory activity of IgGs. However, evaluating the structure-activity relationship (SAR) of antibody Fc glycosylation has been hindered using simplified in vitro models in which antibodies are often displayed in monomeric forms. Presenting antibodies in monomeric forms may not accurately replicate the natural environment of the antibodies when binding their antigen in vivo. To address these limitations, we used different Fc-containing molecules, displaying their Fc domains in monovalent and multivalent fashion. Given the inhibitory role of Fc gamma receptor IIb (FcγRIIb) in autoimmune and inflammatory diseases, we focused on evaluating the impact of Fc sialylation on the activation of FcγRIIb. We report for the first time that in human cellular systems, sialic acid mediates the induction of FcγRIIb phosphorylation by IgG-Fc when the IgG-Fc is displayed in a multivalent fashion. This effect was observed with different types of therapeutic agents such as sialylated anti-TNFα antibodies, sialylated IVIg and sialylated recombinant multivalent Fc products. These studies represent the first report of the specific effects of Fc sialylation on FcγRIIb signaling on human immune cells and may help in the characterization of the anti-inflammatory activity of Fc-containing therapeutic candidates.

Psychological stress is widely acknowledged as a major contributor to immunosuppression, rendering individuals more susceptible to various diseases. The complex interplay between the nervous, endocrine, and immune systems underlies stress-induced immunosuppression. However, the underlying mechanisms of psychological-stress-induced immunosuppression remain unclear. In this study, we utilized a restraint stress mouse model known for its suitability in investigating physiological regulations during psychological stress. Comparing it with cold exposure, we observed markedly elevated levels of stress hormones corticosterone and cortisol in the plasma of mice subjected to restraint stress. Furthermore, restraint-stress-induced immunosuppression differed from the intravenous immunoglobulin-like immunosuppression observed in cold exposure, with restraint stress leading to increased macrophage cell death in the spleen. Suppression of pyroptosis through treatments of inflammasome inhibitors markedly ameliorated restraint-stress-induced spleen infiltration and pyroptosis cell death of macrophages in mice. These findings suggest that the macrophage pyroptosis associated with restraint stress may contribute to its immunosuppressive effects. These insights have implications for the development of treatments targeting stress-induced immunosuppression, emphasizing the need for further investigation into the underlying mechanisms.

Vaccine efficacy determined within the controlled environment of a clinical trial is usually substantially greater than real-world vaccine effectiveness. Typically, this results from reduced protection of immunologically vulnerable populations, such as children, elderly individuals and people with chronic comorbidities. Consequently, these high-risk groups are frequently recommended tailored immunisation schedules to boost responses. In addition, diverse groups of healthy adults may also be variably protected by the same vaccine regimen. Current population-based vaccination strategies that consider basic clinical parameters offer a glimpse into what may be achievable if more nuanced aspects of the immune response are considered in vaccine design. To date, vaccine development has been largely empirical. However, next-generation approaches require more rational strategies. We foresee a generation of precision vaccines that consider the mechanistic basis of vaccine response variations associated with both immunogenetic and baseline health differences. Recent efforts have highlighted the importance of balanced and diverse extra-neutralising antibody functions for vaccine-induced protection. However, in immunologically vulnerable populations, significant modulation of polyfunctional antibody responses that mediate both neutralisation and effector functions has been observed. Here, we review the current understanding of key genetic and inflammatory modulators of antibody polyfunctionality that affect vaccination outcomes and consider how this knowledge may be harnessed to tailor vaccine design for improved public health.

Intravenous immunoglobulin (IVIG) is the mainstay of therapy for humoral immune deficiencies and numerous inflammatory disorders. Although the use of IVIG may be supplanted by several targeted therapies to cytokines, the ability of polyclonal normal IgG to act as an effector molecule as well as a regulatory molecule is a clear example of the polyfunctionality of IVIG. This article will address the mechanism of action of IVIG in a number of important conditions that are otherwise resistant to treatment. In this commentary, we will highlight mechanistic studies that shed light on the action of IVIG. This will be approached by identifying effects that are both common and disease-specific, targeting actions that have been demonstrated on cells and processes that represent both innate and adaptive immune responses.

Clinical manifestations and laboratory parameters of haemostasis were investigated in 23 children with newly diagnosed immune thrombocytopenia (ITP) before and after intravenous immunoglobulin (IVIg) treatment. ITP patients with platelet counts of less than 20 × 109 /L and mild bleeding symptoms, graded by a standardized bleeding score (BS), were compared with healthy children with normal platelet counts and children with chemotherapy-related thrombocytopenia. Markers of platelet activation and platelet apoptosis in the absence and presence of platelet activators were analysed by flow cytometry; thrombin generation in plasma was determined. ITP patients at diagnosis presented with increased proportions of platelets expressing CD62P and CD63 and activated caspases, and with decreased thrombin generation. Thrombin-induced activation of platelets was reduced in ITP compared with controls, while increased proportions of platelets with activated caspases were observed. Children with a higher BS had lower proportions of CD62P-expressing platelets compared with those with a lower BS. IVIg treatment increased the number of reticulated platelets, the platelet count to more than 20 × 109 /L and improved bleeding in all patients. Decreased thrombin-induced platelet activation, as well as thrombin generation, were ameliorated. Our results indicate that IVIg treatment helps to counteract diminished platelet function and coagulation in children with newly diagnosed ITP.

Intravenous immunoglobulin (IVIG) is a promising immune-modulatory therapy for limiting harmful inflammation and associated secondary tissue loss in neurotrauma. Here, we show that IVIG therapy attenuates spatial learning and memory deficits following a controlled cortical impact mouse model of traumatic brain injury (TBI). These improvements in cognitive outcomes were associated with increased neuronal survival, an overall reduction in brain tissue loss, and a greater preservation of neural connectivity. Furthermore, we demonstrate that the presence of the main inhibitory FcγRIIB receptor is required for the beneficial effects of IVIG treatment in TBI, with our results simultaneously highlighting the role of this receptor in reducing secondary damage arising from brain injury.

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.