Although strong genetic determinants of multiple sclerosis (MS) exist, the findings of migration studies support a role for environmental factors in this disease. Through rigorous epidemiological ...investigation, Epstein-Barr virus infection, vitamin D nutrition and cigarette smoking have been identified as likely causal factors in MS. In this Review, the strength of this evidence is discussed, as well as the potential biological mechanisms underlying the associations between MS and environmental, lifestyle and dietary factors. Both vitamin D nutrition and cigarette smoking are modifiable; as such, increasing vitamin D levels and smoking avoidance have the potential to substantially reduce MS risk and influence disease progression. Improving our understanding of the environmental factors involved in MS will lead to new and more-effective approaches to prevent this disease.
Immunoglobulin gamma (IgG) antibodies are key effector proteins of the immune system. They recognize antigens with high specificity and are indispensable for immunological memory following pathogen ...exposure or vaccination. The constant, crystallizable fragment (Fc) of IgG molecules mediates antibody effector functions such as complement-dependent cytotoxicity, antibody-mediated cellular cytotoxicity, and antibody-dependent cell-mediated phagocytosis. These functions are regulated by a single N-linked, biantennary glycan of the heavy chain, which resides just below the hinge region, and the presence of specific sugar moieties on the glycan has profound implications on IgG effector functions. Emerging knowledge of how Fc glycans contribute to IgG structure and functions has opened new avenues for the therapeutic exploitation of defined antibody glycoforms in the treatment of cancer and autoimmune diseases. Here, we review recent advances in understanding proinflammatory IgG effector functions and their regulation by Fc glycans.
Binding of the complement component C1q to the CH2 domain of antigen-bound immunoglobulin gamma (IgG) activates the classical complement pathway and depends on its close proximity to Fc fragments of ...neighboring antibodies. IgG subclasses contain a highly conserved asparagine 297 (N)-linked biantennary glycan within their CH2 domains, the core structure of which can be extended with terminal galactose and sialic acid residues. To investigate whether Fc-glycosylation regulates effector functions of human IgG subclasses, we cloned the antigen-binding region of the CD20-specific monoclonal antibody rituximab into IgG isotype expression vectors. We found that Fc-galactosylation enhances the efficacy of CD20-targeting complement-fixing antibodies for C1q binding and complement-mediated tumor cell lysis. Increased efficacies were restricted to IgG1 and IgG3 subclasses indicating that Fc-galactosylation alone is not sufficient for IgG2 and IgG4 to acquire complement-fixing properties. Addition of terminal galactose to the N-glycan specifically improved binding of C1q without changing antigen- and FcγRIIIa-binding affinities of IgG isotypes. These data indicate that Fc galactosylation can be harnessed to enhance the complement-activating properties of IgG1 and IgG3 antibodies.
IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory ...properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions.
Sialic acid-binding immunoglobulin-type lectins (SIGLECs) are membrane receptors that are preferentially expressed on immune cells and recognize sialylated proteins, lipids, and RNA. Sialic acids and ...signaling through SIGLECs are increasingly recognized for their essential roles in immune system homeostasis as well as nervous system development, plasticity, and repair. Dysregulated sialylation and SIGLEC dysfunctions contribute to several chronic diseases of the central nervous system (CNS) in which current therapeutic options are very limited. While only a few therapies targeting SIGLECs are currently being tested in clinical trials, the area emerged as one of the most dynamic and active fields in glycobiology and drug development. This review highlights recent insights into sialic acid and SIGLEC function in CNS pathologies and illustrates opportunities and challenges for the development of sialic acid-based and SIGLEC-targeted therapies for neurological diseases.
Sialic acids and sialic acid-binding immunoglobulin-type lectins (SIGLECs) are increasingly recognized for their essential roles in central nervous system development, plasticity, and repair.Only a few therapies targeting sialic acids and SIGLEC functions are currently being tested in clinical trials.Genetic variants and increased expression of the SIGLEC molecule CD33 are associated with the evolution and severity of Alzheimer’s disease (AD) and mechanistically linked to AD pathology through impaired clearance of amyloid-β by microglial cells. A monoclonal antibody with SIGLEC CD33 antagonistic activity is currently being evaluated in patients with AD.Sialic acid mimetics can improve axonal regrowth and promote functional recovery in preclinical models of spinal cord injuries.Immune inhibitory functions of sialic acids and SIGLEC signaling can be exploited to limit microglial neurotoxicity and inflammation-induced CNS tissue damage.Glycoproteomics and glycolipidomics approaches to catalogue biologically relevant SIGLEC ligands in CNS disease conditions are evaluated to identify promising targets and to guide the development of SIGLEC-based therapies towards clinical trials.Engineering therapeutic platforms that allow distinction between SIGLEC agonism versus antagonism and increase bioavailability within the CNS parenchyma will further improve the potential of SIGLEC-targeted therapies for neurological diseases.
Inflammasomes are multimeric protein complexes that can sense a plethora of microbe‐ and damage‐associated molecular signals. They play important roles in innate immunity and are key regulators of ...inflammation in health and disease. Inflammasome‐mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL‐18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune‐mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177–188
Natural killer (NK) cells were viewed traditionally as cytotoxic effector cells whose rapid killing of infected and transformed cells without preactivation provides a first line of defense prior to ...the initiation of an adaptive immune response against infection and tumor development. However, it has become clear that NK cells interact with various components of the immune system, and therefore have the potential to function as regulatory cells. While NK cells can assist in dendritic cell (DC) maturation and T-cell polarization, increasing evidence indicates that NK cells can also prevent and limit adaptive (auto) immune responses via killing of autologous myeloid and lymphoid cells. Investigating immunoregulatory NK-cell functions might generate exciting insights into the reciprocal regulation between NK-cell-mediated innate immunity and adaptive immune responses, improve our capacity to monitor these cells as surrogate markers for disease activity and treatment responses in autoimmune diseases, and, perhaps, provide new prospects for NK cell-directed therapies.
Immunoglobulin G (IgG) molecules are glycoproteins and residues in the sugar moiety attached to the IgG constant fragment (Fc) are essential for IgG functionality such as binding to cellular Fc ...receptors and complement activation. The core of this sugar moiety consists of a bi-antennary heptameric structure of mannose and N-acetylglucosamine (GlcNAc), further decorated with terminal and branching residues including galactose, sialic acid, fucose, and GlcNAc. Presence or absence of distinct residues such as fucose and sialic acid can dramatically alter pro- and anti-inflammatory IgG activities which could be harnessed for immunotherapeutic purposes. Here we review recent advances in understanding the role of the IgG-Fc glycan during immune responses and for immunotherapy with a focus on sialic acid and intravenous immunoglobulin (IVIG) treatment.
Intravenous immunoglobulin (IVIg)-a preparation of polyclonal serum IgG pooled from thousands of blood donors-has been used for nearly three decades, and is proving to be an efficient ...anti-inflammatory and immunomodulatory treatment for a growing number of neurological diseases. Evidence from controlled clinical trials has established IVIg as a first-line therapy for Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. IVIg is also an effective rescue therapy in some patients with worsening myasthenia gravis, and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. IVIg has been tested in some neurodegenerative disorders, but a controlled study in Alzheimer disease yielded disappointing results. Despite its widespread use and therapeutic success, the mechanisms of action of IVIg are poorly understood. Several hypotheses, based on the function of either the variable or constant IgG fragments, have been proposed to explain IVIg's immunomodulatory activity. This Review highlights emerging data on the mechanisms of action of IVIg related to its anti-inflammatory activity, especially that involving the cellular Fcγ receptors and Fc glycosylation. We also summarize recent trials in neurological diseases, discuss potential biomarkers of efficacy, offer practical guidelines on administration, and provide a rationale for experimental trials in neuroinflammatory disorders.
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