IgG subclass and Fc glycosylation shifts are linked to the transition from pre- to inflammatory autoimmune conditions

Abstract

A crucial factor for the development of inflammatory autoimmune diseases is the occurrence of antibodies directed against self-tissues and structures, which leads to damage and inflammation. While little is known about the cause of the development of mis-directed, disease-specific T and B cells and resulting IgG autoantibody responses, there is increasing evidence that their induction can occur years before disease symptoms appear. However, a certain proportion of healthy individuals express specific IgG autoantibodies without disease symptoms and not all subjects who generate autoantibodies may develop disease symptoms. Thus, the development of inflammatory autoimmune diseases seems to involve two steps. Increasing evidence suggests that harmless self-directed T and B cell and resulting IgG autoantibody responses in the pre-autoimmune disease stage might switch to more inflammatory T and B cell and IgG autoantibody responses that trigger the inflammatory autoimmune disease stage. Here, we summarize findings on the transition from the pre-disease to the disease stage and vice versa, e.g. by pregnancy and treatment, with a focus on low-/anti-inflammatory versus pro-inflammatory IgG autoantibody responses, including IgG subclass and Fc glycosylation features. Characterization of biomarkers that identify the transition from the pre-disease to the disease stage might facilitate recognition of the ideal time point of treatment initiation and the development of therapeutic strategies for re-directing inflammatory autoimmune conditions.

mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine

“…IgG Fc-mediated effector functions are influenced by the induced IgG subclass and the IgG Fc N -glycosylation pattern. Human IgG1 and IgG3 subclasses have been described to convey the highest potential to activate immune cells via classical activating Fcγ receptors (FcγRs) and the classical complement pathway via C1q ( 20 – 24 ). These IgG subclasses can form hexamers, thereby facilitating the interaction with the six-arm C1q molecule ( 21 , 25 – 29 ).…”

“…Agalactosylated (G0) IgG Abs have been linked to severe conditions in inflammatory (auto-) immune diseases, whereas IgG sialylation has been associated with a decreased affinity of IgG to classical activating FcyRs and lower or anti-inflammatory effects ( 21 , 24 , 36 , 37 , 44 – 52 ). The functional analysis of differently glycosylated IgG Abs is complex because single terminal glycan residues may in addition interact with glycan binding receptors, such as galectins, siglecs, and C-type lectin receptors ( 37 , 44 , 53 – 55 ).…”

Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases

“…AAb are prevalent in the general population and are thus not systematically associated with clinical symptoms 10 . However, in some individuals, through genetic, environmental, and/or hormonal mechanisms, a pro‐inflammatory trigger can amplify their production and modify their isotypes and glycosylation.…”

Autoreactive IgE: pathogenic role and therapeutic target in autoimmune diseases

“…However, in some individuals, through genetic, environmental and/or hormonal mechanisms, a pro-inflammatory trigger can amplify their production and modify their isotypes and glycosylation. Toll-like receptors (TLR) and intracellular nucleic acid sensing molecules engagement, through inflammatory signals, can lead to autoreactive B and T cells proliferation and maturation 1,3,[10][11][12] . Some of these immune signals also initiate class switch recombination (CSR) allowing B cells to switch the constant region of their BCR from IgM to another isotype 13,14 .…”

“…While AAb of IgM isotype may generally be protective against AbAID, IgG AAb are mostly pathogenic. IgG subclasses differ in the activation of complement pathways and in engaging inhibitory and/or activating Fc receptors for IgG (FcγR), and differences in post-translational modifications influence their pro-or antiinflammatory properties 8,10 . The pathogenicity of IgA and IgD AAb still needs further characterization, but recent evidence points to the pathogenicity of IgE AAb and highlights IgE as a potent therapeutic target in a number of AbAID 15 .…”