Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

Abstract

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients’ IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID.

Anti-neuronal IgG4 autoimmune diseases and IgG4-related diseases may not be part of the same spectrum: a comparative study

“…Importantly, antigen-specific IgG4 directly cause neurological symptoms of IgG4-AID (28), while the pathogenic mechanisms of IgG4 in IgG4-RLD are currently not well understood. So far, only very few target antigens have been described in IgG4-RLD (29), but these are mostly located intracellularly.…”

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

“…Examples include antibodies specific to MuSK, a protein that is instrumental in the agrin-LRP4 pathway leading to AChR clustering (213); LGI1, a secreted protein that stabilizes the transsynaptic complex between the pre and postsynaptic receptors, ADAM23 and ADAM22 (169,214,215); and the protein complex of contactin-1, neurofascin-155 and caspr-1, which anchors myelin loops to the axon at the Ranvier paranode (216). A further interesting aspect of autoantibody-mediated neurological diseases is HLA restriction seen in patients as compared to healthy controls, likely meaning that specific antigenic peptides are better presented to T cells by specific HLA alleles (217,218). This is relevant to B cell function, as B cells can pick up antigens with the B cell receptor (BCR) and process them and effectively present them via MHC II to T cells (219).…”

Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects

“…What differs from one disease to another is the triggered and activated immune pathway. The immune pathway elicited in each disease appears to be driven by a genetically determined background [115][116][117][118][119][120][121][122]. The different immune mediators involved account, in turn, for the pathogenetic, histological and clinical differences among these diseases.…”