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.

Keywords: HLA class II; HLA-DQB1; HLA-DRB1; IgG4 autoimmune disease; MHC; autoimmunity; etiology.

Figure 1

Proposed IgG4 autoantibody targets. ADAMTS13, disintegrin and metalloproteinase with thrombospondin motifs 13; ANCA, antineutrophil cytoplasmic antibodies; AR, Aldose reductase; BP180; BP230, bullous pemphigoid antigen 180/230; CNTN1, contactin 1; Caspr1/2, contactin associated protein1/2; Dsg1/3, desmoglein 1/3; DPPX, dipeptidyl-peptidase-like protein 6; GPIHBP1, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1; IFN I, type I interferon, IgLON5, IgLON family member 5; IL-17A/17F/22, interleukin-17A/17F/22; Lam332, Laminin 332; LGI1, leucine-rich, glioma inactivated 1; MuSK, muscle-specific kinase; NF140/155/186; Neurofascin 140/155/186; PLA2R, phospholipase A2 receptor; SOD2, manganese superoxide dismutase; THSD7A, thrombospondin type-1 domain- containing 7A.

Figure 2

Genes with potential association to IgG4-AID reported in the EBI GWAS catalog (85). Data represents 17 studies investigating four Ig4G-AIDs (Pemphigus vulgaris, Pemphigus foliaceus, Membranous glomerulonephritis, Eosinophilic granulomatosis with polyangiitis; median of 4 studies per disease). The GWAS catalog reports multiple associations per disease and multiple genes mapped to the association signal, so reported genes do not necessarily represent independent associations. The gene MTCO3P1 is a pseudogene located next to HLA-DQB1 in the HLA class II region. Only genes reported more than once are shown. [GWAS catalog accessed on 03.11.2020).

Figure 3

Allele frequency of the HLA-DQB1*05:02 allele in Europe [Source: The Allele Frequency Net Database (AFND)].

Figure 4

HLA class II molecule structure and interaction with T-cell receptor.

Figure 5

Theory of IgG4 induction. Presentation of distinct self- peptides via HLA class II in medullary thymic epithelial cells (mTECs) or antigen-presenting cells (APCs) to developing autoreactive CD4+ T-cells via the T-cell receptor (TCR) may influence their fate toward differentiation into regulatory T-cells (Tregs). This may be influenced by polymorphisms in the beta-chain of the HLA-DR molecule, and/or the type of peptide presented to the TCR. In the periphery, Tregs may respond to their autoantigen by producing anti-inflammatory cytokines IL-10 and TGF-beta. IL-10 may then induce a class switch of autoreactive B-cells toward IgG4. The B-cell may then differentiate into plasma cells, producing autoreactive IgG4. IgG4 then bind their self-antigen, and depending on the location of the epitope, may cause a blocking effect and induce pathogenicity or not.