Targeting IgG in Arthritis: Disease Pathways and Therapeutic Avenues

Abstract

Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the clinical disease. Autoantibodies (rheumatoid factors, anti-citrullinated peptide/protein antibodies) are present in RA patients’ sera for a long time before the onset of clinical disease. Prior to arthritis onset, in the autoantibody response, epitope spreading, avidity maturation, and changes towards a pro-inflammatory Fc glycosylation phenotype occurs. Genetic association of epitope specific autoantibody responses and the induction of inflammation dependent and independent changes in the cartilage by pathogenic autoantibodies emphasize the crucial contribution of antibody-initiated inflammation in RA development. Targeting IgG by glyco-engineering, bacterial enzymes to specifically cleave IgG/alter N-linked Fc-glycans at Asn 297 or blocking the downstream effector pathways offers new avenues to develop novel therapeutics for arthritis treatment.

Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis

“…Autoantibodies after binding to their target antigens trigger downstream inflammatory cascades either directly or in the form of immune complexes [26]. At this effector phase of arthritis, activation of different pathways of complement [27,28] and FcγR-bearing immune cells contributes to cartilage destruction either directly or by promoting the secretion of inflammatory cytokines and matrix lysing enzymes ( Figure 2) [29]. At the same time, antibodies binding to collagen type II (CII) can also induce target damage independent of inflammatory mediators or cells [30].…”

Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

“…Currently, immunoglobulins and Fc fragments are used in the treatment of certain diseases, for example, thrombocytopenic purpura (ITP) [118], rheumatoid arthritis [119], and nephrotoxic nephritis [120]. A study of Fc glycosylation in inflammatory arthritis, ITP, and epidermolysis of bullosa acquisita (EBA) models showed that when sialic acid was removed from Fc fragments, it made IVIg unable to exhibit anti-inflammatory activity [8].…”

Immunopathogenic Mechanisms and Novel Immune-Modulated Therapies in Rheumatoid Arthritis

“…In addition, pathogenic autoantibodies contribute significantly to antibody-initiated inflammation in RA progression. Targeting IgG by glyco-engineering bacterial enzymes to specifically cleave IgG and alter N-linked Fc-glycans or blocking the downstream effector pathways offers a novel opportunity to develop therapeutics for RA treatment in the future [135]. Novel drugs targeting IL-12/IL-23 axis have been proven effective in the treatment of severe psoriasis and psoriatic arthritis (i.e., ustekinumab targeting the IL-12/23 p40 subunit that inhibits IL-12 and IL-23 activity and guselkumab targeting IL-23) [136].…”