IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti–Citrullinated Protein Antibody–Associated or Isotype‐Switched IgA Responses

Abstract

Objective To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM‐RF) and IgA‐RF with a newly developed enzyme‐linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses. Methods Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region. Results In a screening panel of 93 sera that were previously found to be IgM‐RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM‐RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM‐RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti‐IgG3 reactivity. Samples without detectable anti‐IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti‐IgG4–negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA‐RF, as compared to restricted RF responses. In a cohort of IgM‐RF+ and/or anti–citrullinated protein antibody (ACPA)–positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+/ACPA– patients, while RF+/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response. Conclusion IgG subclass–specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA‐associated polyspecific responses.

Genetic and epigenetic alteration of the programmed cell death 1 in rheumatoid arthritis

“…Several lines of evidence support this concept. First, citrullination is causatively linked to the development of ACPA while ACPA‐containing immune complexes induced epitope spreading and maturation of RF response and thus RF production . Second, in parallel with PDCD1 association with RF seropositivity in our study, genetic studies also demonstrated CTLA4 , another negative regulator of immunity, associated with RF seropositivity but not ACPA seropositivity .…”

Impact of mixed cryoglobulinemia on patients with spontaneous hepatitis C virus clearance: A 13‐year prospective cohort study

“…Supportively, in a study of 295 837 adults without rheumatoid arthritis, RF was shown to associate with a greater risk of all‐cause and cancer mortality . Specifically, RF is the autoantibody first found in rheumatoid arthritis and is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG‐Fc . In addition, RF is the main component of cryoglobulin and is mainly elevated in people with infectious and autoimmune diseases .…”

“…The inflammation present on tumour microenvironment is characterized by infiltrating leukocytes, which produce a variety of cytotoxic mediators and cascade to oncogenesis . Collectively, elevated RF levels indicate a situation of exaggerated autoimmunity or inflammation, which increases the risk of incident cancer in patients with spontaneous HCV clearance. The precise basis demands further investigation, and the RF‐associated pathway may be the therapeutic target to prevent the development of cancer.…”

Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: The spark that lights the fire in rheumatoid arthritis?

“…7 Epithelial cells, which are at the forefront of mucosal protection, frequently harbor proteins bearing the same posttranslational modifications that are targeted by diseasespecific autoantibodies. 26 Disease-related autoantibodies in patients with RA include the IgA isotypes of RF, ACPA, and anti-MAA, 7,27 which is notable given the density of IgA-producing plasma cells found in the mucosal immune system 28 and ectopic lymphoid tissues that can develop at mucosal surfaces and act to present antigen and drive mature local and systemic immunologic responses. 29,30 Janssen et al 31 recently demonstrated associations of mucosal inflammation with low-level increases in RA-associated autoantibodies (including RF and ACPAs) in patients without articular signs or symptoms of RA but with the alternative diagnoses of chronic bronchiectasis, cystic fibrosis, or periodontitis (PD).…”