The rheumatoid arthritis-associated autoantibodies to filaggrin label the fibrous matrix of the cornified cells but not the profilaggrin-containing keratohyalin granules in human epidermis

Abstract

SUMMARYSince they were first described, serum TgG antibodies to the stratum corneum of rat oesophagus epithetium. highty specific for rheumatoid arthritis (RA). have been consensuatty catted antikeratin antibodies (AKA). However, we recently demonstrated that they actually recognize three new proteins of rat oesophagus epithetium distinct from cytokeratins. and also human epidermat fitaggrin. In this work we provided further evidence that AKA and RA-associated anti-fitaggrin autoantibodies are the same antibodies. Moreover, analysing by indirect immunofluorescence on human skin a large series of 212 well characterized RA sera and anti-fitaggrin autoantibodies purified from RA sera by affinity chromatography. we demonstrated the specific binding of AKA to the stratum corneum of human epidermis and the absence of any staining of the granular keratinocytes. This binding was confirmed and the AKA antigen precisety locatized in human epidermis by immunoelectron microscopy. The antigen was found to be restricted to the fitaggrincontaining intraceltular fibrous matrix of the corneocytes, up to the desquamating cetls. In contrast. MoAbs directed to human filaggrin and to profitaggrin. its precursor, not onty stained the intracettutar matrix ofthe tower corneocytes but atso the keratohyatin granutes of the granular cetts, where profitaggrin is stored. These results reinforced by the absence of immunoblotting reactivity of RA sera to profilaggrin suggest that the epitopes recognized by AKA are absent from profilaggrin. Their identification may provide more insight into the pathogenesis of RA.

Antibodies to citrullinated proteins: molecular interactions and arthritogenicity

“…The AKA can also be detected in RF‐negative patients and in patients with early RA (7). APF and AKA both recognize the same antigen, which is the cytokeratin filament‐aggregating protein filaggrin (7–10). Purified filaggrin from human epidermis has been used in RA diagnosis and led to the detection of anti‐filaggrin autoantibodies (AFAs) (11).…”

Rheumatoid factors and anticyclic citrullinated peptide antibodies in pediatric rheumatology

“…Testing for APF and AKA did not become commercially popular, because assessment was difficult to perform and interpret. In 1995, APF and AKA were found to be identical, and filaggrin was the antigenic target for both [22][23][24]. Filaggrin is a protein expressed during the terminal differentiation of epithelial cells of mammalian skin and esophagus.…”

Epitope Specificity of Anti-Citrullinated Protein Antibodies

“…Another ACPA, the anti-keratin antibody, was discovered in 1979 in RA sera [57]. Both antibodies recognize the cyto-keratin filament-aggregating protein filaggrin [58,59,60]. Nevertheless, as epidermal filaggrin is not expressed in the joints, it cannot be considered as a joint-specific autoantigen that drives an anti-filaggrin response.…”