Carbamylated Proteins as a Biomarker for Sjogren’s Syndrome

September 16, 2015
Norman Bauman

Autoantibodies against carbamylated proteins in Sjögren’s syndrome could be used as a new biomarker.

Autoantibodies against carbamylated proteins have been associated with rheumatoid arthritis, and now, a new study shows they could be used as a biomarker for primary Sjögren’s syndrome.   Reporting in the Sept. 8 online issue of Annals of Rheumatic Diseases researchers say the presence of anti-carbamylated proteins in patients with primary Sjögren’ssyndrome, is strongly associated with increased focal lymphocytic infiltration, the formation of ectopic germinal center-like structures in minor salivary glands and diminished salivary gland function. This suggests that anti-carbamylated proteins can be used as a biomarker.    “Because of their close association with the degree of focal lymphocytic infiltration of the minor salivary glands, formation of ectopic GC-like structures and diminished salivary flow, it is reasonable to suggest anti-CarP status as an additional biomarker in the serological profile of patients with pSS (primary Sjögren’s syndrome),” the researchers wrote.   Led by Piotr Mydel MD, PhD, of the University of Bergen, Norway, researchers investigated the presence and prognostic value of autoantibodies against carbamylated proteins (anti-CarP) in the serum of patients with primary Sjögren’s syndrome.   They measured serum levels of anti-carbamylated proteins in 78 Norwegian patients with primary Sjögren’s syndrome and 74 matched controls, and analyzed exocrine gland function, degree of salivary gland inflammation, signs of ectopic germinal center formation and immunological markers.    Of the patients with primary Sjögren’s syndrome, 27% were positive for anti-carbamylated IgG antibodies. Levels of anti-carbamylated proteins correlated positively with total IgG, IgM, rheumatoid factor and β2-microglobulin. This indicates that the upregulation of anti-carbamylated protein occurs in the context of a generalized increase in B cell activity, they observed. After adjusting for confounding factors, patients who were positive for anti-carbamylated protein, had significantly higher focus score.

Source:  Annals of Rheumatic Diseases  

“Even taking into consideration our relatively small cohort we believe that anti-carbamylated protein antibodies offer new possibilities for identifying patients with more active disease and at risk of developing additional comorbidity,” the researchers wrote.   Autoantibodies against carbamylated proteins (anti-CarP) have been associated with joint pain and destruction in patients with rheumatoid arthritis. Sjögren’s syndrome has been associated with several other autoantibodies, such as antibodies against the Fc portion of IgG (rheumatoid factor), muscarinic acetylcholine type 3 receptor, carbonic anhydrase, alpha-fodrin, and, to a lesser extent, cyclic citrullinated peptide.   “New serological markers, allowing early detection, could lead to closer patient follow-up and more timely application of immunosuppresive agents. This would limit irreversible tissue damage and reduce mortality related to the comorbidity,” the researchers wrote.  

Worse Disease Outcomes with Anti-Carbamylated Protein Antibodies 

  This is the first study of antibodies against carbamylated proteins and disease manifestations of primary Sjögren’s syndrome where they are associated with more severe disease.    “Positive anti-carbamylated protein status coincided with 9.2-fold higher odds of having developed germinal center-like structures in the minor salivary glands,” the researchers wrote. Conversely, individuals with germinal center-like structures, who generally have worse disease outcome, also presented with significantly higher levels of anti-carbamylated protein antibodies.    Citrullination and carbamylation are post-translational modifications of proteins at lysine and other residues that change the function of proteins, harming organs directly and also indirectly by provoking autoimmune reactions. While anti-citrullinated protein antibodies (ACPAs) have a well-established role in rheumatoid arthritis, anti-carbamylated protein antibodies also seem to play a role in rheumatoid arthritis and other rheumatological diseases.    Sjögren’s syndrome is characterized by progressive infiltration of mononuclear cells into lacrimal and salivary glands. Most patients experience severe symptoms of ocular and oral dryness (keratoconjunctivitis sicca and xerostomia, respectively) and functional impairment of the respective glands.   Nearly all proteins undergo post-translational modifications. Carbamylation adds a cyanate group to a lysine or other residue, while citrullination hydrolyzes an imine group to a ketone. Protein carbamylation is a cyanate-dependent, non-enzymatic conversion of lysine residues to homocitrulline, and conversion of N-terminal amino acid groups to α-carbamyl amino acids. Lysine is positive, and homocitrulline is neutral, so carbamylation changes the charge distribution of proteins, which changes the protein’s function. Carbamylation is driven by cyanate, and cyanate is in equilibrium with urea, so carbamylation is markedly increased in renal insufficiency.    Another carbamylation mechanism was recently discovered in the immune system. Activated neutrophils release myeloperoxidase, which catalyzes the conversion of thiocyanate to cyanate, also leading to carbamylationv.   

RELATED ARTICLES

 

References:

Bergum B, Koro C, Delaleu N, et al.

Antibodies against carbamylated proteins are present in primary Sjogren’s syndrome and are associated with disease severity. Annals of Rheumatic Diseases.

Online Sept. 8, 2015. doi: 10.1136/annrheumdis-2015-207751