Specific glycosylation of á1-acid glycoprotein characterises patients with familial Mediterranean fever and obligatory carriers of MEFV

Background—Familial Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response. Objective—To determine the state of inflammation in homozygotic and heterozygotic MEFV genotypes. Methods—CRP and SAA were studied by enzyme linked immunosorbent assay (ELISA). The glycosylation of the acute phase protein, á1-acid glycoprotein (AGP), was visualised with crossed aYnoimmunoelectrophoresis with concanavalin A as diantennary glycan-specific component and Aleuria aurantia lectin as fucosespecific aYnity component. Results—FMF attacks were associated with an increase (p<0.05) in the serum inflammation parameters CRP, SAA, and AGP. The glycosylation of AGP showed an increase(p<0.05)infucosylatedAGPglycoforms, whereas the branching of the glycans remained unaVected. The glycosylation of AGP in the MEFV carrier group, compared with that in a healthy control group, was characterised by a significant increase (p<0.05) in branching of the glycans, whereas the fucosylation remained unaVected. Conclusion—The findings suggest an FMF-specific release of cytokines, resulting in a diVerent glycosylation of AGP between a homozygotic and heterozygotic MEFV genotype. (Ann Rheum Dis 2001;60:777–780) Familial Mediterranean fever (FMF) is an inherited autosomal recessive inflammatory disease aVecting mainly north African Jewish, Armenian, Turkish, and Arab populations. In more than 80% of the cases, one or two conservative missense mutations are identified. Most of the mutations are in exon 10 at the carboxy terminal portion of the putative protein encoded by the MEFV gene on chromosome 16p. 3 The MEFV gene encodes a protein of 781 amino acids termed pyrin or marenostrin, which is mainly expressed in mature granulocytes and is supposed to play a part in the down regulation of inflammation mediators. Mutations in the MEFV gene are thought to lead to uncontrolled neutrophil activation and migration to serosal tissues. Clinically, FMF is characterised by recurrent attacks of fever, with one or more of the following manifestations: peritonitis, pleuritis, arthritis, myalgia, and erysipelas-like skin lesions. Colchicine is the preferred treatment in FMF and 65% of patients obtain a complete remission, some 20–30% show significant improvement with a reduction in the number and severity of attacks, but between 5 and 10% do not respond to the drug. 9 Attacks of FMF are associated with an intense inflammatory response and as a result the acute phase reactants C reactive protein (CRP), fibrinogen, and serum amyloid A (SAA), the erythrocyte sedimentation rate, and white blood cell count rise sharply. 11 á1-Acid glycoprotein (AGP), another positive acute phase protein, has not been studied in detail before in FMF. AGP not only rises during inflammation but also undergoes structural modifications, resulting in a change of both the degree of branching and the extent of á3-fucosylation of its glycans. This results in the appearance of a variety of AGP glycoforms in plasma. The change in extent of á3-fucosylation is not unique for AGP but has also been described for haptoglobin and á1-protease inhibitor. 16 An increase in á3-fucosylation is accompanied by an increased expression of serum blood group determinant sialyl Lewis X. The state of inflammation— that is, acute or chronic, can be determined by analysing the glycosylation of AGP. During an acute inflammation, as found after an acute insult such as extensive burns or bacterial sepsis, a decrease in branching of the glycans in combination with increased á3-fucosylation has been found. 13 17–26 In contrast, in patients with chronic inflammatory disorders like rheumatoid arthritis or insulin dependent diabetes mellitus, an increased branching with a further increase of á3-fucosylation can be found. 14 27 28 Therefore, the changes in relative occurrence of AGP glycoforms, diVering in degree of branching and extent of fucosylation, can shed more light on the state of inflammation than the CRP and SAA concentrations alone. In this study we used the serum concentrations of CRP, SAA, and AGP and the Ann Rheum Dis 2001;60:777–780 777 Department of Medical Chemistry, Institute for Inflammation and Inflammatory Diseases, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands