genetic factors necessary to break tolerance against carbamylated proteins such

Genetic factors necessary to break tolerance against

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genetic) factors necessary to break tolerance against carbamylated proteins such a fibrinogen remains to be eluci- dated. Although the molecular structures of homocitrulline and citrulline are very alike, ACPA and anti-CarP are distinct autoantibody classes, with anti-CarP being present in both ACPA-positive and ACPA-negative patients [ 2 ]. Moreover, anti-CarP is associated with radiographic progression in pa- tients negative for RF and ACPA. Diagnostic classification of RA patients did not improve by adding anti-CarP testing, as RF and ACPA are already good predictors for disease [ 40 ]. Assays to test for the presence of anti-CarP most often use fetal calf serum (FCS), containing a mixture of carbamylated proteins. The exact autoantigens that anti-CarP bind in vivo remains unclear. Anti-acetylated protein antibodies The latest addition to AMPAs in RA patients is anti-acetylated protein antibodies which have been described in approximate- ly 40% of RA patients, mainly in the ACPA-positive group. Detection rates in seronegative RA patients were comparable to patients with resolving arthritis, rendering it unlikely that these antibodies will be a new biomarker helpful for diagnos- ing RA [ 3 ]. However, anti-acetylated protein antibodies might provide useful new insights in pathophysiology, especially in the era in which the microbiome seems to become increasing- ly important. Acetylation is an enzymatic process, which can be affected by bacteria, although the underlying mechanism is unclear. Therefore, anti-acetylated antibodies could provide a possible new link between microbiome dysbiosis and the de- velopment of autoimmunity in RA [ 3 , 41 ]. Development of the autoantibody response over time The presence of the different autoantibodies in serum of (future) RA patients can be detected years before actual dis- ease onset [ 42 44 ]. Most research on the details of the auto- antibodies response prior to clinical disease manifestation is done on ACPA. From all RA patients, 50% presents with ACPA. About 4 years before disease onset, 50% of the pa- tients that will be ACPA positive will harbor ACPA. At that time point, the ACPA levels start to increase. The profile of citrullinated antigens recognized expands extensively and isotype switching occurs. These events predict RA develop- ment in patients with undifferentiated arthritis and correlate with a rise in inflammatory cytokine levels [ 45 49 ]. Also, the Fc glycosylation pattern changes before disease onset. Galactosylation decreases while fucosylation increases, lead- ing towards a more pro-inflammatory phenotype of the anti- bodies [ 50 ]. There is one feature of ACPA, which strikingly differs from the normal development of antibody responses. In general, during B cell maturation, class switching, somatic hypermutation, and affinity maturation are physiological pro- cesses occurring in germinal centers. B cells producing anti- bodies with sufficient avidity will proliferate, improving the 440 Semin Immunopathol (2017) 39:437 446
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efficacy of the immune response. In contrast to an immune
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