Background Recent evidence suggests a link between deficient states of the ubiquitous protease inhibitor alpha-one antitrypsin (A1AT), and autoimmunity in vitro.1 The most common phenotype in Ireland is MM, however heterozygous individuals for the Z allele (i.e. MZ) have increased activation of the TNF α system, a key cytokine in the pathogenesis of inflammation in rheumatoid arthritis (RA).2
Previous studies of the prevalence of allelles associated with deficient states of A1AT in RA have given conflicting results.3,4
Objectives We set out to examine the A1AT phenotype of an RA cohort, and to determine if heterozygosity is associated with higher levels of auto-antibodies for ANA, RF and anti-CCP.
Methods Qualitative detection and characterisation of A1AT phenotypes in 135 RA patients was performed using the Hydrasys electrophoresis platform (Sebia) and the Hydragel 18 A1AT Isofocusing kit (Sebia).
A cohort of 1,100 randomly selected individuals from the voting registry in Ireland were used to determine the overall prevalence of phenotypes in Ireland.1 Fisher's exact test was used to test for a correlation between allelic status and RA. Antibody dilution factors for ANA and titres for RF and ACPA were available for all patients for RF (n=135), and for anti-CCP in 118 of the patients. The Mann Whitney U-Test was employed to determine differences in median levels of antibodies between the cohorts.
Results Higher concentrations of ANA were associated with heterozygosity for A1AT when compared with homozygous states (p=0.045, see fig 1), and this was not observed for RF or anti-CCP titres.
There was no difference between the prevalence of the homozygous MM phenotype and the heterozygous phenotypes i.e. MZ or MS in patients with RA and the control group.
Conclusions ANA is a non-specific marker of many auto-immune conditions. A direct role has been observed for A1AT in regulating neutrophil degranulation in the innate immune system,1 and the higher titres of ANA seen in those heterozygote for A1AT alleles may implicate A1AT in the adaptive immune response, for example RA.
Bergin DA, Reeves EP, et al. The Circulating Proteinase Inhibitor α-1 Antitrypsin Regulates Neutrophil Degranulation and Autoimmunity. Science Translational Medicine. 2014;6(217):217ra1
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Reviews Immunology. 2007;7(6):429-42.
Cox DW, Huber O. Association of severe rheumatoid arthritis with heterozygosity for alpha 1-antitrypsin deficiency. Clin Genet. 1980;17(2):153-60.
Cox DW, Huber O. Rheumatoid arthritis and alpha-1-antitrypsin. Lancet. 1976;1(7971):1216
Disclosure of Interest None declared