Adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the ASIA syndrome

Abstract

Adjuvants may induce autoimmune diseases in susceptible individuals, a phenomenon recently defined as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Patients with both antiphospholipid antibodies (aPL) and the genetic coagulopathy factor V Leiden (FVL) are frequently found. We therefore evaluated whether adjuvant can induce aPL in heterozygous FVL mice. aPL were measured in naïve mice and at 1 and 5 months after immunization with either complete or incomplete Freund's adjuvant (CFA, IFA) in FVL and control C57/B6 background mice. We defined antibody levels 3 SD above the mean of C57/B6 mice immunized with adjuvant as positive (specificity of 99%). For β(2)GPI-dependent aPL, 28.6% (6/21) of FVL mice 5 months after immunization with adjuvant (both IFA and CFA) were positive compared with 4.8% (1/22) of FVL mice 1 month after adjuvant and 0% of naïve FVL and C57/B6 mice (0/16, p < 0.001). aPL levels correlated with behavioral hyperactivity in the staircase test. FVL mice immunized with adjuvant did not develop β(2)GPI-independent aPL. We hypothesize that the FVL aPL association is not a coincidence, but that chronic coagulation defects combined with external inflammatory stimuli analogous to adjuvant may induce aPL and also antiphospholipid syndrome, thus supporting the notion of ASIA.

On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives

“…This datum is consistent with both evidence from clinical case reports [30,103,[105][106][107][108][109][110] and data from murine models where different adjuvants, such as Alum and MF59 [111][112][113][114][115] were characterised by several mechanisms of action.…”

Coagulopathy triggered autoimmunity: experimental antiphospholipid syndrome in factor V Leiden mice

“…The most reasonable explanation for this late and prolonged elevation of aPL antibody levels in FVL Q/Q mice is that of an ongoing process, such as the chronic exposure of the immune system to activated components of the clotting system, which include β 2 -GPI. This is in line with our recent publication describing spontaneous development of specific pathogenic aPL (β 2 GPI-dependent) autoantibodies in genetically hypercoagulation-prone FVL mice immunized with adjuvant alone [34]. Interestingly, adjuvant-immunized FVL mice exhibited hyperactivity behavior compared with non-immunized FVL mice, which correlated with the autoantibody level [34].…”

Vaccine Adverse Events Reported during the First Ten Years (1998–2008) after Introduction in the State of Rondonia, Brazil

“…Additionally, regarding immunologic effects, epidemiological studies have suggested an association of Thimerosal and patch-test sensitivity; countries that eliminated Thimerosal from vaccines such as Austria, Denmark, Poland, and the USA [26] observed a decrease in Thimerosal patch-test reactions. Moreover, both experimental [27] and clinical [28] studies have addressed autoimmune (autoinflammatory) syndrome induced by adjuvants (ASIA) in association with some adjuvanted vaccines. Although this emerging information is not part of the AEFI recording system the collected data are nevertheless shaping perceptions among health workers and stakeholders.…”