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When APS (Hughes syndrome) met the autoimmune/inflammatory syndrome induced by adjuvants (ASIA)

  1. M Blank1
  2. E Israeli1
  3. Y Shoenfeld1,2
  1. 1Zabludowitz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
  2. 2Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases
  1. Yehuda Shoenfeld, Zabludowitz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel Email: shoenfel{at}post.tau.ac.il

Abstract

Vaccination of healthy individuals is the most effective approach to protect the public from infections and prevent the spread of many infectious diseases all over the globe. Licensed vaccines are mostly safe, but in rare cases they may be associated with humoral response to self-antigens due to molecular mimicry, epitope spread, bystander activation or polyclonal triggering. Moreover, the clinical picture of autoimmune conditions following post-vaccination is rarer. Nevertheless, anecdotal case reports on the flare of autoimmune response with clinical manifestations were reported. Herein, we discuss this topic in relation to post-vaccination-induced antiphospholipid antibodies following tetanus toxoid vaccine, HBV and influenza associated in rare cases with antiphospholipid syndrome clinical manifestations. We will discuss the possible mechanisms which pertain to ASIA (Shoenfeld syndrome).

Introduction

Autoimmune diseases have been reported to associate or to follow a diverse list of vaccinations.1,2 This is not surprising since autoimmune diseases are known to be caused by infections.3 5 On the one hand, one can assume that vaccine may lead to autoimmunity via the infection agent ingredient being recombinant, weakened, or synthetic. Such mechanisms as molecular mimicry and polyclonal activation may be involved. Yet, recently a new syndrome was defined: ASIA (autoimmune syndrome induced by adjuvants),6 eluding to the important role of the adjuvant ingredients in the vaccine. This syndrome encompasses all the auto-reactive conditions associated with vaccines, but also those emerging following silicone implants which ruptured and invaded neighbouring tissues. In addition, the syndrome may include clinical conditions such as the Gulf syndrome chronic fatigue syndrome and the sick building syndrome.7,8 The common denominator to all of the above clinical circumstances is the existence of an adjuvant which chronically stimulates the immune system.7

The classical antiphospholipid syndrome (APS), the ‘Hughes syndrome’, is characterized by the presence of antiphospholipid antibodies (aPL) which bind negatively-charged phospholipids, platelets and endothelial cells mainly via the plasma protein beta-2-glycoprotein-I (β2GPI).9 The disease is manifested by recurrent fetal loss, thromboembolic phenomena, thrombocytopenia and multi-organ involvements such as heart, CNS, kidney and skin.10 APS is one of the autoimmune conditions which has been found to be induced by infections.11,12 Therefore, it would not be a surprise to find that in low instances APS may be related to vaccination, such as the tetanus vaccine.11 16

APS and tetanus toxoid vaccine

Long ago, when we deciphered the enigma of the infection-APS relationship, we noted the molecular mimicry between some β2GPI peptides and the tetanus vaccine.11 Antibodies directed to the shared epitope induce an experimental APS in naïve mice.11 Human anti-β2GPI monoclonal Abs (mAbs), originated from an APS patient with recurrent fetal loss, were introduced to a hexapeptide phage display library, resulting in the identification of three synthetic peptides, having homology to diverse bacteria viruses, parasites and tetanus toxoid (TT) by using a protein database.15 One of the synthetic peptides, TLRVYK, was found by our group to be the common structure for β2GPI and TT molecules (appears three times in the TT, not as a linear peptide but as conformational mimotopes) as illustrated by ribbon three-dimentional structures of β2GPI and TT.11 Naïve BALB/c mice, immunized with TT, developed antibodies directed to β2GPI and to diverse structures of TT and became sick. Therefore, in order to study the effect of TT-β2GPI-related antibodies on the induction of experimental APS, we isolated the TT/β2GPI antibodies. The Abs from the TT-immunized mice were affinity purified on a column composed of TLRVYK synthetic peptide. Anti- TT/β2GPI Abs bound β2GPI and TT with high affinity, in a dose-dependent manner. Passive transfer of the affinity purified anti-TLRVYK Abs to naïve mice induced the experimental model of APS manifested by a high significant percentage of fetal loss, prolonged coagulation time and thrombocytopenia.11

Zivkovic et al.,14,15 confirmed the association between TT and experimental APS. TT hyperimmunized mice and passive mice transferred with anti-TT monoclonal antibody cross-reactive with β2GPI, caused increased fetal loss and low fecundity in BALB/c mice.14 Furthermore, hyperimmunization of BALB/c mice with TT in aluminium hydroxide, glycerol or CFA, resulted in elevated circulating antibodies to TT, β2GPI, gangliosides, laminin and induced fetal loss.14,15 A decrease in fecundity was recorded only in C57BL/6 mice immunized with alhydrogel adjuvant associated with an increase in low affinity anti-β2GPI IgG antibodies and Th1 prevalence. These observations led to the notion that the immune response of mice to TT depends on the genetic background and the specific adjuvant used for immunization. This is an analogue to the HLA dependency of the macrophage myofascitis syndrome induced following a HBV vaccine containing aluminium, which emerges only in individuals with specific HLA.7

Several case reports showed the possibility of triggering antiphospholipid syndrome following tetanus vaccination: two healthy young males who received a diphtheria-tetanus vaccination and were diagnosed with clinically and serologically proven antiphospholipid syndrome, manifested a few months after a diphtheria-tetanus vaccine.16 A patient was reported who presented neck pain, paroxysmal tonic spasms, a positive Lhermitte’s sign and spastic quadriplegia, and later developed bilateral optic neuritis and had clinical and biochemical features of APS. The authors did not exclude the possibility that the APS appearance was associated with the tetanus injection they received.

APS post-hepatitis B virus vaccination

A search of PubMed revealed that elevated titers of anti-cardiolipin (aCL) antibodies (β2GPI-dependent or -independent) occurred frequently following viral infections or vaccination. Enhanced circulating autoantibodies directed to phospholipid (cardiolipin, β2GPI) and lupus anticoagulant were identified in the sera of hepatitis B virus (HBV)-infected APS patients.17 The most frequently identified aPL in these patients were of the IgM isotype, which were persistently detected over a 12-week period.17 However, patients with chronic hepatitis develop β2GPI-independent aPL.18 In all cases of aPL related to the HBV vaccine, they were not associated with thrombosis after hematological manifestations of the APS.

DNA hepatitis B vaccination was given to 85 healthy students.19 One month post-vaccination, a minority of individuals showed changes in IgG or IgM aCL, anti-β2GPI or lupus anticoagulant (p < 0.001). Among subjects in whom changes of IgG anti-β2GPI were observed, a significantly higher number of increased (8/85) than decreased (2/85) values were found (p < 0.01). One of the explanations for the HBV vaccination induced anti-β2GPI antibodies may be a result of β2GPI binding to recombinant hepatitis B surface antigen (rHBsAg).17 The phospholipid binding site on the β2GPI fifth domain is targeted by rHBsAg.20

APS post-influenza virus vaccination

The association between the influenza vaccine and Guillain–Barre syndrome was suggested following a rise in disease prevalence after the swine flu vaccine campaign in 1976.21 As for APS, rare cases of APS clinical manifestations were reported: a patient presenting ischemic stroke 4 days after influenza vaccination associated with secondary APS to lupus. Toplak et al.22 reported on the production of anti-β2GPI and in some LA in 15% of 92 healthy medical workers up to 6 months post-influenza vaccination. Persistently elevated levels of autoantibodies were observed in seven (8%) participants and two showed progressively increased levels of IgM, aCL or IgA anti-β2GPI, respectively. So far, no APS clinical picture has been documented, although no one can predict the future clinical presentation of the second hit trigger in genetically predisposed individuals for APS. Tarjan et al.23 found that repeated influenza vaccination in clinically stable SLE patients with low disease activity may result in increased production of anti-β2GPI antibodies, and therefore may increase the risk of thrombotic manifestations.

Current proposed mechanisms

Several mechanisms were proposed to explain the role of the adjuvants in ASIA syndrome that may trigger autoimmune cascade.24 29 For prophylactic vaccines in humans, the adjuvants used are alum, oil in water emulsions (MF59, AS03, AS04) and the TLR4 ligand monophosphoryl lipid A (MPL) absorbed to alum.24 Over the years, since the discovery of the adjuvant in 1926, it has been shown that alum triggers interleukin (IL)-1β production. Recently, it was proposed that alum may activate caspase 1, through inflammasomes containing the cytosolic receptor Nlrp3.25 The authors suggested that alum may function by signalling through specific receptors of innate immunity defined as pattern recognition receptors (PRRs), by inducing the accumulation of uric acid. Uric acid, a major metabolite of nucleic acids and a potential DAMP (damage-associated molecular pattern) when crystallized, was proposed to be an endogenous adjuvant capable of triggering T-cell responses by iDC recruitment and T-cell activation after alum immunization.26 The mild cytotoxic activity of alum may act as an endogenous danger signal (DAMP) and can alert the innate immune system through the activation of various PRR signalling pathways.27 Lately, Marichal et al.28 showed using mice models, that alum-induced cytotoxicity resulted in the release of host DNA, which acts as a DAMP, mediating the adjuvant activity of alum on adaptive immune responses. Extracellular host DNA is known to be a DAMP, involved in an increasing number of immune processes and diseases, for example, lupus or chronic polyarthritis.29

The TLRs, as one of the major key points in the adoptive immune processes were found to have a role also as a response to adjuvants and a potential target for developing novel vaccines such as ASO4.24 Several new adjuvants that are currently in clinical and pre-clinical trials target the toll-like receptor pathway, such as TLR3, TLR4, TLR5, TLR7/8 agonists and, in the most advanced clinical studies, TLR9 agonists.24,30

Although there are rare cases of elevated levels of circulating anti-β2GPI Abs upon post-vaccination, one has to keep in mind that the memory cells are waiting for a second hit. This may come in time, by molecular mimicry or non-specifically by bystander activation or by adjuvant triggering, the common denominator of most vaccines during lifetime, and induce the development of the clinical picture of APS in genetically susceptible individuals. Therefore, these all strengthen the importance of ASIA and should be kept in mind during clinical work and research.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interests

Y S has appeared in court for patients suffering from ASIA.

References

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