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The Role of Infection in the Pathogenesis of Catastrophic Antiphospholipid Syndrome — Molecular Mimicry?

General factors such as prolonged bed rest, hypercholesterolemia, or accompanying hypertensive vascular disease/nephrotic syndrome do not, however, seem to play any role in triggering these catastrophic events. However, trauma such as surgical interventions (even minor, such as a dilatation and curettage or repair of tendons) or investigative procedures (ERCP) have been reported preceding catastrophic APS, and in many instances these procedures are combined with other triggering events such as withdrawal of longterm anticoagulation with warfarin, for example, the patient then suffering from "rebound" immediate clotting. Recurrent clotting after warfarin withdrawal has been documented as occurring several weeks later¹⁶, and then mainly involves large vessels in patients with the classical APS. Drug administration has been implicated in a minority of patients (e.g., administration of oral contraceptives or sulfur containing diuretics for example)¹⁷.

Pregnancy and the puerperium, both associated with hormonally induced alterations in the homeostatic clotting milieu, thereby predisposing to coagulation in susceptible patients, has also triggered catastrophic APS.

Clearly, other factors might be involved to result in such a devastating microvasculopathy and its attendant severe morbidity and mortality. One of these important triggers is infection, whether clinical or subclinical.

Bacterial infection has been associated with the development of catastrophic APS in 26% of a recent series⁴, and in 6 of 8 patients described by Rojas-Rodrigues, et al in this issue¹⁸. Kitchens¹⁹ has described 6 patients -- multi-organ thromboses followed pneumonia in one and gram negative septicemia in another. The report by Hayem, et al²⁰ is a clear illustration of catastrophic APS being triggered by well documented Salmonella typhi infection in a patient with a positive Widal test as well as positive blood cultures. The episode of catastrophic APS occurred 3 weeks after the onset of typhoid fever successfully treated with ofloxacin (fluoroquinolone). This patient responded dramatically to plasmapheresis. The authors suggested that S. typhi antigens, particularly lipopolysaccharides, might have immunological and prothrombotic effects in patients vulnerable for the APS. Lipid A, found on the outer surface of gram negative bacteria, has been shown to induce ß₂-glycoprotein I (ß₂-GPI) dependent anticardiolipin antibodies (aCL) and lupus anticoagulant²¹.

It should be emphasized that antiphospholipid antibodies (aPL) have historically been strongly related to infection. The seminal VDRL test (an antibody directed to cardiolipin) was originally related to syphilis and only in patients with SLE was it attributed to a "false positive" reaction²². Following the description of aCL and their pathogenetic role in the APS^23-26, many reports have appeared on the frequency of occurrence of a variety of aPL in infections (viral, bacterial, parasitic)^27-31. Following the discovery of the ß₂-GPI cofactor, it was claimed that pathogenic (e.g., autoimmune) aPL antibodies are ß₂-GPI dependent (or even anti-ß₂-GPI per se!), while the nonpathogenic aPL bind directly to aPL (as in the VDRL) reaction and are ß₂-GPI independent. Later it became clear that this classification and characterization was not as clear-cut. Indeed, both kinds of autoantibodies may be detected in both conditions, that is, infections and autoimmune diseases³². It is conceivable that the nonpathogenic aPL are induced by common infections. These kinds of aPL may be "switched on" (e.g., by a "second hit") to a pathogenic type by several mechanisms, for example, idiotype change, somatic mutations at the CDR3 of the Ig structure, increase in avidity, change in specificity, and other processes³³.

Recently, additional evidence was reported to point to an infectious relationship to aPL induction. ß₂-GPI was shown to induce aPL upon active immunization in mice and in rabbits^34-37. After production of the aPL the mice presented with the full diverse manifestations of experimental APS³⁵.

With the use of several monoclonal anti-ß₂-GPI antibodies and using the phage library display technique of a hexapeptide library, 3 peptides were identified. These 3 peptides were found to reside on 3 different domains of the "sushi" structure of ß₂-GPI. The peptides were recognized by aCL antibodies of patients with APS, and were shown to prevent experimental APS induced by active immunizations with ß₂-GPI³⁸. Interestingly, the 3 sequences were also detected on membranes of diverse viruses, bacteria, and parasites. Thus it seems that by molecular mimicry some of these infectious agents can induce not only aPL, but also pathogenic anti-ß₂-GPI antibodies.

Further support has been lent to this notion of infection–
aCL relationship by Gharavi, et al³⁹, who investigated the Genebank database and identified 7 proteins with sequence homology to GDKU and GDKU2 proteins, which are the sequence in ß₂-GPI shown to be the major phospholipid binding site on ß₂-GPI. The peptide sequences are of interest because they are also part of many human viruses to which humans are commonly exposed. These viral peptides compete with ß₂-GPI peptides on binding to aPL. Moreover, immunization of groups of mice with these peptides, conjugated in bovine serum albumin in Freund’s adjuvant, produced high levels of aPL and anti-ß₂-GPI antibodies.

These studies revealed that aPL and anti-ß₂-GPI antibodies with properties similar to those found in patients with APS can be induced by immunization with ß₂-GPI-like phospholipid-binding viral and bacterial products.

Thus it seems that an additional enigma of the APS has been deciphered in this decade, namely, the etiopathogenesis⁴⁰. In this respect APS most probably does not differ from, although it is not as common as, other autoimmune diseases, since the environmental trigger must hit someone already harboring the other components of the mosaic of autoimmunity, such as genetic predisposition (e.g., makeup of the MHC) and immune system defects (e.g., IgA or complement deficiency), as well as abnormalities of the hormonal milieu^41,42. Thus, it is not surprising that a catastrophic exacerbation may result from exposure to several common viral or bacterial infections. We found that ciprofloxacin, a common quinolone having, among other properties, the ability to induce production of the cytokine interleukin 3 (IL-3)⁴³, a cytokine found to be deficient in mice^44,45 and subjects with APS, can in fact benefit mice induced with the experimental APS. Therefore, perhaps an infectious etiology for the APS, especially its catastrophic variant, should be considered more seriously and frequently and appropriate antibiotic therapy instituted.

Another interesting aspect of the infection–APS relationship encompasses atherosclerosis⁴⁶. Recently, aPL⁴⁷ and ß₂-GPI⁴⁸ were found to be involved in the pathogenesis and enhancement of the atherosclerotic process. Thus, an additional bidirectional relationship between infection and autoimmunity is unravelled that expands far beyond the APS to a more widespread clinical condition — atherosclerosis⁴⁹.

RONALD A. ASHERSON, MD, FACP, FCP(SA), FRCP(Lond), FACR,
The Rheumatic Diseases Unit,
Department of Medicine,
Groote Schuur Hospital,
University of Cape Town School of Medicine,
Cape Town, South Africa;

YEHUDA SHOENFELD, MD,
Head, Department of Medicine B,
Chaim Sheba Medical Center,
Tel Hashomer,
Tel Aviv, Israel.

Address reprint requests to Dr. Asherson.

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