The central finding of this paper is a close association between APLA and certain clinical and neuroradiologic features of MS. We surmise that previous studies failed to detect this association because they did not distinguish clinical states of the patients, or used methods unable to make this discrimination.
The frequency of MS plasma positive for APLA in this study was higher than in most but not all previous reports, since as noted in the introduction, Ijdo and colleagues found 88% positivity [20
]. The number of tests performed on each specimen in our study was larger than most and would help to increase the likelihood of finding at least one positive test in a given subject. Furthermore, few if any prior studies clearly separated exacerbation from remission, resulting in a reduced apparent prevalence, since we clearly show a much greater frequency of positivity in exacerbation.
Our finding of IgM exclusively (no IgG) was also unexpected but is not entirely inconsistent with prior reports since most find a preponderance of IgM over IgG. For example, Sugiyama et al found 14 of 32 positive for IgM but only 3 of 32 positive for IgG [27
]. It is unlikely that our finding of exclusively IgM reflects a systematic methodological error since other studies in progress at the same time (such as of ITP) revealed nearly equal numbers of IgG and IgM seropositivity. Additionally, another recent study on clinical and neuroimaging correlates of autoreactive antibodies in MS patients revealed similar finding [33
]. Through a retrospective study, the investigators determined that APLA mainly of IgM type was present in 55% of their study subjects with MS. It remains unknown now why, in our MS subjects, exclusively IgM APLA was found; however, we hypothesize that since the subjects in this study were all newly diagnosed they had not yet class-switched to IgG. Alternatively, one may suggest that a class-switching occurs in a small fraction of APLA+ MS patients, but majority of these APLA+ MS patients are defective in class-switching [34
The clinical significance of the findings of this study is unknown; however, there are two broad possibilities: first, that APLA in MS may contribute causally to the disease pathogenesis, or that APLA are secondary (epiphenomenal) with no role in promotion of the inflammatory cascade of MS. Regarding the first concept, it is important to point out that our assay of aPC, aPS, aPE and aCL does not identify the specific plasma antigen responsible for a positive test. As remarked in the introduction, many APLA antigens are now known, and certainly many more exist, therefore it is possible that APLA in MS are directed against some specific antigen that could be involved, for example, in compromise of the BBB. A number of available reports document cross-reaction of some APLA with endothelial cells and platelets [35
], raising the possibility that the rise of specific types of APLA in the MS subjects could trigger exacerbations by further compromise of the BBB. We have shown complex effects of plasma from MS patients on brain microvascular endothelial cells in tissue culture [40
It should be stressed that our assay against the four pure phospholipids will detect any PL-binding protein, not necessarily those thus far identified as APLA. It is therefore possible that we are detecting an antigen specifically involved in compromise of the BBB, possibly responsible for the endothelial activation that we reported in exacerbations of MS [42
It is of interest that only anti-β2GPI, which is believed to be a risk factor for thrombosis, was not associated with MS radiologic imaging, while anti-FVII was most closely associated (Table ). The pathophysiological significance of these findings remain unclear but it may be relevant to note that FVIIa is closely associated with tissue factor (TF), FXa, and TF pathway inhibitor (TFPI) in normal hemostasis, and that TF has numerous actions apart from thrombosis and hemostasis [43
In light of these findings, further investigation of APLA in a larger cohort of MS subjects is warranted to clarify the significance of these autoantibodies in MS. Further understanding the role of these autoantibodies in MS subjects may eventually translate into more effective treatments.