ME/CFS, Lyme disease, anti-cardiolipin antibodies and mast cells

By Paolo Maccallini

Antibodies to cardiolipin in ME/CFS

In 2009 a group from the University of Hawaii at Mânoa searched for anti-cardiolipin antibodies (anti-CA Abs) in ME/CFS (1)↑. Surprisingly, they found that anti-CA Abs were present in 38/40 (95%) of serum samples. Positive samples were all of the IgM serotype, and four of them were also of the IgG serotype. This study followed a previous one by the same group in which presence of the phospholipid cardiolipin (CL) was demonstrated in sera from 117/328 (91,2%) of CFS patients, while only 7,7% of serological samples from healthy subjects harboured this molecule (2)↑. As CL is a component of the inner membrane of mitochondria, this research group suggested an alteration of the inner membrane of mitochondria with consequent exposure of CL and immune system response to it, as an underlining mechanism for CFS pathophysiology (1)↑. It is worth noting that anti-CL Abs are present in 22,7% (53/233) of healthy subjects, according to one research group who found an association of positive serum samples with neuropsychological impairment in elderly normal subjects. In contrast with CFS patients, in healthy subjects, there is a prevalence of the IgG serotype (3)↑.

Antibodies to cardiolipin in autoimmune diseases

Anti-CL Abs have been reported in autoimmune and infectious diseases. In Behçet’s disease, 13/70 (24.28%) patient sera reacted against CL, mainly with IgG serotype, in one 1984 study. An association between anti-CA and retinal vascular disease in this cohort was reported (4)↑. In systemic lupus erythematosus 32/59 (54.2%) patients have elevated serum Abs against CL in a Swedish study where no correlation with particular clinical features was reported (5)↑. In rheumatoid arthritis, anti-CA are present in 55/173 patients (32%) and they are associated with rheumatoid nodules, but not with a history of thrombosis (6)↑.

Antibodies to cardiolipin in Lyme disease and other infectious diseases

In HIV-1 anti-CL are reported in 36% of patients (7)↑ and they may be elicited in some cases through molecular mimicry, by HIV-1 envelope (ENV) (8)↑. Anti-CA is a common finding in infectious mononucleosis (IM), and a research group found the IgM serotype (IgG was not tested) to be elevated above two standard deviations compared to the control sera, in 13/35 (37%) sera from IM patients. In this study, it was also reported that anti-CA from two of the IM sera did react with the membrane of EBV-transformed lymphocyte and proposed that B cells infected with EBV would generate new epitopes of altered phospholipids which could subsequently become a target for anti-cardiolipin antibodies (9)↑. Anti-CA have also been associated with other infections, as leprosy (caused by bacteria from the genus Mycobacterium) where 22/33 patients were reported to be anti-CA positive, tuberculosis (also caused by bacteria from the same genus) with 16/30 patients positive to anti-CA (10)↑, hepatitis C virus where 28/75 patients were reported to have positive anti-CA (11)↑, Q fever (infection by Coxiella burnetii) where 17/26 have been reported to have high levels of anti-CA antibodies (12)↑ and others (13)↑. Anti-cardiolipin antibodies may occur in patients with Lyme disease too, particularly in those with neurologic abnormalities. In a 1993 study, anti-CA antibodies of the IgG serotype were found in 50% of patients with neuroborreliosis (14)↑. This is of interest since EBV and other infections have been linked to CFS, both as a mere trigger of the disease and as root causes able to perpetuate the symptomatology through a chronic low-grade active infection (15)↑.

A possible role for anti-cardiolipin antibodies in cognitive abnormalities

 Anti-CA have been shown to cross-react with the brain phospholipids cephalin and sphingomyelin (16). As a population of autoantibodies directed against central nervous system tissue, they may thus be theoretically linked to the cognitive dysfunctions described in ME/CFS and Lyme disease.

 A possible mechanism for the genesis of anti-cardiolipin antibodies

 Auto-antibodies against human antigens can be induced by infectious agents through the mechanism of molecular mimicry, and other mistakes of the host immune system. When the antigen targeted by an autoantibody has a cytoplasmic collocation (which is the case of cardiolipin), usually phenomena of cellular damage (such as apoptosis, intracellular infections, autoimmune disease etc.) are believed to be necessary (but not sufficient) to the rise of the pathologic immune response (17)↑, (18)↑. Thus, the presence of anti-CA in ME/CFS and in Lyme disease may reflect both a post-infectious immunological phenomenon or an ongoing damage to host tissues or an ongoing infection, or a combination of those processes.

Nevertheless, we can also propose a completely different mechanism for anti-cardiolipin Ab induction, which doesn’t rely on previously described mechanisms. It has been recently described in vitro the ability of human mast cells to release (without degranulation) components of their own mitochondria when stimulated with the pro-inflammatory substance P, or with IgE and their relative antigens (19)↑. Although this appears to be a physiological response of mast cells to infections and other triggers, we have to consider that in ME/CFS proofs of an abnormal activity of mast cells have been recently presented: mast cells appear to be more numerous in blood and more prone to antigen presentation in ME/CFS patients than they are in healthy people (20)↑. Moreover, there is a recently defined disorder due to abnormal activity of mast cells, whose name is mast cell activation syndrome (MCAS), which has been linked to fatigue, brain fog, and orthostatic intolerance (21) ↑ and thus may have some relationship with ME/CFS (22)↑.

Thus, a possible explanation for the presence of anti-cardiolipin in ME/CFS is the abnormal exposure of the immune system to mast cells mitochondria, with consequent induction of a specialized immune response against this phospholipid. This mechanism could also be present in neuroborreliosis where anti-CA have been reported too, as we know that mast cells are activated in vitro by the spirochete Borrelia burgdorferi sl (23)↑.

Conclusions

The presence of anti-cardiolipin antibodies is very high in ME/CFS and -to a less extent- in neuroborreliosis. It may explain at least some aspects of the cognitive impairment described in these debilitating diseases, given that anti-cardiolipin Abs are reported to react against some neuronal antigens, and are associated with cognitive decline. The abnormal synthesis of anti-CA Ab may be due to molecular mimicry which follows the infectious trigger, to ongoing infections, to cellular damage or to abnormal mast cells activation, or to a combination of these mechanisms.

For a possible link between mast cells and post-exertional malaise, please see this post.

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