Anti-neuronal autoimmunity in Lyme disease

Introduction

Neurological sequelae of chronic Lyme disease include encephalopathy, myelopathy and peripheral neuropathy. These have generally been attributed to either persistent infection or pathogen-induced autoimmunity (IOM, Institute of Medicine, 2011)↑.

Anti-HSP60 antibodies

In 1988, Sigal et al. found that sera from patients with neurological manifestations of Lyme disease had IgM antibodies that bound to normal human axons, whereas binding was absent or weak in patients without neurologic findings (Sigal, et al., 1988)↑. In 1993, Dai et al. proved that a monoclonal antibody (H9724) specific for the 41-kDa flagellar protein of Borrelia burgdorferi, cross-reacted with human axons. The cross-reacting protein was identified as chaperonin-HSP60 (Dai, et al., 1993)↑. It was also proven in the same year, that human sera from Lyme patients which bound to human axons, also bound to HSP60 (Sigal, 1993)↑. In 2001, evidence was provided that addition of H9724 to neuroblastoma cell cultures blocks in vitro spontaneous and peptide growth-factor-stimulated neuritogenesis. It was reported that H9724 bound to an intracellular target in cultured cells with negligible, if any, surface binding (Sigal, et al., 2001)↑.

Neuroborreliosis		Garia-Monco et al, October 1995 (Garcia-Monco, et al., 1995)↑
Method	Antigen	Standard. Primary and secondary Ab	Secondary antibody, substrate	Results
ELISA indirect	Gangliosides (CM, asialo-GM1, GM1)	Rabit antisera to asialo-GM1 and GM1, Horseradish peroxidase-conjugated anti-rabit Ig (polyvalent)	Horseradish peroxidase-conjugated anti-rat IgM	Rats immunized with borrelia non-protein antigens showed sera reactivity against gangliosides, and rats immunized with gangliosides showed reactivity against borrelia antigens. Borrelia antigens elicited mainly an IgM response.
			Horseradish peroxidase-conjugated anti-rat IgG

Anti-ganglioside antibodies

In European studies, a marked IgM reactivity to ganglioside GM1 in the cerebrospinal fluid of neuroborreliosis patients has been reported  (Weller, et al., 1992)↑. In a 1993 study, 29% of patients with neuroborreliosis and 59% of patients with syphilis had IgM reactivity to gangliosides with a Gal (beta 1-3) GalNac terminal sequence (GM1, GD1b, and asialo-GM1). Given the clinical associations of patients with neuroborreliosis and syphilis with IgM reactivity to gangliosides sharing the Gal (beta 1-3) GalNac terminus, the authors suggested that these antibodies could represent a response to injury in neurological disease or a cross reactive event caused by spirochetes (García-Moncó, et al., 1993)↑. In 1995, the molecular mimicry hypothesis was investigated by the same research group. They found that immunization of mice with nonprotein Borrelia burgdorferi antigens induced high levels of IgM antibodies to asialo-GM1 and GM1. Moreover, immunization with asialo-GM1 cross-reacted with antigenic determinants present in B. burgdorferi. These experimental results are consistent with the hypothesis of a microbial origin for some of these potentially autoreactive antibodies. This situation is analogous to the induction of antibodies to GM1 after infection with Campylobacter jejuni, where the origin of cross-reactivity has been attributed to the LPS of this bacterium, which carries sugar sequences similar or identical to those in ganglioside GM1. The predominance of IgM antibodies in rats immunized with nonprotein Borrelia burgdorferi antigens in the recognition of asialo-GM1 and GM1 suggests a T-cell-indipendent mechanism for development of these antibodies. This would be consistent with the T-cell-indipendent genesis of antibodies to LPS and to carbohydrates in general (Garcia-Monco, et al., 1995)↑. In Table 1 I have reported some experimental settings for this study.

Anti-cardiolipine antibodies

Anti-cardiolipin antibodies may occur in patients with Lyme disease, particularly in those with neurologic abnormalities. The IgM serotype was found in 7/28 serum samples while the IgG serotype was found to be positive in 4/28 serum samples. Higher IgM anti-CA positivity tended to be associated with neurologic diseases (Mackworth-Young, et al., 1988)↑. In another study, anti-CA antibodies of the IgG serotype were found in 50% of patients with neuroborreliosis (García-Moncó, et al., 1993)↑. On anti-cardiolipin antibodies please see also this post.

Anti-neuronal antibodies

In 2005, antibodies against two of the OspA peptides were found to react with neurons in human brain, spinal cord and dorsal root ganglia (DRG) by immunohistochemistry (Alaedini, et al., 2005)↑. In 2010 anti-neural antibodies reactivity was seen in serum specimens from 41 of 83 (49,4%) Lyme patients with chronic complaints, both seropositive and seronegative. Serum antibodies from those patients were found to be positive for anti-neuronal antibody reactivity by immunoblotting stained cortical pyramidal neurons, as well as neurons of DRG. Antibody binding to some glial cells of the brain and DRG was also observed (Chandra, et al., 2010)↑. The same test was performed on 51 ME/CFS patients and no significant difference in the prevalence of anti-neuronal antibody reactivity was found, in comparison with healthy controls (Ajamian, et al., 2015)↑. In a 2013 study, it was observed that nearly half of the patients enrolled, who had a history of Lyme disease and persistent cognitive symptoms, showed increased serum antibody reactivity to neuronal antigens (Jacek, et al., 2013)↑.

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