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|NI FEATURE: THE EDITORIAL DEBATE III-- PROS AND CONS
|Year : 2017 | Volume
| Issue : 5 | Page : 973-974
Enigmas in immunobiology of Guillain-Barré syndrome: Ganglioside antibodies and beyond!
Madhu Nagappa1, Monojit Debnath2, Arun B Taly1
1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India
2 Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India
|Date of Web Publication||6-Sep-2017|
Arun B Taly
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Nagappa M, Debnath M, Taly AB. Enigmas in immunobiology of Guillain-Barré syndrome: Ganglioside antibodies and beyond!. Neurol India 2017;65:973-4
Guillain-Barré syndrome (GBS), a prototype autoimmune disorder of peripheral nerves, has heterogeneous risk determinants, course, severity and outcome, electrophysiology, pathology and immune trajectories. The key antigenic targets are gangliosides; the frequency and types of ganglioside antibodies reported in literature are governed to some extent by electrophysiological sub-types and clinical variants included in the cohorts. An antibody, whose expression depends on the type of antecedent infection, binds to specific gangliosides in the peripheral nerves and influences the development of neurological signs. This is true with respect to certain subtypes, for example, GT1a antibody in pharyngo-cervico-brachial, and GQ1b antibody in Miller-Fisher variants. Correlation with other variants is not consistent.
In this issue, Naik and colleagues present their data on IgG antibodies to GM1, GM2, GM3, GD1a, GD1b, GT1b and GQ1b in 73 patients with GBS. Though a retrospective study, it is an important one because of the number of anti-ganglioside antibodies detected and the large cohort size. Forty-one (56.2%) patients showed ganglioside antibodies with 23 being positive for multiple antibodies. Ganglioside antibodies were significantly positive in the axonal subtype. It may be noted that majority of subjects with ganglioside antibodies had acute inflammatory demyelinating polyradiculoneuropathy (AIDP) [n = 21, 51.2%], while acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) were seen in 11 (26.8%) and 5 (9.8%) patients respectively. Whether subtyping was based on electrophysiological observations at admission or at two weeks is not explicit. This has to be given due cognizance as electrophysiology varies with the day of illness besides being operator dependant. In an earlier report, 30% of patients with ganglioside antibodies who initially showed AIDP were eventually reclassified as AMAN on sequential studies.
The commonest antibody reported by Naik and colleagues is GT1b, in contrast to other studies that showed GM1 and GD1a antibodies to be the most frequent. In an earlier study, the same group reported that IgM GM2 antibody was the commonest in pediatric GBS, while GM3 and GD1b antibodies predominated in the AMAN subtype. Interestingly, this study also reported GT1b antibodies in 50% of children with AIDP and 22.7% of the AMAN subtype. It may be hypothesised that regional differences in prevalence and etiologies of antecedent infections determine the patterns of antibodies. But, Nair and colleagues show lack of correlation between ganglioside antibodies and antecedent infections, dysautonomia, and mechanical ventilation. This is an interesting observation given the fact that ganglioside antibodies arise from ‘molecular mimicry’ between epitopes shared by microbes and gangliosides. Presence of ganglioside antibodies has previously been reported to be associated with worse prognosis, albeit inconsistently.
Methodological differences preclude comparison of ganglioside antibodies across various studies. Antigen preparation, metrics and spectrum of gangliosides used vary greatly. The amount of gangliosides used for assaying antibodies range from 7.5ng to 500ng.,, Some studies tested only IgG and others analysed both IgG and IgM antibodies.,, While most studies used the enzyme linked immunosorbent assay (ELISA) technique,, the immunodot assay has been used uncommonly. Recent studies used the combinatorial glycoarray, which permits screening of large number of samples for multiple gangliosides and their complexes simultaneously. Studies also differ in cut-off values of optical density (0.1 to 0.5) used to define positivity by ELISA.,, Some authors analysed antibodies by developing in-house ELISA assays, while others used commercially available kits. When carefully examined, in-house assays outperform commercially available kits; this calls for global consensus on standards and techniques, in addition to a systematic scrutiny of in-house assays and commercial kits.,
Do ganglioside antibodies really matter?
It is widely acknowledged that ganglioside antibodies play an important role in the pathogenesis of GBS, especially the axonal forms. Nerve injury in GBS begins with the binding of antibodies against gangliosides at specific loci in peripheral nerves. Infections are common triggers for GBS. Only a fraction of subjects with infection develop GBS. Microbial and host factors that determine whether the infection is self-limiting or leads to GBS remain to be unravelled. These are only some of the several enigmas in GBS.
The impact of ganglioside antibodies ranges from reversible functional impairment, partial axonal injury to complete axonal transection. Some antibodies such as GD1a, may also impair axonal regeneration and therefore recovery. These factors are reflected as disease severity and outcome. Ganglioside antibodies are not unique to GBS as they are demonstrable in patients with other neurological and non-neurological disorders and in healthy subjects. Perhaps ganglioside antibodies vary in their ability to induce inflammatory reactions and therefore disease. Rabbits immunised with GM1 develop paralysis only in the presence of leucocyte granulation and complement activation, while those without evidence of inflammation do not develop paralysis. This is independent of GM1 antibody titres. GM1 antibodies cause a pure motor syndrome, while GD1b antibodies cause a pure sensory syndrome even though they are equally distributed on the peripheral nerves. Thus, it is difficult to draw a parallel of GBS with ganglioside antibodies.
Immunobiology beyond ganglioside antibodies
The significance of detecting antibody to a single purified ganglioside in experimental assays viz ELISA is debated. Gangliosides on neuronal membranes cluster with cholesterol and glycosyl-phosphatidyl-inositol anchored proteins to form ‘micro-domains’ or lipid rafts in vivo. This phenomenon can be demonstrated by testing for antibodies against ‘ganglioside complexes’ (GSC) formed by a combination of gangliosides. Here, a patient may harbour antibodies against the GSC formed by two gangliosides but not against the individual ganglioside forming the GSC. Microbial molecular mimicry may play a role in the generation of GSC antibodies similar to ganglioside antibodies. Antibodies against GSCs and other glycolipid complexes are emerging as markers of various clinical features and pathological subtypes of GBS.,,,, Interestingly, antibody activity against GSCs formed by mixtures of three or four gangliosides is often decreased. Hence, GSCs of two gangliosides are appropriate antigenic targets for further studies to understand the pathobiology of GBS.
In the present study, Naik and colleagues exclusively focussed on ganglioside antibodies. Prospective comprehensive studies to understand the complex role of infectious and non-infectious triggers as well as novel antigens in the pathobiology of GBS may help in initiating preventive measures and in developing targeted therapies.
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