FM and anti-SGC IgG 2023

Stimulated by Krock et al 2023.[1]

FM – fibromyalgia
SCG – satellite glial cell
IgG – immunoglobulin G
DRG – dorsal root ganglion / ganglia
HC – healthy controls
OAK – osteoarthritis of the knee
FIQ – fibromyalgia impact questionnaire
PPT – pressure pain threshold
CPM – conditioned pain modulation
HLA – human leucocyte antigen
HLA-B27 – a specific HLA associated with the development of ankylosing spondylitis
SLE – systemic lupus erythematosis

key to acronyms

This topic first came up in July 2021, when teams from Liverpool and Stockholm presented translational data supporting the possibility that FM can be caused by autoimmunity targeting SGCs in the DRG. See the previous blog discussion: Transfer of FMS with IgG.

I have been waiting for more news on this subject, and now we have a paper in the journal Pain from the same Stockholm team combined with a team from Montreal. They report on how levels of anti-SGC IgG are associated with FM symptoms in two cohorts – one from Sweden and one from Canada. There were around 30 FM patients and a similar number of healthy controls (HC) in each of the cohorts, plus a cohort of 10 patients each with OAK and HC from Sweden. So, in total, around 149 humans, several mice for creating SGC and DRG cell cultures, and 6 human dorsal root ganglia donors, were involved in the set of studies making up this paper.

Serum was taken from all the live human subjects, and they completed the FIQ if relevant, and had PPTs and CPM measured. The cell cultures and slices of human DRG were used to examine the degree of IgG binding from serum samples of patients with FM, patients with OAK, and healthy controls (HC).

There was significantly more binding of IgG to SGCs with serum from FM patients than that from HCs, but the total quantity of IgG was the same on average.

OAK serum did not contain elevated levels of SGC-reactive IgG. There was significantly more binding of IgG to SGCs with the serum from both FM cohorts when compared to that of the OAK cohort.

Neither patient group had elevated levels of IgG that bound to sensory neurons in DRG neuron-enriched cell cultures.

FM IgG binding to SGCs positively correlated with pain intensity and was associated with disease severity. The Swedish cohort of FM patients was divided into a severe and a mild group to determine this association with disease severity.

Finally, IgG binding was examined using human DRG slices from 6 different donors. The severe FM group serum demonstrated significantly higher levels of binding to human SCGs, but not to the soma or axons of human neurons or other DRG tissues.

So why would FM patients have autoantibodies attaching to SGCs? As chance would have it a relevant review that caught my eye was published in BMJ Medicine this week.[2] Its title drew me in to see whether or not FM got a mention: Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies.

FM did get a mention and it wasn’t in the section on controversies; however, whilst a variety of viral and other infections have been loosely implicated no clear culprit or culprits have been identified.

The paper included a figure that summarised five possible mechanisms of chronic pain after infection:

• Central sensitisation
• Antimicrobial toxicity
• Molecular mimicry (ie cross-reactivity in the host immune response)
• Epitope spreading
• Bystander activation

Well, the last three seemed the most relevant, and of those, the last two were not so familiar to me, so I felt the need to investigate. An epitope is the part of an antigen that is recognised by the immune system, and while we are on the subject of -topes, a paratope is the part of an antibody that binds to an epitope.

Epitope spreading occurs in both B and T cells, and apparently contributes to autoimmune diseases.[3] I was already familiar with the concept of certain immune cells chewing up foreign material and then presenting fragments (now I can call them epitopes) on their cell surface for other immune cells to inspect. This process can clearly cause some degree of variation in chewing, or cutting up, the original antigen into small fragments and hence variation in epitope formation.

What I had not come across was something called somatic hypermutation, which is a process occurring in B cells when they are producing antibodies to a particular epitope or antigen. This is a deliberate process of mutation in the gene encoding the variable portion of the antibody. Roughly every thousand base pairs there is a single nucleotide substitution (ie A–T is swapped for G–C or vice versa), and thus a subtle alteration in the shape of the final paratope (antigen binding site). In this way, a whole series of similar antibodies are produced with a varying degree of affinity for the original antigen. The ones with the highest affinity subsequently get produced in bulk.

Whilst deliberate subtle variation in antibody shape confers an advantage in mounting effective immune responses to foreign invaders, it also increases the risk of cross-reactivity to self, and hence autoimmunity.

Bystander activation is the process by which auto-reactive B and T cells undergo activation without exposure to a specific antigen, but as a result of being in the neighbourhood of an inflammatory milieu. This process has also been implicated in some autoimmune diseases.[4]

So, before long we may find the culprit organism that triggers some cross-reactivity to SCGs, and hence, the underlying cause of the more severe forms of FM. Alternatively, there may be an underlying genetic predisposition hidden within the system for self-identification (the major histocompatibility complex) such as in ankylosing spondylitis (ie HLA-B27). More likely, as in the case of SLE, there will be both and exogenous trigger and an endogenous predisposition.

References

1          Krock E, Morado-Urbina CE, Menezes J, et al. Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms. Pain Published Online First: 22 March 2023. doi:10.1097/j.pain.0000000000002881

2          Cohen SP, Wang EJ, Doshi TL, et al. Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies. BMJ Med 2022;1:e000108. doi:10.1136/bmjmed-2021-000108

3          Cornaby C, Gibbons L, Mayhew V, et al. B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol Lett 2015;163:56–68. doi:10.1016/j.imlet.2014.11.001

4          Pacheco Y, Acosta-Ampudia Y, Monsalve DM, et al. Bystander activation and autoimmunity. J Autoimmun 2019;103:102301. doi:10.1016/j.jaut.2019.06.012

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Declaration of interests MC