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Abstract.
Vaccination is one of the most successful public health programs in the history of medicine. As result of global immunization campaigns, several dreaded diseases have been eradicated. Nevertheless, modern excessive vaccination with persistent immune system hyperstimulation can theoretically lead to the development of autoimmune illnesses in predisposed individuals. Unfortunately, vaccine safety has become a medical dogma; vaccine adverse event reports are often shunned as anti-vax propaganda.

Independent clinicians from different parts of the world have described the onset of a chronic debilitating illness soon after HPV vaccination. This illness is characterized by headache, fatigue, widespread pain, dizziness nausea and abnormal limb movements, among other vexing symptoms. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome, postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, or fibromyalgia. Profound dysautonomia and small fiber neuropathy have been reported in these cases.

This purported Post-HPV vaccination syndrome resemble other contested vaccine-related illnesses such as Macrophagic Myofasciitis and Gulf War Illness. We propose that vaccine-triggered, immune-mediated autonomic dysfunction and small fiber neuropathy could lead to the development of these post- vaccination syndromes in genetically susceptible individuals. Dorsal root ganglia may play a key role in the pathogenesis of these syndromes. These para-vertebral ganglia house the pain-transmitting small nerve fiber nuclei, each individual nucleus is enveloped by immune-competent glial cells. Lymphocytes, macrophages, and different pro-nociceptive mediators populate DRG. Communicating nerves tightly link DRG with the para-vertebral sympathetic chain. Dorsal root ganglia are able to actively trapped antigen specific antibodies including vaccines. We proposed that in susceptible individuals vaccines may be trapped at the dorsal root ganglia inducing inflammation, dysautonomia and small fiber neuropathy.

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Dorsal root ganglia; fibromyalgia Pandora´s box?

Manuel Martínez-Lavín MD

Chief, Rheumatology Department. National Institute of Cardiology. Mexico

Fibromyalgia (FM) is a stress-related disorder. Psychological distress, physical trauma, infections and/or autoimmune stressors are frequent FM drivers. The autonomic nervous system is the main stress-response force. Autonomic dysfunction (dysautonomia) is prevalent in FM patients. Heart rate variability analyses in FM individuals show changes consistent with ongoing sympathetic hyperactivity associated to hypo-reactivity to stress. FM pain has clear neuropathic features, it is a stimulus-independent pain accompanied by allodynia and paresthesia. Skin biopsy and corneal confocal microscopy have shown small nerve fiber pathology in FM patients. Therefore, the key issue in FM research is to define how, and where in the body, diverse stressors are transformed in neuropathic pain.

Humans have 31 pairs of dorsal root ganglia (DRG) lying along the spine. DRG possess unique pro-nociceptive physio-anatomy, these paravertebral ganglia have pain generating pseudo-unipolar structure. DRG lie outside the blood-brain barrier, so different infective agents, immune complexes and/or pro-nociceptive cytokines can gain direct DRG access. On the other hand, DRG are surrounded by meningeal layers and by cerebrospinal fluid, so they may serve as port of entrance to the central nervous system. DRG can sequester antigen-specific antibodies. These paravertebral ganglia house the pain-transmitting small nerve fiber nuclei, each individual nucleus is enveloped by immune-competent glial cells. Lymphocytes, macrophages, and different pro-nociceptive mediators populate DRG. Communicating nerves tightly link DRG with the paravertebral sympathetic chain. Specific DRG sodium channels (Nav1.7-9) modulate neuropathic pain transmission.

In the rodent model, different physical, chemical, and environmental (“psychological”) stressors induce DRG inflammation and neuropathic pain. There is a clear female oriented sexual dimorphism in DRG nociceptive pathophysiology.

New clinical evidence supports DRG as the main FM pain factory. Most FM individuals have objective evidence of small nerve fiber pathology. Small nerve fiber neuropathy is a denervating disease. Intra-DRG nuclei degeneration may explain the characteristic distal small nerve axonal atrophy. We described the association of DRG Nav1.7 rs6754031 GG genotype with severe FM, we also found that FM women without severe anxiety/depression display strong correlation between corneal denervation with small nerve fiber neuropathy symptoms. Immunoglobulin G from FM patients induces hyperalgesia in mice. In such instances, immunohistochemical and Western blot analyses detected FM patients IgG in mice DRG, but not in brain or spinal cord tissue.

In conclusion:

Unfolding evidence proposes DRG as the key FM neural hub where different stressors, including psychological distress, are converted into neuropathic pain. This novel proposal can be tested using advanced DRG neuroimaging or in-vitro DRG culture assays. DRG nociceptive mediators are attractive target for the development of more specific FM analgesic medications. Stress response system malfunction (dysautonomia) explains FM multisymptomatic features.

References:

Martinez-Lavin. Clin Rheumatol 2021;40:788

Ramirez et al. J Clin Rheumatol 2021; doi: 10.1097/RHU.0000000000001592

Goebel et al. J Clin Invest. 2021;131:e144201. doi: 10.1172/JCI144201.