Anjali James

Introduction. Guillain-Barré syndrome (GBS) is an immune-mediated condition characterized by an acute onset of ascending flaccid paralysis.^1,2 ​Campylobacter jejuni is the most identified infectious agent of GBS. C. jejuni elicits GBS through a mechanism known as molecular mimicry, in which the host’s immune system makes antibodies against bacterial surface sugars that also mimic gangliosides on the host’s neuronal axons and the autoantibodies attack the host’s nervous system, leading to GBS.³ This mechanism initiates a T-helper-17 immune response which elevates pro-inflammatory cytokines and is the target of interest in the treatment of GBS.^4.5 Methods. Cytokine markers in plasma of IL-10 knockout, GBS induced mice with a known C.jejuni strain were examined to see if a Th-17 mediated immune response would occur.^5,6 Currently, in clinical practice, GBS patients undergo Lymphoplasma Exchange (LPE) in which pathological materials in the plasma are removed in exchange for healthy, balanced plasma.⁷ Experimental autoimmune neuritis (EAN), a classical model that mirrors GBS in mice, was used to look at the effect of a RORγt inhibitor drug on IL-17 and transcription factor expression changes.⁸ PR-957, a known STAT3 transcription factor inhibitor was tested on mice with EAN.⁹ Decitabine, an FDA-approved immunosuppressive chemotherapeutic drug was used as a prophylactic and immunomodulatory treatment in GBS-induced mice.¹⁰ Results. Three cytokines found in the Th-17 pathway, IL-6, IL-17A, and IL-22, were found to be significantly elevated in CSF of GBS patients. IL-6 plays a critical role in the lineage commitment of TH17 cells by inducing transcription factors RORC and STAT3.^5,6 A decrease in Th-17 cytokines and an increase in T-regulatory cells with LPE correlated with improvement in neurological deficit scores. Treg cells inhibit RORγt function, the transcription factor associated with Th17, which in turn reduces the differentiation of Th17 cells and suppresses GBS-associated inflammation.⁷ The RORγt inhibitor drug delayed the onset of EAN and significantly decreases the neurological severity in the mice.⁸ PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and inflammatory infiltration down-regulation of STAT3 at the protein level, and also a reduction in RORγt and IL-17 production at the transcriptional level.⁹ Decitabine alleviated GBS symptoms by increasing T-reg cell numbers and reducing Th-17 pathway cytokines.¹⁰ Conclusion. C. jejuni is the hallmark infectious agent that results in GBS through the mechanism of molecular mimicry which elicits a Th-17 mediated immune response and an increase in the associated pro-inflammatory cytokines. The targets for GBS treatment include transcription factors in the Th-17 pathway, STAT3, and RORγt, along with pro-inflammatory cytokines IL-6 and IL-17. Currently, LPE works by removing pro-inflammatory cytokines and adding T-reg cells to suppress induction of the pathway. Pr-957 and Decitabine are two promising therapeutic agents that alleviate GBS through the immunomodulation of the Th-17 pathway components in post-infectious GBS.

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