Guillain–Barré syndrome (GBS) is an acute immune-mediated disorder of the peripheral nervous system characterized by rapidly progressive weakness and areflexia. Increasing evidence indicates that a variety of bacterial and viral infections, including cytomegalovirus, Zika virus, Epstein–Barr virus, Mycoplasma pneumoniae, and SARS-CoV-2 (COVID-19), are implicated in the pathogenesis of GBS (1–3). These infections are thought to trigger aberrant immune responses through mechanisms such as molecular mimicry, in which antibodies produced against pathogen antigens cross-react with components of peripheral nerves, leading to inflammation, demyelination, and axonal injury.

In the experimental autoimmune neuritis (EAN) rat model of GBS, circulating lymphocytes and macrophages have been observed to infiltrate and adhere to the endoneurial interstitium of the sciatic nerve (4). Exogenous administration of non-specifically activated T cells induces perivascular infiltration within the endoneurium of peripheral nerves, which, in combination with anti-myelin antibodies, leads to dose-dependent demyelination and axonal degeneration (5).

Recent studies have shown that patients with GBS harbor self-reactive memory CD4⁺ T cells with a Th1-like phenotype, as well as CD8⁺ T cells that recognize peripheral nerve myelin antigens. Moreover, myelin-reactive T cells have been identified within the peripheral nerves of one patient, further supporting the notion that T cells play a pivotal role in mediating peripheral nerve pathology in GBS (6).

In this study, clinical data and laboratory findings from patients with GBS were collected to investigate the associations between peripheral blood lymphocyte subsets—particularly CD4⁺ T cells and CD8⁺ T cells—and disease onset, severity, and the requirement for mechanical ventilation.

GBS generally follows a self-limiting clinical course; however, a subset of patients may develop severe complications, including respiratory failure requiring mechanical ventilation. Intravenous immunoglobulin (IVIG) and plasma exchange remain the primary therapeutic approaches for GBS. However, despite these treatments, approximately one-third of patients still require mechanical ventilation, 5% ultimately die, and about 20% experience poor long-term outcomes (10, 11). Súkeníková L and colleagues reported that patients with AIDP exhibited CD4⁺ T cells in their peripheral blood that responded to P2, P0, or PMP22 antigens (6). This study demonstrated that elevated CD8⁺ T cell counts and decreased NK cell counts in peripheral blood lymphocyte subsets were associated with an increased risk of GBS. Our results suggest that combining CD8⁺ T cell counts and CD4⁺ T cell counts with EGRIS scores shows enhanced discriminative ability in identifying GBS patients who required mechanical ventilation. This combined approach may help improve risk stratification in clinical practice; however, given the retrospective design of this study, further validation in prospective cohort studies is needed. Moreover, decreased peripheral blood CD4⁺ T cell counts were identified as an independent risk factor for mechanical ventilation, with lower CD4⁺ T cell levels corresponding to higher risk. In the EAN rat model, CD4⁺ T cell expression in the sciatic nerve reached peak levels. These results suggest that CD4⁺ T cells may migrate from the bloodstream into peripheral nerves, contributing to neuroinflammation and demyelination.

Previous studies have shown that patients with GBS exhibit a lower proportion of CD4⁺ T cells and a higher proportion of CD8⁺ T cells in peripheral blood compared with healthy individuals (12). In this study, the absolute counts of peripheral blood CD4⁺ and CD8⁺ T cells and the proportion of CD4⁺ cells were lower in GBS patients than in healthy controls, whereas the proportion of CD8⁺ T cells was comparable between the two groups. Notably, an increased absolute count of CD8⁺ T cells was independently associated with GBS. Yang M et al. reported that synergistic interactions between effector/memory CD8⁺ T cells and costimulatory macrophages are critical for initiating autoimmune-mediated peripheral neuropathy (13). Moreover, depletion of CD4⁺ T cells accelerate the onset of GBS and increases its likelihood, while CD8⁺ T cells may exert pathogenic effects during the development and progression of the disease (14).

Our study shows that both the absolute number and proportion of NK cells in the peripheral blood of patients with GBS are significantly reduced. Consistent with previous reports, NK cell activity decreases in peripheral blood after GBS onset, whereas it is markedly increased in the cerebrospinal fluid, suggesting a redistribution of NK cells to sites of inflammation. Moreover, the reported association between NK cell counts and the therapeutic efficacy of intravenous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) further underscores the clinical relevance of NK cells in immune-mediated neuropathies (15–17). Together, these findings suggest that reduced NK cell levels may reflect impaired immune regulation, thereby increasing susceptibility to immune-mediated neurological injury.

In this study, lower NK cell counts were associated with a higher likelihood of developing GBS. In parallel, transcriptomic and bioinformatics analyses based on an in vitro myelination model using mouse dorsal root ganglion cultures revealed that NK cell–mediated cytotoxicity and B cell receptor signaling pathways may participate in peripheral myelination through molecules such as FCGR, RAC2, and PLCG2 (18). These observations indicate that NK cells may not only influence disease susceptibility but also contribute to the regulation of peripheral nerve myelin homeostasis.

A growing body of evidence indicates that NK cells play a crucial role in neuroimmune regulation and represent important potential therapeutic targets in neuroimmunology diseases (19). Reduced peripheral NK cell numbers or impaired cytotoxic function have been widely reported in several autoimmune disorders, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, and type 1 diabetes mellitus. Meanwhile, the accumulation of NK cells in affected tissues—such as the pancreas in type 1 diabetes, hair follicles in alopecia areata, and muscle tissue in juvenile dermatomyositis—suggests that a decrease in circulating NK cells may reflect tissue recruitment rather than absolute depletion (20).

It should be noted, however, that although decreased peripheral NK cell levels were associated with increased susceptibility to GBS in our cohort, evidence from other inflammatory contexts indicates that NK cells may also exert pathogenic effects. For example, in patients with multiple sclerosis, viral infection can induce excessive NK cell activation, partly mediated by the activating receptor NKG2C, thereby promoting immune-mediated myelin injury (21). Taken together, these findings support the concept that NK cells play dual and context-dependent roles in immune-mediated neurological diseases: under physiological conditions, they may exert protective effects through immune regulation, whereas excessive or dysregulated activation in specific inflammatory environments may exacerbate tissue damage.

This study found that, compared with healthy controls, patients with GBS had a reduced absolute count of peripheral blood B cells but an increased relative proportion. Previous studies have similarly reported a marked elevation in peripheral blood B cell proportions during the acute phase of GBS, which correlates positively with Hughes scores. As the disease progresses, the proportion of B cells gradually declines, particularly during the early and late recovery phases (22). Brunn et al. found that B cells play a dual role in both the early and recovery phases of EAN, functioning as immunomodulators as well as pro-inflammatory mediators (23).

This study found that lymphocyte counts, NLR, and PLR in routine blood tests were associated with the need for mechanical ventilation in patients with GBS. Some studies have reported that routine blood NLR and PLR may serve as independent risk factors for severe GBS and the requirement for mechanical ventilation, and that their combination can provide effective predictive biomarkers (24, 25). Studies from multiple countries indicate that the modified Erasmus GBS respiratory failure score may serve as a practical clinical tool for predicting the risk of mechanical ventilation in patients with GBS (8, 26). This analysis included sex, age, CD8⁺ T cell count, CD4⁺ T cell count, and the EGRIS score. The results showed that older age, a higher EGRIS score, and a lower CD4⁺ T cell count were independently associated with the need for mechanical ventilation in patients with GBS. The Hughes and MRC scores were not included in the model because they were highly correlated with the EGRIS score.

Previous studies have shown that T cell-mediated immune responses against myelin proteins (especially P2 and P0) drive peripheral nerve injury (27, 28). In an EAN rat model, circulating T cells cross vascular endothelial cells and the basement membrane 10–15 days after immunization and adhere to the inner wall of small veins, leading to sciatic nerve demyelination (29). This study found that CD4⁺ T cell infiltration was increased in the sciatic nerve of EAN rats in the early, peak, and late stages of the disease, with the most significant increase in the peak stage. The reduction of peripheral blood CD4⁺ T cells in GBS patients may be related to the migration of CD4⁺ T cells from the blood circulation to the peripheral nerves (30). This study observed decreased peripheral blood CD4⁺ T cell counts in patients with GBS, along with increased CD4⁺ T cell infiltration in the sciatic nerves of EAN rats, which may indicate a potential role for CD4⁺ T cells in disease progression. However, direct comparisons between human and animal data should be interpreted with caution due to species differences and variations in sampling time points. Future studies are warranted to investigate changes in peripheral blood CD4⁺ T cells in EAN rats and their relationship with CD4⁺ T cell infiltration in the sciatic nerves, which could help clarify the potential link between systemic and local immune responses in GBS.

In conclusion, our study highlights the clinical relevance of peripheral blood lymphocyte subsets in GBS demonstrating their associations with disease severity and the need for mechanical ventilation. These findings underscore the potential value of immune profiling in risk stratification and clinical decision-making in patients with GBS.

Nonetheless, several limitations should be considered. The relatively small sample size limits the robustness of multivariable analyses, and validation in larger, independent cohorts is warranted. In addition, although immunofluorescence in the EAN rat model confirmed the presence of CD4⁺ T cells in peripheral nerves, this approach provided limited quantitative insight into immune cell infiltration. Moreover, direct evidence of CD4⁺ T cell involvement in human peripheral nerves remains lacking, and the target antigens in GBS have yet to be clearly defined. Therefore, the immune responses observed in this experimental model cannot be directly extrapolated to human disease.

Taken together, future studies integrating larger clinical cohorts with quantitative immune profiling in both experimental models and human tissues—including cerebrospinal fluid and, when feasible, peripheral nerve samples—will be essential to clarify the pathogenic role of specific lymphocyte subsets and to strengthen the translational relevance of these findings.