Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy

Abstract

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.

Bridging the Divide: An Integrated Neurobio-Psycho-Social Approach to Treating Antibody Negative Inflammatory Encephalitis in a School-Aged Child

“…36 Compared to healthy controls, individuals with AE have a lower proportion of naive T-regulatory cells, lower proportion of circulating effector memory Tregulatory cells expressing CCR6, and higher circulating effector memory T-regulatory cells. 36,37 Similarly, expansion of CD14+ and CD16+ monocytes, both of which are active in macrophage-mediated cellular processes, have also been reported in persons with AE. 38 Aberrations in peripheral immune function can also be present in individuals with systemic autoimmune disease and must be interpreted with caution.…”

Disorders related to antineuronal antibodies: Autoimmune epilepsy

“…70 Recently, circulating plasmablasts and follicular helper T-cells have been reported to be increased in autoantibody-positive autoimmune epilepsy, including patients with NMDAR-, LGI1-, and MOG-antibodies. 71…”

“…Particularly in NMOSD, an autoantibody against astrocytes involved in the disease pathogenesis, plasmablasts are elevated in peripheral blood mononuclear cells and produce pathogenic autoantibodies 70 . Recently, circulating plasmablasts and follicular helper T‐cells have been reported to be increased in autoantibody‐positive autoimmune epilepsy, including patients with NMDAR‐, LGI1‐, and MOG‐antibodies 71 . Increasing evidence showing the dynamics of plasmablasts in relation to disease activity in autoantibody‐associated autoimmune diseases, including autoimmune epilepsy, highlights the potential of this B‐cell subset as a representative immune phenotype termed “autoimmune plasmablastosis.” 71 In addition, these patients have an abnormal immune background of B‐cell differentiation.…”

“…Recently, circulating plasmablasts and follicular helper T‐cells have been reported to be increased in autoantibody‐positive autoimmune epilepsy, including patients with NMDAR‐, LGI1‐, and MOG‐antibodies 71 . Increasing evidence showing the dynamics of plasmablasts in relation to disease activity in autoantibody‐associated autoimmune diseases, including autoimmune epilepsy, highlights the potential of this B‐cell subset as a representative immune phenotype termed “autoimmune plasmablastosis.” 71 In addition, these patients have an abnormal immune background of B‐cell differentiation. Inducible T‐cell costimulator (ICOS) and its ligand are required for active regulation of B‐cell responses by interacting with ICOS on T follicular helper (Tfh) cells and ICOS ligands on B‐cells and are involved in IgG production.…”

“…Inducible T‐cell costimulator (ICOS) and its ligand are required for active regulation of B‐cell responses by interacting with ICOS on T follicular helper (Tfh) cells and ICOS ligands on B‐cells and are involved in IgG production. ICOS‐expressing circulating Tfh cells were increased in autoantibody‐positive autoimmune epilepsy, suggesting that the dynamics of enhanced B‐cell differentiation are involved in autoimmune epilepsy similar to other autoantibody associated diseases such as myasthenia gravis and idiopathic thrombocytopenic purpura 71–73 …”