A substantial number of Rasmussen syndrome patients have increased IgG, CD4⁺ T cells, TNFα, and Granzyme B in CSF

Abstract

Summary Purpose: We studied the immunologic molecules in cerebrospinal fluid (CSF) and discussed their evolutional changes in pediatric patients with Rasmussen syndrome (RS). Methods: CSF samples collected from 27 patients with RS (average onset age, 7.5 ± 5.6 years) were studied. Cell count, protein, glucose, albumin, chloride, and immunoglobulin G (IgG) levels were measured by conventional methods. Surface markers of lymphocytes in CSF were examined by a cell sorter. Granzyme B, interferon γ (IFNγ), interleukin 4 (IL‐4), tumor necrosis factor α (TNFα), and IL‐12 in CSF were quantitated by enzyme‐linked immunosorbent assay (ELISA). Autoantibodies against GluR ε2 (NR2B) were examined by immunoblot. Results: The data of the first CSF examination showed that IgG levels (Mann‐Whitney U test, p < 0.01), CD4+ T cells (p = 0.02), TNFα levels (p < 0.01), and Granzyme B levels (p < 0.01) were elevated compared with disease controls. White blood cell count, IFNγ level, IL‐12 level, and Granzyme B level were elevated, especially in the early stage of disease. CD4+ T cells, CD8+ cells, CD3+ T cells, IgG levels, and TNFα levels were elevated at all stages of disease evolution. Protein levels and albumin levels were elevated in the progressed stage. Autoantibodies against GluR ε2 (NR2B) (IgG) were found in 50% of patients in the early stage, and the positive rate was low at the progressed stage. Discussion: The present findings suggest that complex pathophysiologic mechanisms involving CD4+ T cells and CD8+ T cells change evolutionally during the progression of RS. A crucial cytotoxic process occurs in the early stage, and declines in the progressed stage.

Peripheral leukocyte profile in people with temporal lobe epilepsy reflects the associated proinflammatory state

“…Granzyme A produced by CD8 + and NK cells could be involved in cytokine production and apoptotic response in epilepsy. Interestingly, in Rasmussen encephalitis, granzyme B and TNF were increased in the CSF [19].…”

“…DAMPs generated in the brain after seizures would induce a cascade of events leading to local and systemic inflammation ( Figure 9). Indeed experimental studies have demonstrated that there is continuous recruitment of peripheral cells into the brain following seizures, with a parallel between the activation of immune cells in the CNS and in the periphery [3,[19][20][21][22].…”

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

“…In addition to plasma, GrB is also present in the synovial fluid (SF) of rheumatoid arthritis (RA) patients, the cerebrospinal fluid (CSF) of multiple sclerosis (MS) and Rasmussen encephalitis patients, as well as the bronchoalveolar lavage (BAL) in chronic obstructive pulmonary disease (COPD) and lung inflammation. [122][123][124][125] Although the GrB inhibitor PI-9 is present in normal human plasma, GrB retains 70% of its activity in the plasma, suggesting that PI-9 does not efficiently inhibit GrB activity in the blood. 126,127 There is a lack of evidence for an endogenous extracellular GrB inhibitor that is physiologically effective, thus its extracellular activity may be largely unregulated in contrast to other ECM proteases such as MMPs, which are tightly regulated by the tissue inhibitors of metalloproteases.…”

The Emerging Role of Gamma-Delta (γδ) T cells in Neurological Diseases and Rasmussen Encephalitis

“…This study advanced the authors to the idea of having pronounced Th1 immune response in the early phase of the disease that declines 1 to 2 years in the disease course. Since the higher levels of IFN-γ in cerebrospinal fluid in the earlier stages of RE was reported by Takahashi et al [14], detection of large numbers of CD4+ and CD8+ lymphocytes from the same specimen from which the high levels of IFN-γ were detected, are consistent with an initial Th1 response.…”