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TLR4, IL-6, IL-18, MyD88 and HMGB1 are highly expressed in intracranial inflammatory lesions and the IgG4/IgG ratio correlates with TLR4 and IL-6


Hirofumi Hirano, MD, PhD, Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City 890-8520, Japan. Email:


We determined distribution of plasma cells and IgG4/IgG index and factors associated with the index in intracranial inflammatory lesions. Specimens of nine patients were analyzed immunohistochemically using antibodies against CD45, CD68, CD3, CD4, CD8, CD20, CD138, lambda chain, kappa chain, IgG, IgG4, IL-1α, IL-6, IL-18, toll-like receptor (TLR) 2, TLR4, high-mobility group box 1 (HMGB1), tumor necrosis factor-alpha (TNF-α), myeloid differentiation factor 88 (MyD88), and anaplastic lymphoma kinase (ALK). The relationship between all the factors was assessed using Spearman's rank correlation coefficient (ρ). Negative ALK staining was observed in all the patients. Plasma cells were detected in eight patients with varying degrees. The highest number of neutrophils, but no plasma cells, was observed in a patient with the shortest history of inflammation. IgG4/IgG index was independent of the number of plasma cells. The index was relatively highly correlated with IL-6 (ρ = 0.7271) and TLR4 expression (ρ = 0.7246). IL-6 expression was highly correlated with TLR4 expression (ρ = 0.8042). IL-18 was maximally expressed in all the patients. TLR4 expression was strong, but TRL2 expression was weak. Positive HMGB1 staining was observed in all the patients, predominantly in the nuclei, but also in the cytoplasm in four patients. The cytoplasmic expression strongly correlated with IL-1α expression (ρ = 0.9583). The cytoplasmic colocalization of HMGB1 and IL-1α was histologically confirmed in cells with collapsing nuclei by the double-staining method. The IgG4/IgG indexes varied case by case. IL-6 and TLR4 expressions may influence IgG4/IgG index. The nuclei of cells with both IL-1α and HMGB1 expressions in the cytoplasm collapse in the cell death stage. The cooperative high expression of TLR4, IL-6, IL-18, MyD88 and HMGB1 suggest their critical roles in the inflammation circuit.