The role of leukocyte p38 MAP kinase in immune-mediated peripheral polyneuropathies: distinct modulation by intravenous immunoglobulins.

BACKGROUND

Chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) are rare immune-mediated peripheral polyneuropathies with insufficiently elucidated etiopathogenesis. Mitogen activated protein kinases (MAPK), the intracellular energy sensor AMP-activated protein kinase (AMPK), and the master metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) regulate immune responses through various mechanisms, including autophagy.

METHODS

We used immunoblotting to analyze AMPK/mTORC1 signaling, autophagy, and the activation status of the MAPK family members p38, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) in peripheral blood mononuclear cells (PBMC) of 17 treatment-naïve CIDP patients and 7 MMN patients already on chronic intravenous immunoglobulin (IVIg) therapy.

RESULTS

Compared with age/sex-matched controls, PBMC from CIDP and MMN patients showed higher levels of active (phosphorylated) p38 MAPK, whereas autophagy and AMPK/mTORC1, ERK, and JNK pathways were not significantly altered. The amounts of p38 MAPK in PBMC negatively correlated with muscle strength in MMN, but not CIDP. The treatment of CIDP patients (n = 9) with IVIg did not affect the activation status of AMPK, MAPK, or autophagy in PBMC. In contrast, IVIg treatment reduced the phosphorylation of p38 MAPK, ERK, and AMPK in PBMC from MMN patients (n = 6), and the decrease in phospho-p38 MAPK levels correlated with improved hand grip strength.

CONCLUSIONS

Together, this exploratory study indicates that leukocyte p38 MAPK modulation might be involved in disease activity and therapeutic effect of IVIg in MMN, but not CIDP.