Mitogen-activated protein kinases, or MAPKs, are a family of signaling enzymes that operate inside virtually every cell of the body. When a cell receives an external cue, such as a stress signal, a cytokine, or an antigen encounter, these kinases relay the message from the cell surface to the nucleus by a chain reaction of phosphorylation events. The family includes three major branches: p38, which is strongly associated with inflammation and cellular stress responses; extracellular signal-regulated kinase (ERK), which typically drives proliferation and differentiation; and c-Jun N-terminal kinase (JNK), which responds to stress and can trigger programmed cell death. Because immune cells rely heavily on these cascades to orchestrate their activation and effector functions, researchers have long suspected that MAPK signaling might be disturbed in autoimmune diseases, including those affecting the peripheral nerves.

The Belgrade team, led by Marina Stamenkovic and Irena Vukovic as co-first authors under the supervision of Vladimir Trajkovic and Verica Paunovic, went beyond the MAPK family to examine a broader metabolic network. They also measured the activity of AMP-activated protein kinase (AMPK), an intracellular energy sensor that switches cells into conservation mode when fuel is scarce, and mechanistic target of rapamycin complex 1 (mTORC1), the master growth regulator that AMPK antagonizes. Together, these pathways govern autophagy, the cellular recycling process by which cells digest their own damaged components. Autophagy has emerged in recent years as a critical regulator of immune cell behavior, and earlier work by some of the same investigators had linked reduced AMPK signaling in blood mononuclear cells to the severity of Guillain-Barré syndrome, another immune-mediated neuropathy.

To test whether these pathways are altered in chronic immune neuropathies, the researchers collected peripheral blood mononuclear cells, the mixed population of lymphocytes and monocytes that circulates in the bloodstream, from 17 patients with CIDP who had not yet received any immunotherapy, and from 7 patients with MMN who were already on chronic maintenance therapy with intravenous immunoglobulin (IVIg). They compared these samples with cells from age- and sex-matched healthy controls, using immunoblotting, a laboratory technique that separates proteins by molecular weight and detects them with specific antibodies, to quantify the phosphorylated, active forms of the signaling enzymes as well as markers of autophagy flux.

The results were strikingly selective. In both CIDP and MMN patients, the levels of phosphorylated, active p38 MAPK in circulating mononuclear cells were significantly higher than in healthy controls. In contrast, the activity of ERK and JNK, the other two MAPK branches, was not significantly altered, and neither were the AMPK/mTORC1 metabolic axis nor the autophagy markers. This specificity matters because it suggests that p38 activation is not a nonspecific consequence of chronic illness or inflammation but a distinctive feature shared by these two related yet clinically distinct neuropathies. The finding also aligns with earlier animal studies in which p38 and other MAPKs were found to be activated in the sciatic nerves of rats with experimental autoimmune neuritis, the laboratory model of human immune-mediated demyelinating neuropathy.

Perhaps the most intriguing clinical correlation emerged from the MMN group. The amount of p38 MAPK protein in patients’ blood cells was negatively correlated with their muscle strength, meaning that patients with more of this kinase in their leukocytes tended to have weaker muscles. Notably, this correlation was absent in CIDP, hinting that p38 may track disease activity differently in the two conditions. MMN is characterized by purely motor deficits, often beginning in the hands, and muscle strength is the principal measure by which clinicians judge disease progression and treatment response. A blood-based molecular correlate of strength, if confirmed, could eventually complement the clinical scales and electrophysiological tests currently used to monitor these patients.

The therapeutic dimension of the study came from comparing patients before and after IVIg treatment. Intravenous immunoglobulin is a pooled preparation of antibodies harvested from thousands of healthy donors, and it is a mainstay of therapy for both CIDP and MMN, though the two diseases differ in their longer-term management. Among nine CIDP patients who received IVIg, the treatment did not change the phosphorylation status of AMPK, any of the MAPKs, or the autophagy markers in their blood cells. Among six MMN patients, however, IVIg produced a measurable biochemical effect: it reduced the phosphorylation of p38 MAPK, ERK, and AMPK in their mononuclear cells. Crucially, the magnitude of the drop in phospho-p38 levels correlated with the improvement in hand grip strength, directly linking a molecular change in circulating immune cells to a functional clinical outcome.

These divergent responses raise fascinating questions about how IVIg works and why the same therapy might engage different mechanisms in different diseases. Previous research has shown that IVIg can suppress inflammatory signaling in monocytes, including NF-κB and p38 MAPK activation driven by tumor necrosis factor-alpha, and can induce autophagy in peripheral blood mononuclear cells. The new findings are consistent with the idea that in MMN, IVIg dampens a p38-centered inflammatory program in leukocytes, and that this immunological cooling accompanies, and may contribute to, the recovery of motor function. In CIDP, by contrast, the lack of detectable signaling change suggests either that IVIg acts through mechanisms not captured by these particular readouts, or that the relevant immune events occur in tissue-resident cells rather than in the circulating pool sampled by the researchers.

The authors are careful to frame the study as exploratory, and the limitations are real. The patient cohorts are small, particularly the MMN group, and the CIDP patients were treatment-naïve while the MMN patients were already on therapy, an asymmetry that complicates direct comparison between the diseases. Immunoblotting of bulk mononuclear cells also averages signals across heterogeneous cell populations, so the p38 elevation could reflect changes in a specific subset of lymphocytes or monocytes rather than a uniform shift. Nevertheless, the correlation between phospho-p38 reduction and grip strength improvement in MMN provides a concrete, testable hypothesis for future studies with larger cohorts and longitudinal sampling.

The findings also carry translational promise. Pharmacological inhibitors of p38 MAPK have been developed for decades, and one such inhibitor, losmapimod, recently showed encouraging results in a phase 2b trial for facioscapulohumeral muscular dystrophy, demonstrating that p38 blockade can be pursued safely in neuromuscular disease. The safety concerns that have historically shadowed p38 inhibitors, including effects on liver function and stress responses, remain relevant, but a circulating biomarker that identifies which patients are most likely to benefit could transform trial design. For now, the study’s central message is that a single stress-activated kinase in blood cells may serve as both a window into disease activity and a readout of therapeutic response in multifocal motor neuropathy, offering researchers a molecular thread to follow in the search for more precise treatments for these rare, disabling conditions.

Subject of Research: The role of leukocyte p38 MAP kinase signaling in immune-mediated peripheral polyneuropathies and its modulation by intravenous immunoglobulin therapy

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

Article References: Stamenkovic, M., Vukovic, I., Milosevic, E., Peric, S., Paunic, A., Anicin, A., Basta, I., Bozovic, I., Palibrk, A., Ivanovic, V., Trajkovic, V., & Paunovic, V. (2026). The role of leukocyte p38 MAP kinase in immune-mediated peripheral polyneuropathies: distinct modulation by intravenous immunoglobulins. Journal of Neurology, 273(10), Article 627. https://doi.org/10.1007/s00415-026-14106-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14106-3

Keywords: p38 MAPK, CIDP, multifocal motor neuropathy, intravenous immunoglobulin, peripheral neuropathy, immune cell signaling, AMPK, mTORC1, autophagy, ERK, JNK, biomarker