Migraine is a prevalent neurological disorder characterized by severe, recurrent headaches accompanied by symptoms, such as nausea, photophobia, and phonophobia, significantly affecting the quality of life of millions of people worldwide. Although the neurovascular pathway, involving blood vessel dilation and neurogenic inflammation, has been a cornerstone in understanding migraine pathophysiology. Emerging evidence suggests that immune dysregulation plays a pivotal role in the onset and progression of migraine. This review uniquely synthesizes recent advances linking immune regulatory pathways to migraine, an area that has not been widely explored in the literature. Specifically, we highlighted the involvement of CD4 + CD25 + regulatory T (Treg) cells, interleukins, and pro-inflammatory and anti-inflammatory cytokines, which have been implicated in pain signaling and immune imbalance in patients with migraine. Furthermore, genetic studies have provided compelling evidence by identifying associations between migraine susceptibility and immune-related polymorphisms, particularly in forkhead box P3 (FOXP3) and nuclear factor of activated T cells (NFAT). Moreover, the higher prevalence of migraine in individuals with comorbid autoimmune diseases further supports the hypothesis of a shared pathophysiological mechanism. Despite the growing recognition of immune involvement in migraine, its precise mechanisms remain unclear. By integrating key immune biomarkers and genetic insights, this review proposes a novel framework for understanding the immune-mediated pathways in migraine progression. Future research should focus on elucidating the specific immunological mechanisms underlying migraine, which could open new avenues for innovative, targeted therapeutic strategies.

Neuroimmune communication plays an important role in allergic inflammation, but the neuroimmune regulation of allergic rhinitis remains unclear.

The goal of this study was to investigate the role of CD4-positive T lymphocyte (CD4+ T cells) adhesion to D-U87 neuron-like cells in mediating allergic rhinitis CD4+ T cell differentiation.

D-U87 neuron-like cells were derived from the human glioblastoma U87 cell line. CD4+ T cells were isolated from human peripheral blood using a magnetic separation technique. In vitro coculture of D-U87 neuron-like cells and CD4+ T cells was established. The number of adherent CD4+ T cells was counted using a fluorescence microscope. The percentages of CD4+IFNγ+ and CD4+IL4+ T cells and the levels of IFNγ and IL4 cytokines in the supernatant were measured by flow cytometry.

The results showed that the number of adherent CD4+ T cells in patients with allergic rhinitis was significantly higher than that in healthy controls. In allergic rhinitis, the percentage of CD4+IL4+ T cells was significantly increased in the adherent group compared with that in the nonadherent group. Moreover, blocking ICAM1 and E-selectin decreased the number of adherent CD4+ T cells and the percentage of CD4+IL4+ T cells in allergic rhinitis.

Adhesion contributes to CD4+IL4+ T cell differentiation in the in vitro coculture system of D-U87 neuron-like cells and allergic rhinitis CD4+ T cells, which may provide new insights into therapeutic strategies for allergic rhinitis.

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

Parasympathetic nerve hypersensitivity contributes to the severity of allergic rhinitis (AR), but the precise mechanism underlying neuroimmune regulation in patients with AR remains unclear. This study investigated the effect of cholinergic nerve inhibition on AR CD4⁺ T-helper (Th)2-cell polarization and the underlying regulatory mechanism in vitro.

An in-vitro neuroimmune coculture model of D-U87 cells and CD4⁺ T cells was established. D-U87 cells with cholinergic neuron characteristics were used as cholinergic neuron models. CD4⁺ T cells were derived from peripheral blood monocytes from AR patients (n = 60) and control subjects (n = 40). Th1- and Th2-cell percentages were measured by flow cytometry. Proteins involved in related signaling pathways were analyzed by protein chip assay and Western blotting.

The Th2-cell percentage among CD4⁺ T cells from AR patients was significantly increased after coculture with D-U87 cells and was decreased by ipratropium bromide (IB) treatment. In contrast, the Th1-cell percentage among control CD4⁺ T cells was significantly increased after coculture with D-U87 cells, but was unaltered by IB treatment. Furthermore, phosphorylated Akt (p-Akt) protein levels increased in CD4⁺ T cells from both controls and AR patients after coculture with D-U87 cells and decreased after IB treatment. However, higher p-Akt levels were observed in cells from AR patients than in cells from control subjects. Moreover, Akt inhibition decreased Th2-cell percentage in AR patients.

In-vitro cholinergic nerve inhibition with IB decreased AR CD4⁺ T-cell polarization into Th2 cells partially through an Akt-dependent mechanism.

The immune system is critically involved in the development and maintenance of chronic pain. However, T cells, one of the main regulators of the immune response, have only recently become a focus of investigations on chronic pain pathophysiology. Emerging clinical data suggest that patients with chronic pain have a different phenotypic profile of circulating T cells compared to controls. At the preclinical level, findings on the function of T cells are mixed and differ between nerve injury, chemotherapy, and inflammatory models of persistent pain. Depending on the type of injury, the subset of T cells and the sex of the animal, T cells may contribute to the onset and/or the resolution of pain, underlining T cells as a major player in the transition from acute to chronic pain. Specific T cell subsets release mediators such as cytokines and endogenous opioid peptides that can promote, suppress, or even resolve pain. Inhibiting the pain-promoting functions of T cells and/or enhancing the beneficial effects of pro-resolution T cells may offer new disease-modifying strategies for the treatment of chronic pain, a critical need in view of the current opioid crisis.

This study was designed to investigate the impact of astrocyte and lymphocyte (LC) interactions in the blood-brain barrier (BBB) on the pathogenesis of multiple sclerosis (MS).

Primary rat brain microvascular endothelial cells (rBMECs) and astrocytes isolated from Sprague-Dawley rats were used to establish in vitro BBB models. Transendothelial electrical resistance (TEER) and permeability were compared between rBMEC monocultures and rBMEC/astrocyte co-cultures to evaluate the validity of each as a BBB cell model. rBMEC/LC co-cultures and rBMEC/astrocyte/LC tri-cultures were established to evaluate inflammatory responses in MS by measuring the gene expression levels of nerve growth factor (NGF), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), interleukin 17 (IL-17), interferon γ (IFN-γ), and forkhead box P3 (Foxp3).

The rBMEC/astrocyte co-cultures exhibited higher TEER values and lower lymphocyte permeabilities than those of rBMEC monocultures. Compared to the rBMEC mono-cultures, the rBMEC/astrocyte/LC tri-cultures showed significantly decreased NGF, IL-17, and IFN-γ and increased MMP-2 and Foxp3 expression. Furthermore, the tri-cultures exhibited decreased NGF, IL-17, and IFN-γ expression compared to the rBMEC/astrocyte co-cultures, and increased MMP-2 expression compared to that shown by the rBMEC/LC co-cultures. MMP-9 expression did not vary significantly between the four established BBB cell models.

These results suggest that the synergistic effect between astrocytes and LCs may increase the expression of MMP-2 and decrease that of IL-17 and IFN-γ at the BBB. Furthermore, the use of rBMEC/astrocytes/LC tri-cultures enabled us to test the synergistic effect between astrocytes and LCs and their roles in MS pathogenesis.

Thrombospondin-1-deficient (TSP-1^-/-) mice are used as an animal model of Sjögren's Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren's Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1^-/- and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1^-/- compared to WT mice, but tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1^-/- mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1^-/- compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1^-/- mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1^-/- mice age.

Objectives: Immune responses in migraine are poorly characterized, yet implicated in the disease pathogenesis. This study was carried out to characterize purinergic profiles of T-cells in patients with episodic migraine without aura (MWoA) to provide mechanistic evidence for ATP and adenosine involvement in modulation of immune regulation in migraine. Methods: Peripheral blood samples were obtained from patients with migraine (n = 16) and age-matched control subjects (n = 21). Subsets of T-cells were identified by flow cytometry based on specific membrane markers. Results: Migraine patients showed reduced total T-cell counts in the peripheral blood. Whereas the total number of CD3+CD4+, CD3+CD8+, or regulatory T lymphocytes (Treg) was not changed, the proportion of Treg CD45R0+CD62L- and CD45R0-CD62L- cells was increased. Interestingly, in migraine, less Treg cells expressed CD39 and CD73 suggesting disrupted ATP breakdown to adenosine. The negative correlations were observed between the duration of migraine and the relative number of CD73+CD39- Tregs and total number of CD73-positive CD45R0+CD62L+ Tregs. Conclusion: Obtained data indicate that T-cell populations are altered in episodic migraine and suggest the involvement of Tregs in the pathophysiology of this disorder. Reduced expression of CD39 and CD73 suggests promotion of ATP-dependent pro-inflammatory and reduction of adenosine-mediated anti-inflammatory mechanisms in migraine.

Alzheimer's disease (AD) is an inexorable neurodegenerative disease that involves neuroinflammation in the brain, in addition to abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. Evidence shows that human cord blood-derived multipotent stem cells (CB-SCs) can modulate autoimmune responses by altering regulatory T cells (Tregs). Our previous study found that CB-SCs could regulate the peripheral immune system of AD patients in vitro, mainly increasing the proportion of Tregs and anti-inflammatory cytokines. To further investigate the effects of lymphocytes co-cultured with CB-SCs on AD, the APP/PS1 mice received monthly transplants of lymphocytes co-cultured with CB-SCs for 4 months. Then, the ethological and biochemical experiments were conducted. We found that APP/PS1 mice injected with lymphocytes co-cultured with CB-SCs showed improved spatial learning, which significantly correlated with fewer Aβ plaques in brain. The present study also indicated that lymphocytes co-cultured with CB-SCs could promote the protective and reparative cytokines in the peripheral blood and brain to alleviate neuroinflammation in AD mice. These findings conclude that the systemic transplantation of lymphocytes co-cultured with CB-SCs can improve cognitive and pathological impairment of APP/PS1 mice via an immunomodulatory effect.