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Anti-Hu syndrome is a paraneoplastic neurologic disease seemingly associated with an efficient antitumoral immune response against HuD protein expressed by both small cell lung cancer (SCLC) and neurons. Since anti-Hu antibodies are not pathogenic, and oligoclonal CD8(+) T cells infiltrate neoplastic and nervous tissues, we examined MHC class I-restricted immunogenicity of human HuD. Among 14 HuD-derived peptides potentially immunogenic in HLA-A*0201 restriction, 10 had actual in vitro binding capacity to the HLA molecule, 8 elicited specific cytotoxic T lymphocytes (CTLs) in a humanized murine model after peptidic vaccination, 2 also elicited specific CTLs in healthy humans, and 1 was naturally processed and presented to the immune system.

Infiltration of activated lymphocytes and monocytes is a key phenomenon in the pathogenesis of Guillain-Barré syndrome (GBS) and experimental autoimmune neuritis (EAN). To investigate the role of chemokines, we determined the blood and nerve tissue expression of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, and its receptor CCR2 in GBS and EAN. MCP-1 circulating levels (ng/ml) in GBS were increased at the time of progression, peaked at the time of plateau and normalized with recovery. MCP-1 circulating levels were the highest in the most disabled patients. The number of circulating CCR2 positive cells was lower in patients with GBS than in healthy subjects (p<0.004). In GBS, MCP-1 expression was observed in epineurial and endoneurial vessels, on infiltrating cells, Schwann cells and in the endoneurial extracellular matrix. Some CCR2 positive cells were observed in nerve biopsies of GBS patients. In EAN, a slight positivity for MCP-1 was observed in the sciatic nerve. There was no circulating CCR2 positive cells. However, at the time of plateau, a conspicuous infiltration of CCR2 positive cells was observed in the sciatic nerve that was no longer observed at the time of recovery. These results suggest that MCP-1 and CCR2 may participate to the recruitment of circulating mononuclear cells in nerve tissue in EAN and GBS.

T-cell clones of unknown significance (TCUS), assessed by monoclonal or oligoclonal T-cell patterns in PCR-DGGE, were detected in blood of 7/9 patients with anti-Hu syndrome. Clonal patterns were also detected in 2/2 neoplastic lymph nodes, and in 2/2 inflamed dorsal root ganglia from three patients. Only some T-cell clones found in target tissues were also detected in blood or non-target tissues, and likely corresponded to TCUS. In one patient, an identical T-cell clone was found in both neoplastic lymph node tissue and dorsal root ganglia, but not in blood. Dorsal root-infiltrating lymphocytes were cytotoxic CD8(+) TIA-1(+) T-cells. They were often found in close contact to sensory neurons, most of which expressed MHC-1. Taken together, these data support a direct effector role of cytotoxic CD8(+) T-cells, the same clones being likely operative in sensory neuron damage and immune-mediated tumor growth control.

Intraneural inflammation, that reflects emigration of immune cells from blood to nerve tissue, is a critical event in Guillain-Barré syndrome pathogenesis. To investigate the adhesion and transmigration phases of leukodiapedesis, we determined in a series of patients with GBS: (1) circulating levels of soluble forms of adhesion molecules (sICAM-1 and sVCAM-1); (2) attachment capacities of circulating lymphocytes to rICAM-1 and rVCAM-1; (3) fibronectin-penetrating capacities of circulating lymphocytes; and (4) lymphocyte intracellular concentrations of MMP-9 at the different phases of GBS and in healthy controls. Circulating levels of sVCAM-1 and sICAM-1 were above normal values at the time of progression, markedly increased at the time of plateau (sVCAM-1: P<0.03; sICAM-1: P<0.02), and tended to normalize during recovery. The percentage of cells with attachment capacities to rVCAM-1 and to rICAM-1 decreased from progression to recovery by 30 and 31%, respectively (P<0.02). The number of circulating lymphocytes with fibronectin penetrating capacities was lower than controls at the time of progression (P<0.01), then progressively increased to reach values higher than controls at the time of late recovery (P<0.02). Cellular concentrations of MMP-9 in circulating lymphocytes paralleled their fibronectin penetrating capacities. These results suggest early emigration of lymphocytes into nerve, followed by shedding of adhesion molecules from endothelium, and late decrease of lymphocyte adhesion capacities. Plateau and recovery are associated with accumulation in the vascular compartment of still proteolytically active lymphocytes that can no longer adhere to endothelial cells. Modulation of the adhesion step of leukodiapedesis may be crucially involved in the switch from progression to plateau of GBS.

Guillain-Barré syndrome (GBS) is an inflammatory disorder that may implicate proinflammatory cytokines such as TNF-alpha in its pathogenesis. We determined serum levels of TNF-alpha and the specific antagonists sTNF-Rs p55 and p75 in 24 patients with GBS at days 1, 15 and 30 of hospitalization. Patients were in the progression phase of the disease at day 1, and in the recovery phase at day 30. They were classified as able to walk (stage A), confined to bed (B), or under assisted ventilation (C). All patients underwent plasma exchange within day 1-12. At day 1, TNF-alpha levels were elevated in 15/24 patients, and sTNF-Rs were elevated in 21/23. TNF-alpha levels had not decreased at day 15, and dropped at day 30 (p < 0.04), whereas sTNF-R p55 remained elevated at day 15 and day 30. The TNF-alpha/sTNF-Rs ratio, estimating active TNF-alpha unbound to sTNF-Rs, decreased from day 1 to day 30 (p < 0.05). A positive correlation was found between disease severity and sTNF-R serum levels (p < 0.01). In conclusion, elevated circulating sTNF-Rs assesses activation of the TNF-alpha system in almost all patients with GBS and correlates positively with disease severity. Drop of TNF-alpha contrasting with sustained elevation of sTNF-R p55 during recovery suggests that sTNF-R p55 may be important in the fading of the neural inflammatory effect of TNF-alpha in GBS.