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Sera from 71 patients with primary Sjögren's syndrome (PSS) and from 102 patients with systemic lupus erythematosus (SLE) were tested by immuno-dot blotting against HuD, Ri, Yo and amphiphysin recombinant proteins. For Ri, Yo and amphiphysin antigens, no immunoreactivity was found in the 173 sera tested. One PSS patient with a clinical picture of subacute sensory neuronopathy had high titers of anti-Hu antibodies. An extensive search for an underlying tumor was initially negative but a small cell lung cancer was eventually discovered three years later. Another patient with SLE and a clinical picture of demyelinating polyradiculoneuropathy had anti-Hu antibodies. Repeated search for an underlying tumor remains negative after five years follow-up in this young non-smoking patient. In addition, the neuropathy progressively improved and the anti-Hu antibodies titer slowly decreased from 1:8000 to 1:2000, making the diagnosis of paraneoplastic syndrome unlikely in this patient. This study indicates that the detection of anti-Hu antibodies in patients with known symptomatic systemic autoimmune diseases such as PSS or SLE should induce the same work-up than the detection of these antibodies in the absence of other immune diseases, i.e. repeated search for occult cancer during several years. As illustrated by our first patient, this strategy may be fruitful. Nevertheless, the clinician should know that anti-Hu antibodies may exceptionally (0.6% in this series) occur in systemic autoimmune disorders with neurological complications, in the absence of an underlying neoplastic disease.

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associated with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies, also called the "anti-Hu syndrome," is believed to result from an immune response triggered by tumor antigens and misdirected to the neurons. To further assess the issue of cell-mediated immunity in this disease, the peripheral blood lymphocyte surface phenotype was studied in 15 patients suffering from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein was used to stimulate in vitro peripheral blood mononuclear cells of 10 seropositive patients and of 10 patients from each control group. Phenotypic analysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO+CD4+) T cells in the seropositive group in comparison with the two control groups. Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [3H]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells revealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant increase of the interferon-gamma/interleukin-4 ratio was found in culture supernatants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protein is an antigenic target for autoreactive CD4+ T cells, presumably of the Th1 subtype, which could therefore be directly involved in cell-mediated injury of the nervous system as well as in antitumoral immunity.

Paraneoplastic neurological diseases are a group of neurological disorders associated with neoplastic tumors but not due to tumoral extension, metabolic, infectious, vascular or toxic complications of these tumors or their treatment. In the majority of paraneoplastic neurological disorders, circulating autoantibodies directed against neurons have been found in the serum and/or the CSF suggesting, and in some cases implicating, autoimmunity in the pathophysiology of these diseases. The finding of autoimmune phenomena during the course of paraneoplastic neurological disorders is of importance: from a practical point of view, since the detection of anti-neuronal autoantibodies is of great diagnostic help and should lead to the thorough search of the associated tumor often at an early stage of its development; from a theoretical point of view, these disorders represent a peculiar type of molecular mimicry. Tumoral neontigens having structural homology or identity with neuronal autoantigens elicit autoreactivity. The immunological effector mechanisms involved in the pathophysiology of paraneoplastic syndromes appear to differ according to the disease: autoantibodies are pathogenic in Lambert-Eaton syndrome whereas, in paraneoplastic cerebellar degeneration and in the Hu syndrome, the cellular immune response might play a greater role.

A 67-year-old woman was admitted for intestinal pseudoobstruction associated with peripheral sensitive neuropathy. Jejunal biopsies performed during laparotomy, showed axonal degeneration and lympho-plasmocytic infiltration in myenteric plexus. High titer of seric anti-Hu antibodies suggested a paraneoplastic syndrome. Thoracic CT scan showed mediastinal lymph nodes. Their histological examination confirmed the diagnosis of metastatic small-cell lung carcinoma. Her condition gradually deteriorated despite supportive parenteral nutrition, chemotherapy, steroids and intravenous immunoglobulins. She died 12 months after the onset of symptoms.

We report a patient with erythema gyratum repens (EGR), in whom a bronchial carcinoma was found. Direct immunofluorescence revealed granular deposits of immunoglobulins at the basement membrane zone (BMZ) in the skin, and in the lung tumour. Direct immunoelectron microscopy showed that the immune deposits were localized just beneath the lamina densa. Indirect immunofluorescence revealed circulating anti-BMZ antibodies. Immunohistochemical staining, using anti-transforming growth factor-beta, anti-epidermal growth factor receptor, anti-vimentin and anti-alpha-actin, was found to be more intense in the lesional skin and the lung tumour than in normal tissues. Possible mechanisms in the pathogenesis of EGR are discussed.