| The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3 CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma. ( info) |
12/1800. Acute hemorrhagic leukoencephalitis in patients with acute myeloid leukemia in hematologic complete remission. The authors describe the cases of three patients affected by acute myeloid leukemia, in complete remission, who rapidly developed neurologic symptoms leading to death. Neither clinical characteristics, nor radiological or microbiological procedures, allowed an etiological diagnosis of the neurologic syndrome. Post-mortem examination of the brain showed both macroscopic and microscopic findings compatible with acute hemorrhagic leukoencephalitis. The difficulty in distinguishing this entity from other CNS disease-related complications (e.g. leukemia infiltration, drug toxicity, hemorrhages) should not lead to an underestimation of the true incidence of this complication. We believe that with more attention to the possibility of this complication there would probably be both a greater possibility of collecting clinical informations about the real impact of this dramatic disease and a stronger hope of finding the right treatment for it. ( info) |
13/1800. headache and bilateral visual loss in a young hypothyroid Indian man. We describe the exceptional association of Vogt-Koyanagi-Harada syndrome (VKHS) and hypothyroidism in a 29-year-old man of Indian heritage. VKHS is a rare uveomeningoencephalitic syndrome with probably autoimmune pathogenesis. Nontraumatic uveitis, aseptic meningoencephalitis, vitiligo, alopecia and poliosis are the leading clinical features of VKHS. The reported patient presented with bilateral visual loss and progressive frontal headache. VKHS was diagnosed due to characteristic ophthalmological findings and the diagnosis of aseptic meningitis. Due to the autoimmune pathogenesis, VKHS may be rarely associated with other autoimmune disorders. association of VKHS with autoimmune thyroid disease has been described in the literature in three patients. In the reported case hypothyroidism due to chronic autommune thyroiditis was diagnosed in association with VKHS. Routinely determination of thyroid function in patients with VKHS is recommended. ( info) |
14/1800. Autoimmune atrophic gastritis with hypergastrinemia. Elevation in fasting serum gastrin levels was found in three patients being evaluated for persistent upper abdominal pain without radiographic evidence of peptic ulcer disease. Fiberoptic endoscopy of the upper gastrointestinal tract in each patient revealed characteristic changes of chronic atrophic gastritis. Gastric biopsies showed diffuse chronic inflammation in the lamina propria, a decrease in the number of parietal cells, and "intestinalization" of gastric mucosa. Total achlorhydria was demonstrated after a maximal histalog stimulus; however, serum levels of vitamin B12 and schilling test values were normal in all three patients. Parietal cell antibodies were found in the serum in all patients in a dilution of 1:20 to 1:80. These cases represent autoimmune (type A) chronic atrophic gastritis and should be distinguished from chronic simple (type B) gastritis, in which serum gastrin levels are normal and no parietal cell antibodies are found in the serum. patients with autoimmune gastritis should be observed at frequent intervals for the occurrence of pernicious anemia or gastric carcinoma. ( info) |
15/1800. Increased spontaneous in vitro apoptosis in double negative T cells of humans with a fas/apo-1 mutation. We describe a 17 year old patient suffering from Canale-Smith syndrome (CSS) including chronic lymphadenopathy, splenomegaly, hypergammaglobulinemia and recurrent Coombs positive hemolytic crises. The parents are not consanguine, all other family members including two brothers are healthy. Peripheral blood mononuclear cells of the patient showed an increased rate of CD3 positive, CD4/CD8 double negative t-lymphocytes. in vitro assays showed these cells to have an increased rate of spontaneous apoptosis. Though expression of Fas/Apo-1 (CD95) and Fas-ligand (FasL) was detected on rna- and protein level we found Fas/Apo-1 mediated apoptosis being significantly reduced. Sequencing of the fas/apo-1 gene proved the patient RT and his father to carry a point mutation at position 804 located in exon 9 (death domain) leading to an amino acid substitution. For developing of CSS, a fas/apo-1 mutation seems to be necessary but not sufficient. An additional independent mechanism must be involved in the pathogenesis of human lpr<-phenotype. ( info) |
16/1800. Autoimmune enteropathy with distinct mucosal features in T-cell activation deficiency: the contribution of T cells to the mucosal lesion. BACKGROUND: Autoimmune enteropathy is normally characterised by crypt hyperplastic villous atrophy with enterocyte autoantibodies, activation of mucosal lymphocytes and increased epithelial HLA-DR. This case involved a severely affected Portuguese infant who was found to have lymphocyte activation deficiency and demonstrated correspondingly distinct mucosal features. methods: A female infant of nonconsanguineous parents was treated for vomiting and diarrhoea, first with milk exclusion and then with parenteral nutrition. lymphocyte subsets and immunoglobulin concentrations were normal, but in vitro testing showed no activation in response to phytohaemagglutinin, candida, or purified protein derivative, although the response to interleukin (IL)-2 was intact. interleukin-2 deficiency was excluded. Analysis of jejunal biopsy specimens revealed only mild villous blunting with absent goblet cells, normal epithelial proliferation, and no crypt hyperplasia. The dense infiltrate of CD8 and CD4 T lymphocytes showed normal CD2 and CD3 expression but no activation or proliferation markers. HLA-DR was not increased on epithelium or lymphocytes. Thus, in addition to in vitro evidence for lymphocyte activation deficiency, the mucosal specimens showed no evidence of in situ T-cell activation. RESULTS: After development of overwhelming septicaemia, the patient died at 18 months, just before a planned bone marrow transplant. CONCLUSIONS: These findings confirm significant heterogeneity within autoimmune enteropathy. Formal immune function testing should be performed in all affected infants to identify T-cell activation deficiencies. The distinct mucosal findings suggest that activated T cells usually induce the crypt hyperplastic villous atrophy characteristic of classic autoimmune enteropathy. ( info) |
| OBJECTIVE: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations. SUBJECTS AND DESIGN: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenstrom's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma. SETTING: A university hospital and The State serum Institute in Copenhagen. INTERVENTION: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation. MAIN OUTCOME MEASURES: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas. RESULTS: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in sjogren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations. CONCLUSIONS: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive. ( info) |
18/1800. Subclinical hyperthyroidism and hyperkinetic behavior in children. The authors report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism. Treatment with neomercazole resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy. Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified. ( info) |
19/1800. Sudden hearing loss in a patient hepatitis c virus (HCV) positive on therapy with alpha-interferon: a possible autoimmune-microvascular pathogenesis. Alpha interferon (alpha-IFN) is used for the treatment of various systemic disorders. Side-effects of alpha-IFN therapy can involve numerous organ systems, but sudden hearing loss has only once been recorded. We report a case of sudden hearing loss occurring in a patient with chronic hepatitis c treated with alpha-IFN and recovered five days after the discontinuation of this agent. This is the first record of anti-endothelial cell antibodies detection in a patient with sudden hearing loss. The finding of anti-endothelial cell antibodies suggests an association between sudden hearing loss and microvascular damage during interferon therapy. ( info) |
20/1800. A fatal case of autoimmune thrombocytopenia with an IgM anti-GPIb/IX following one antigen mismatched unrelated donor bone marrow transplantation. We report the case of a 32-year-old patient with ALL who developed autoimmune thrombocytopenia 2 months following allogeneic bone marrow transplantation. An IgM autoantibody against the platelet glycoprotein Ib/IX complex was observed. Treatment with high-dose steroids and intravenous immunoglobulin g failed to produce any benefit and the thrombocytopenia led to fatal gastrointestinal haemorrhage. The possible factors contributing to post-allograft thrombocytopenia and potential management strategies are discussed. ( info) |