Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide.

Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-A(b) molecule that presents only a single peptide (E alpha 52-68) spontaneously develops peripheral nervous system-specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow-derived cells determined disease susceptibility. While the expression of the I-A(b)-E alpha 52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4(+) T cells that can be activated by the I-A(b)-E alpha 52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4(+) T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-A(b)-E alpha 52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A(b)-E alpha 52-68 complex, probably caused by incomplete negative thymocyte selection.

Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration.

Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics, both of which are regulated by Rho family GTPases. Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement. The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicated to mediate membrane extension by functioning upstream of Rac. Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells, physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein, is indispensable for lymphocyte chemotaxis. DOCK2-deficient mice (DOCK2-/-) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2-/- lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished. Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation.

Inflammatory pseudotumor of the spleen: report of a case.

A case of a 45-year-old Japanese man with a splenic inflammatory pseudotumor is described. This benign lesion is rarely reported in the world literature. We preoperatively could not rule out the possibility of a malignant neoplasm, due to the fact that the tumor had grown in size after a 2-year observation. However, after performing a splenectomy, a histological examination of the mass revealed an inflammatory process. Inflammatory pseudotumors often pose diagnostic difficulties because the clinical and radiological findings tend to suggest a malignancy. The clinical and pathological features of such previously reported cases are also reviewed.

Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact.

T cell differentiation in the thymus is driven by positive selection through the interaction of alphabeta T cell receptors (TCRs) with self-peptides bound to self-major histocompatibility complex molecules, yet the influence of the peptide sequence on this process remains unknown. To address this issue, we have compared CD4(+) T cell differentiation between two sets of mouse lines in which MHC class II I-A(b) molecules are occupied with either Ealpha chain-derived peptide ((p)Ealpha) or its variant, (p)60K, with one amino acid substitution from leucine to lysine at P5 residue of TCR contacts. Here, we show that despite the comparable expression of I-A(b)-peptide complex in the thymus, this substitution from leucine to lysine affects efficiency of positive selection, resulting in extremely small numbers of CD4(+) T cells to be selected to mature on I-A(b)-(p)60K complex. Furthermore, we show that, although I-A(b)-(p)Ealpha complex selects diverse T cells, T cell repertoire shaped by I-A(b)-(p)60K complex is markedly constrained. Our findings thus suggest that positive selection is both specific and degenerate, depending on the amino acid residues at TCR contacts of the selecting self-peptides.

Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor beta chain.

The T cell repertoire is shaped by positive and negative selection of thymocytes through the interaction of alpha/beta-T cell receptors (TCR) with self-peptides bound to self-major histocompatibility complex (MHC) molecules. However, the involvement of specific TCR-peptide contacts in positive selection remains unclear. By fixing TCR-beta chains with a single rearranged TCR-beta irrelevant to the selecting ligand, we show here that T cells selected to mature on a single MHC-peptide complex express highly restricted TCR-alpha chains in terms of Valpha usage and amino acid residue of their CDR3 loops, whereas such restriction was not observed with those selected by the same MHC with diverse sets of self-peptides including this peptide. Thus, we visualized the TCR structure required to survive positive selection directed by this single ligand. Our findings provide definitive evidence that specific recognition of self-peptides by TCR could be involved in positive selection of thymocytes.

[Thoracoscopy with two bronchoscopes in 50 patients with pleural effusion of unknown origin].

When performing thoracoscopy in patients with pleural effusion of unknown origin, we used two bronchoscopes simultaneously, one for observation and one for biopsy. A total of 50 patients with pleural effusion of unknown origin were studied. In all of those studies, pleural effusion was exudative, lymphocyte-dominant, had a low level of adenosine deaminase, no malignant cells, and no tuberculosis or other bacteria in pleural effusion smears. Fourteen were out-patients. A catheter was inserted into the pleural space under local anesthesia, and 300 ml to 500 ml of pure oxygen was injected to create a pneumothorax. Two flexible fiberoptic bronchoscopes were used simultaneously, one for observation and one for biopsy. Approximately 1 hour after the examination, the out patients were able to return home. Lesions in the pleural cavity were found in 42 of these 50 patients, and histological diagnosis was possible in 46. This is a simple procedure with no major side effects. The equipment required is familiar to pulmonary physicians, and the diagnostic yield is high.

alpha-Linolenic, eicosapentaenoic and docosahexaenoic acids affect lipid metabolism differently in rats.

Rats were fed purified diets containing 10% fat with constant (n-6):(n-3) polyunsaturated fatty acids [(n-6):(n-3); 2.3-2.6] and polyunsaturated:saturated fatty acids (1) ratios. This was obtained with alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid added at 1 g/100 g diet. Eicosapentaenoic acid and docosahexaenoic acid were added as the ethyl esters. The concentration of plasma cholesterol in rats fed docosahexaenoic acid was significantly lower than in those fed alpha-linolenic acid. The concentration of plasma triglyceride was significantly lower in rats fed eicosapentaenoic acid than in those fed docosahexaenoic acid. Docosahexaenoic acid significantly reduced hepatic cholesterol compared with alpha-linolenic acid and eicosapentaenoic acid. Both eicosapentaenoic acid and docosahexaenoic acid decreased hepatic triglyceride compared with alpha-linolenic acid, but this effect was more pronounced in the docosahexaenoic acid group. There was no significant difference in fecal excretion of neutral and acidic steroids and apparent fat absorption. In rats fed docosahexaenoic acid, the proportion of arachidonic acid in liver microsomal phosphatidylcholine was lower than in those fed eicosapentaenoic acid. The same tendency was observed in plasma, platelet and aortic phosphatidylcholine and liver microsomal phosphatidylethanolamine and phosphatidylinositol. Dietary docosahexaenoic acid, but not eicosapentaenoic acid, significantly decreased aortic production of prostacyclin compared to alpha-linolenic acid, whereas platelet aggregation by collagen was not affected by the difference in dietary (n-3) polyunsaturated fatty acids.