thymic-factor--circulating and Myasthenia-Gravis

The expression of chemokine receptors on peripheral blood lymphocytes and thymocytes of myasthenia gravis (MG) patients was analyzed before and after therapy with special reference to the thymic histopathology. Before therapy, MG patients showed reduced frequency of CD4+ T cells expressing T-helper1 (Th1) type chemokine receptor CXCR3, with a significantly lower frequency in the thymoma group than in the thymic hyperplasia group, while the frequencies of CXCR3-positive CD8+ T cells remained normal irrespective of the thymic pathology. Both CD4+ cells and CD8+ cells of the hyperplasia group showed significantly increased expression of CCR1 on the cells followed by a reduction to the control level after therapy. No significant changes in the frequencies of CCR2, CCR3, CCR4, and CCR5 were observed in either MG group. There was a significant inverse correlation between the percentage of CXCR3-positive CD4+ T cells and the disease severity assessed with the MGFA scale (Fig. 1, r=-0.55, p=0.0047). The CXCR3 expression on CD4+ cells was increased toward the control level long after the initiation of therapy. The thymomas showed significantly higher percentages of CXCR3-positive CD4+CD8- single positive cells than the control thymuses and, though not significantly, the hyperplastic thymuses also showed higher percentages. These results indicated that Th1-type chemokine signalings were altered in the MG patients, particularly those with thymoma, and that the thymus and thymoma are important sites of Th1-type reactions. The slow clinical improvement of MG symptoms after treatment may be explained partly by the gradual normalization of CXCR3-mediated signaling.

Topics: Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Flow Cytometry; Gene Expression Regulation; Humans; Lymphocyte Count; Male; Middle Aged; Myasthenia Gravis; Receptors, Chemokine; Receptors, CXCR3; Thymectomy; Thymic Factor, Circulating; Time Factors

Different age-related immune pathogenetic mechanisms in myasthenia gravis (MG) have been suggested because of restoration after thymectomy (Tx) of altered zinc, thymulin (TH) and T-cell subsets exclusively in early-onset patients (younger <50 years), not in late-onset patients (older >50 years). In this context interleukin-2 (IL-2), interleukin-6 (IL-6) and thymoma are crucial because both involved in MG pathogenesis and correlated with acetylcholine receptors (AchRs) Ab production. Moreover, IL-2 and IL-6 are zinc-dependent, are altered in aging and related with zinc and TH age-dependent declines. Moreover, zinc is relevant for immune efficiency. In order to confirm these different age-related pathogenetic mechanisms further, the role of thymoma, zinc, TH, IL-2 and IL-6 is studied in MG patients with generalized MG with and without thymoma before and 1 month and 1 year after Tx. The high IL-2, IL-6, zinc, and AChR Ab levels observed before Tx are significantly correlated each other in younger MG patients (<50 years) independently by thymoma and in older MG patients (>50 years) with thymoma. No correlations exist in older MG patients without thymoma. Thymulin is not correlated with other parameters considered to be both in younger and older MG patients independently by the thymoma. Thymectomy restores zinc; immune parameters and AChR Ab are exclusively in the younger group, not in the older one. These findings suggest that IL-2 and IL-6, via zinc, rather than TH, may be involved in different age-related pathogenetic mechanisms mainly in early-onset MG. By contrast, thymoma may be involved in MG etiology in late-onset representing, as such, a useful discriminant tool for MG etiology between early and late-onset MG patients. Because autoimmune phenomena may rise in aging, a parallelism with altered immune functions during aging is discussed.

Topics: Adolescent; Adult; Aged; Aging; Female; Humans; Interleukin-2; Interleukin-6; Male; Middle Aged; Myasthenia Gravis; Receptors, Cholinergic; Thymectomy; Thymic Factor, Circulating; Thymoma; Thymus Neoplasms; Time Factors; Zinc

Thymic endocrine activity was assessed by a bioassay to determine the basal activity of thymulin (TH), a zinc dependent hormone, and its in vitro reactivation in two different age groups of patients with myasthenia gravis (MG). Before thymectomy, basal TH plasma levels were increased in patients over the age of 50 years. Plasma zinc levels were increased in all patients, this increment being very high in old patients. One year after thymectomy both TH and zinc plasma levels decreased. While zinc plasma levels were within the normal ranges for their respective ages, TH levels were lower in young and higher in old patients than in age comparable controls. Young patients with MG showed increased CD3,DR positive peripheral T-cells as well as lymphocytes with the CD16,CD56 phenotype. An increment of CD3 positive cells along with CD4 and CD16,CD56 positive cells were found in older patients. Thymectomy partially affected blood lymphocyte representation only in young patients, since CD3,DR T-cells decreased one year after surgery. No significant variations in T-cell representation were found in old patients after thymectomy. Immunosuppression in thymectomized patients did not significantly affected TH and zinc plasma levels. Very high levels of TH and the presence of additional alterations in T-lymphocyte subsets in old patients suggested that differential age related pathogenetic immunological mechanisms might be associated with the disease.

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lymphocyte Count; Male; Middle Aged; Myasthenia Gravis; T-Lymphocyte Subsets; Thymectomy; Thymic Factor, Circulating; Thymus Gland; Zinc

Topics: Adolescent; Adult; Eye; Female; Humans; Male; Middle Aged; Myasthenia Gravis; Thymic Factor, Circulating; Thymus Gland

We investigated by an immunofluorescence assay the presence of the P19 antigen in cultures of human thymic epithelial cells (HTEC). This antigen is acquired during human thymic ontogeny, and in infants and adults most thymic epithelial cells were shown to display P19 antigen. In cultures of normal human thymic epithelium, we observed that the P19 protein was less expressed than in situ. However, the percentage of P19-containing cells increased with culture age, a finding which could be compared to that obtained recently concerning immunodetection of thymulin-containing cells. Indeed, thymic epithelial cells keep their endocrine function in culture and the number of thymulin-positive cells increases as a function of time. Interestingly, the increase of P19 expression was generally parallel to that of thymulin production. These data may reflect functional modifications of the cells in relation to differentiative effects. Similar results were obtained in pathological thymuses described as hyperplasia in M G patients. In contrast, thymomas behaved differently. Among the three benign thymomas tested, two were consistently P19-negative or faintly stained in culture conditions while one was very brightly stained from the onset and remained P19-positive throughout the culture; this finding correlates with studies on frozen sections. Our data show modifications of P19 antigen expression both in culture and in thymomas and suggest that P19 synthesis may be dependent upon components (factors or cells) which are efficient in the thymic microenvironment but partially defective in the cultures or after neoplastic transformation.

Topics: Antigens, Surface; Cells, Cultured; Epithelium; Fluorescent Antibody Technique; Humans; Myasthenia Gravis; Thymic Factor, Circulating; Thymoma; Thymus Gland; Thymus Hyperplasia; Thymus Neoplasms

The localization of the three best-defined thymic hormones, namely, thymulin, thymopoietin and thymosin alpha 1 was studied by immunofluorescence using antibodies directed against these three molecules. With both human thymus frozen sections and cultured cells, thymic hormones were found exclusively in the epithelial component (recognized by its keratin content), in normal as well as pathological thymuses. The double-labeling experiments using the different anti-thymic hormone antibodies showed that the same epithelial cells contained the three hormones. These results suggest that the production of different hormones in the thymus is accomplished by the same epithelial cells.

Topics: Cells, Cultured; Fluorescent Antibody Technique; Freezing; Histological Techniques; Humans; Myasthenia Gravis; Thymalfasin; Thymic Factor, Circulating; Thymoma; Thymopoietins; Thymosin; Thymus Gland; Thymus Hormones; Thymus Hyperplasia; Thymus Neoplasms

Monoclonal antibody assays were employed to monitor modifications induced in human peripheral lymphocyte subsets by thymectomy or the administration of a series of immunomodulating drugs: synthetic thymic factor, cimetidine or various combinations of anti-thymocyte globulin, azathioprine and steroids. In patients with myasthenia gravis, thymectomy produced a gradual progressive decrease in the elevated OKT4/OKT8 ratios associated with this disease until normal ratios were achieved after one year. Administration of synthetic thymic factor to three immunodeficient children for one month produced increased serum IgA levels accompanied by a normalization of proportions of total T cells and T cell subsets. Four of five uremic patients receiving cimetidine exhibited a marked increase in the percentage of OKT8+ T cells observed in subsequent blood samples with a concomitant increase in immature (OKT4+, OKT8+) lymphocytes that suggested an increase in release of such lymphocytes from the thymus. Assessment of 29 longterm renal allograft recipients by repeated T cell monitoring over an extended period of time confirmed the findings of other investigators that an increase in the OKT4+/OKT8+ ratio was predictive of subsequent allograft rejection episodes while subnormal OKT4+/OKT8+ ratios were indicative of possible cytomegalovirus or herpes virus infections.

Topics: Animals; Antibodies, Monoclonal; Cimetidine; Cytomegalovirus Infections; Graft Rejection; Humans; Immune Tolerance; Immunoglobulin A; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Activation; Mice; Myasthenia Gravis; T-Lymphocytes; Thymectomy; Thymic Factor, Circulating

Topics: Adult; Animals; Complement Activating Enzymes; Complement C1q; Complement C3; Complement C9; Epithelium; Female; Fetus; Fibrin; Fluorescent Antibody Technique; Humans; Immune Sera; Immunoglobulin M; Myasthenia Gravis; Pregnancy; Rabbits; Thymic Factor, Circulating; Thymus Gland; Thymus Hormones

The influence of adult thymectomy on several parameters of immunocompetence in patients with myasthenia gravis (MG) was investigated. Since incomplete thymectomy may lead to the presence of thymic remnants, we determined the activity of a thymus-dependent factor in the sera of the MG patients. As measured by several parameters, MG patients showed a normal immunocompetence compared with healthy controls, except in the response to DNCB sensitization in vivo. When tested at least 5 years after thymectomy, MG patients were found to have decreased response to mitogens, and a decreased cytotoxic T cell response in cell-mediated lympholysis. The response to challenge with DNCB in vivo was decreased both in thymectomized and nonthymectomized MG patients. No difference was found in a) the percentage of circulating T, B, non-B/non-T cells; b) the response to allogeneic cells (MLR); c) the antibody-dependent lymphocytotoxicity; d) the production of immunoglobulins in vitro by pokeweed mitogen-stimulated cells; and e) the anamnestic response to antigens in vitro. We conclude that adult thymectomy results in a decrease in the function of some subpopulations of lymphocytes.

Topics: Adult; Aging; Antibody-Dependent Cell Cytotoxicity; Dinitrochlorobenzene; Humans; Immunoglobulins; Lymphocyte Activation; Lymphocytes; Mitogens; Myasthenia Gravis; Skin Tests; Thymectomy; Thymic Factor, Circulating

Topics: Adolescent; Adult; Aged; Aging; Animals; Autoantibodies; Child; Child, Preschool; Humans; Infant; Mice; Mice, Inbred C57BL; Middle Aged; Muscles; Myasthenia Gravis; Receptors, Cholinergic; Thymectomy; Thymic Factor, Circulating; Thymus Gland; Thymus Hormones