Spatial correlation between thyroid epithelial cells expressing class II MHC molecules and interferon-gamma-containing lymphocytes in human thyroid autoimmune disease

In this immunohistochemical study we addressed the question whether aberrant class II MHC expression by thyroid epithelial cells (thyrocytes) in established thyroid autoimmune disease is the result of release of interferon-gamma (IFN-gamma) by adjacent lymphocytes. Thyroids from eight cases of Hashimoto's thyroiditis, 13 cases of Graves' disease and 10 cases of focal thyroiditis were studied. Both thyrocytes expressing class II MHC and lymphocytes containing immunoreactive IFN-gamma were found in all 31 autoimmune thyroids. In a serial section study of these thyroids, IFN-gamma-expressing lymphocytes were found within 50 microns of class II MHC-positive thyrocytes in 89% of 282 randomly selected fields. Conversely, class II MHC-positive thyrocytes were found within 50 micron of aggregates of IFN-gamma-positive lymphocytes in 82% of 272 randomly selected fields. These findings support the view that in established thyroid autoimmune disease expression of class II MHC by thyrocytes is the result of local release of IFN-gamma.     

High potential to tumor necrosis factor alpha (TNF-alpha) production of thyroid infiltrating T lymphocytes in Hashimoto's thyroiditis: a peculiar feature of destructive thyroid autoimmunity

T lymphocytes present in thyroid infiltrates of 6 patients with Hashimoto's thyroiditis (HT) and of 4 patients with Graves' disease (GD) were analyzed at clonal level and their profiles of mitogen-induced lymphokine secretion were characterized. Production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma) was measured in culture supernatants of a total number of 332 T cell clones (TCC) from HT, of 269 TCC from GD infiltrates and of 266 control TCC derived from normal lymphoid tissues. No significant difference was found in the ability to produce IL-2 between TCC from HT or GD infiltrates and control TCC. The proportion of HT- or GD-derived TCC able to produce IL-4 was extremely low (4 and 5%, respectively) in comparison with controls (19%). In contrast, the proportion of interferon-gamma (IFN-gamma)-producing (IFN-P) TCC derived from either HT (87%) or GD (80%) infiltrates was much higher (p less than 0.0005) than that found in controls (59%). In addition, most of IFN-P TCC from either HT or GD usually released higher amounts (p less than 0.002) of IFN-gamma than did control clones. No significant difference was found between GD infiltrates and controls in the proportions of TCC able to secrete TNF-alpha (39% and 47%, respectively), whereas the proportion of TNF-alpha-producing (TNF-P) TCC derived from HT (78%) was significantly higher (p less than 0.0001). In addition, most of both CD8 and CD4 TCC from HT released higher amounts of TNF-alpha than did TNF-P clones from controls or GD. These data suggest that T cells present in autoimmune thyroid infiltrates share a number of functions, such as high production of IFN-gamma, but differ with regard to their ability to secrete TNF-alpha, which is peculiar of most T cells present in the thyroid of HT patients.     

Human lymphoid target cells for the cytokine-inducing seleno-organic compounds.

Several seleno-organic compounds including ebselen are known as antiinflammatory and antioxidant agents. They also have glutathione peroxidase-like activity and are inhibitors of leukotrienes and prostaglandins. We have recently discovered that these drugs are inducers of cytokines, mainly interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) and mitogenic interleukins in human peripheral blood leukocytes (PBL) but not in the mouse or rat lymphoid cells. We described a production of IFN-gamma and TNF-alpha by various subsets of PBL stimulated with 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) or bis [2-(N-phenyl-carbamoyl)]phenyl diselenide. IFN-gamma was produced mainly by E-rosette positive lymphocytes. However, the presence of monocytes was required for the optimal production of IFN-gamma. Also soluble mediators released by monocytes enhanced IFN-gamma synthesis. On the other hand, TNF-alpha was produced mainly by the adherent monocytes. Its synthesis was enhanced by the addition of T or B lymphocytes or conditioned medium from the culture of the stimulated lymphocytes. The relative concentrations of the subsets of lymphocytes or monocytes was important for the maximum production of both IFN-gamma and TNF-alpha. High concentration of lymphocytes inhibited the cytokine production.     

Activated T-lymphocytes induce growth inhibition and prostaglandin E2 release from syngeneic glomerular mesangial cells.

The concept of an active role of T lymphocytes in the initiation and development of autoimmune glomerulonephritis has gradually evolved from recent investigations. In the present study we started in a murine coculture system to directly examine cellular interactions of intrinsic glomerular mesangial cells (MC) and syngeneic T lymphocytes. Lymph node lymphocytes and, moreover, cloned T helper cells specifically affected syngeneic proliferating MC, causing growth inhibition and prostaglandin E2 (PGE2) release. The T cell specificity of mesangial cell responses was confirmed by demonstrating (i) that MC cocultured with other cell types showed no reaction and (ii) that additional activation of T lymphocytes by IL-2 or concanavalin A significantly enhanced the MC responses. Subsequently, we confirmed the presence of T cell factors in the supernatants responsible for the observed effects: interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF). Experiments with combinations of recombinant mouse IFN-gamma and human lymphotoxin or TNF-alpha showed that these lymphokines could substitute for the direct T lymphocyte effects causing a synergistic growth inhibition and PGE2 release from mouse MC. The observed lymphokine activities were not due to mesangiolysis as shown by neutral red uptake of MC. Pointing to the essential role of T helper cell-specific products, IFN-gamma antibodies abolished both the IFN-gamma and the combined IFN-gamma/TNF-alpha effect. Thus, our investigations with syngeneic MC-lymphocyte cocultures demonstrated that cultured MC specifically responded to T lymphocytes and their products.     

Relative increase of inflammatory CD4+ T cells in the cerebrospinal fluid of multiple sclerosis patients and control individuals.

Of three patients with multiple sclerosis (MS) and two non-MS individuals a large number of CD4+ T cell clones was obtained from the cerebrospinal fluid and peripheral blood by direct limiting dilution. The CD4+ T cell clones from cerebrospinal fluid and peripheral blood lymphocytes were compared for their cytotoxic activity and lymphokine production. Cytotoxic capacity of cloned T cells was analysed with the use of anti-CD3 antibodies and target cells bearing Fc receptors for murine IgG. Recently, we demonstrated the existence of two different subsets of human CD4+ T cell clones by phenotypic and functional criteria. One type of CD4+ T cell with anti-CD3 mediated cytotoxic activity, in analogy with murine studies, is the inflammatory or TH1 subtype, the main producer of interleukin (IL-2), interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF)-alpha, -beta, whereas the other type of CD4+ T cell clone lacked anti-CD3 mediated cytotoxicity and produced minimal amounts of IL-2 concomitant with reduced levels of IFN-gamma and TNF-alpha, -beta. The present study demonstrates that among three MS patients, relatively more inflammatory CD4+ T cell clones with cytotoxic activity and IFN-gamma and TNF-alpha, -beta production were derived from the cerebrospinal fluid as compared with peripheral blood lymphocytes. Also among control individuals more inflammatory CD4+ T cell clones could be obtained from the cerebrospinal fluid as from the peripheral blood. The enrichment of inflammatory CD4+ T cells, therefore, appears to be physiological rather than associated with the disease.     

Molecular specificity and functional properties of autoreactive T-cell response in human gastric autoimmunity

Human autoimmune gastritis (AIG) is a chronic inflammatory disorder of the gastric corpus. We have defined the antigen repertoire and the functional properties of in vivo activated CD4+ T cells derived from the gastric mucosa of patients with AIG. A remarkable proportion of the CD4+ T cell clones proliferated in response to H+,K+-ATPase. Six epitopes identified in the alpha chain, and 5 in the beta chain, of gastric K+,K+-ATPase were recognized by autoreactive gastric T cell clones. The majority of the autoreactive T cell clones secreted IFN-gamma and showed a T helper 1 (Th1) profile. All clones produced TNF-alpha,provided help for B cell immunoglobulin production, expressed perforin-mediated cytotoxicity, and most induced Fas-Fas ligand-mediated apoptosis. Data suggest that activation of gastric H+,K+-ATPase-specific Th1 T cells is crucial in the pathogenesis of human gastric autoimmunity and atrophy.     

T cell hyperreactivity in obese strain (OS) chickens. Different mechanisms operative in spleen and peripheral blood lymphocyte activation

The enhanced T cell reactivity (ConA hyperresponsiveness and IL 2 hypersecretion) of spleen lymphocytes of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis has recently been shown to be due to a defect in macrophage-derived non-specific suppressor factors that regulate IL 2 secretion and IL 2-promoted T lymphoblast proliferation in normal healthy animals. In the present study, we present several lines of evidence that the increased T cell response of peripheral blood lymphocytes (PBL) of OS chickens is due to mechanisms entirely different from the described dysregulation of splenic T cells: 1) In contrast to the splenic macrophages, peripheral blood monocytes of OS animals are not deficient in the production of IL 2 antagonistic activity (IAA); 2) therefore, cocultivation of PBL from OS and Normal White Leghorn (NWL) chickens in communicating culture chambers did not abrogate the difference in Con A response as previously observed with spleen lymphocytes. 3) Immunofluorescence with a monoclonal antibody (INN CH 16) against the chicken IL 2 receptor revealed enhanced numbers of mitogen activatable T cells in OS PBL but not OS spleen lymphocytes. 4) After prolonged Con A stimulation of PBL, OS and NWL lymphoblasts did not differ from each other in functional aspects. In contrast to this, Con A lymphoblasts from OS spleens exhibited enhanced staining with INN CH 16 in parallel with an increased proliferative response to IL 2. Thus, the primary T cell dysfunction involved in the development of autoimmune disease in OS chickens is the result of at least two separate regulatory defects.     

T细胞受体Vβ基因在自身免疫性甲状腺病病变组织中的表达及意义

目的研究国人Graves病、桥本甲状腺炎甲状腺内浸润T淋巴细胞的T细胞受体(TCR)Vβ基因家族的利用,发现优势利用基因,为阐明自身免疫性甲状腺病(AITD)的T细胞克隆的分布模式及防治提供依据.方法穿刺或手术取得12例Graves病、15例桥本甲状腺炎病人的甲状腺组织,提取RNA.抽取5例Graves病、5例桥本甲状腺炎和7例正常人之外周静脉血,分离外周血淋巴细胞(PBL),提取RNA.以24个Vβ基因家族特异的寡核苷酸为上游引物,以一个Cβ特异的寡核苷酸为下游引物,进行逆转录-聚合酶链反应,比较各个Vβ基因家族的表达.结果Graves病及桥本甲状腺炎患者甲状腺内TCRVβ基因家族的平均表达阳性数分别为(5.3±1.2)个,(13.4±3.0)个;而且Vβ3、Vβ5和Vβ8的表达在Graves病更常见.以上两组病人及正常对照PBL之TCRVβ基因家族的平均表达分别为(23.0±1.0)个,(22.2±1.3)个和(22.4±1.7)个.结论Graves病甲状腺内淋巴细胞的TCRVβ基因显示明显的限制性利用,某些Vβ家族的使用率更高,提示寡克隆扩增的甲状腺抗原特异性T细胞可能与Graves病的发病有关,这可能有重要的治疗意义.相反,桥本甲状腺炎病变内TCRVβ利用的限制性较差或无限制性,可能与随疾病进展,非特异性免疫机制的介入有关.     

CD4+ T-cell clones from autoimmune thyroid tissue cannot be classified according to their lymphokine production

In order to define whether CD4+ T cells from autoimmune and non-autoimmune thyroid tissue could be classified according to their mediator production, lymphokine production was studied in 63 thyroid-derived CD4+ T-cell clones from four patients with Graves' disease, one with Hashimoto's thyroiditis, and one with non-toxic goitre (9-12 clones per patient). The production of interleukin 2 (IL-2), gamma interferon (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), lymphotoxin (LT), interleukin 6 (IL-6) and transforming growth factor beta (TGF-beta) was assessed at the mRNA level by slot-blot analysis in unstimulated clones as well as after activation with monoclonal anti-CD3 (OKT3) and IL-2. No lymphokine production was found in unstimulated clones, whereas 56% of the clones produced all six lymphokines simultaneously after stimulation. In the remaining 44% usually not more than one lymphokine was missing from the complete panel. Lymphokine mRNA concentrations varied between different clones and different patients, but, in this small sample, not between the diseases from which the clones were originated. There was a significant correlation between IL-6, LT, and IL-2 mRNA levels and T-cell helper function, which was estimated by the stimulation of thyroid microsomal autoantibody production using autologous peripheral B cells. TGF-beta and IFN-gamma mRNA expression was unrelated to T-cell help. The results demonstrate that intrathyroid T cells from autoimmune and non-autoimmune thyroid disorders cannot be classified according to their lymphokine production, unlike some results with in vitro-induced mouse T-cell clones, where two populations, Th1 and Th2, have been described. Single T cells are capable of producing a whole panel of lymphokines and thus are capable of triggering a multitude of different processes.     

Decreasing TNF-alpha results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced in DBA/1 mice by adoptive transfer of mouse thyroglobulin (MTg)-primed spleen cells. TNF-alpha is an important proinflammatory cytokine and apoptotic molecule involved in many autoimmune diseases. To study its role in G-EAT, anti-TNF-alpha mAb was given to recipient mice. Disease severity was comparable between mice with or without anti-TNF-alpha treatment at days 19-21, the time of maximal severity of G-EAT, suggesting TNF-alpha is not essential for development of thyroid inflammation. However, thyroid lesions resolved at day 48 in anti-TNF-alpha-treated mice, while thyroids of rat Ig-treated controls had fibrosis. These results suggested that reducing TNF-alpha contributed to resolution of inflammation and inhibited fibrosis. Gene and protein expression of inflammatory molecules was examined by RT-PCR and immunostaining, and apoptosis was detected using TUNEL staining and an apoptosis kit. Thyroids of anti-TNF-alpha-treated controls had reduced proinflammatory and profibrotic molecules, e.g., IFN-gamma, IL-1beta, IL-17, inducible NOS and MCP-1, at day 19 compared with thyroids of rat Ig-treated mice. There were more apoptotic thyrocytes in rat Ig-treated controls than in anti-TNF-alpha-treated mice. The site of expression of the anti-apoptotic molecule FLIP also differed between rat Ig-treated and anti-TNF-alpha-treated mice. FLIP was predominantly expressed by inflammatory cells of rat Ig-treated mice and by thyrocytes of anti-TNF-alpha-treated mice. These results suggest that anti-TNF-alpha may regulate expression of proinflammatory cytokines and apoptosis in thyroids, resulting in less inflammation, earlier resolution, and reduced fibrosis.     

Chemokines modulate experimental autoimmune thyroiditis through attraction of autoreactive or regulatory T cells

A critical event in the pathogenesis of experimental autoimmune thyroiditis (EAT) is the entry of thyroid-specific T lymphocytes into the thyroid gland. To investigate the role of soluble mediators in that infiltration, we have assayed the expression of various chemokines in diseased thyroid glands and in cytokine-treated cultures of normal thyroid epithelial cells. MCP-1 (monocyte chemotactic protein-1) and RANTES are produced during EAT and induced in vitro by IFN-gamma, IL-10, TNF-alpha, and IL-1beta. In vitro chemotaxis experiments using immune lymph node (LN) cells showed that RANTES attracted mTg-specific responder LN cells, whereas MCP-1 attracted mTg-specific CD4(+), CD25(+) regulator cells that secreted IL-10. The in vivo transfer of LN T cells attracted in vitro either by RANTES or by MCP-1 confirmed their opposite effects on the course of EAT.     

Graves' disease: phenotypic and functional analysis at the clonal level of the T-cell repertoire in peripheral blood and in thyroid

We have investigated at the clonal level the repertoire of intrathyroid and peripheral T lymphocytes in three patients with Graves' disease using a high efficiency cloning technique. Clonal efficiencies ranged from 10 to 31% for intrathyroid, and from 19 to 100% for peripheral T cells. In Graves' disease the phenotypic analysis showed similar percentages of CD3+ CD4+ CD8- and CD3+ CD4- CD8+ clones in thyroid infiltrates and peripheral blood. The functional evaluation showed similar or lower proportions of cytolytic clones in thyroid infiltrates with respect to peripheral blood. Furthermore, the proportions of intrathyroid and peripheral T-cell clones capable of releasing interleukin-2 and/or gamma-interferon in response to mitogen stimulation were similar. Finally, 44% of intrathyroid clones were neither cytolytic nor able to release IL-2 and gamma-interferon. These results are strikingly different from those obtained in Hashimoto's thyroiditis, where the large majority of intrathyroid T-cell clones are cytolytic and the proportions of clones able to release gamma-IFN are remarkably increased in thyroid infiltrates when compared to those obtained from peripheral blood. Taken together, these data suggest a different role for T lymphocytes in the pathogenesis of the two major human autoimmune thyroid diseases.     

CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients.

The pattern of cytokine production in T cell clones derived from bronchoalveolar lavages (BAL) of active pulmonary tuberculosis (TB) patients was analyzed in clones obtained by limiting dilution procedures which expand with high efficiency either total T lymphocytes, independently of their antigen-recognition specificity, or Mycobacterium tuberculosis-specific T cells. BAL-derived clones, representative of CD4(+) cells from five patients with active TB, produced significantly higher amounts of IFN-gamma than BAL-derived CD4(+) clones from three inactive TB donors or four controls (with unrelated, noninfectious pathology). Average IL-4 and IL-10 production did not differ significantly in the three groups. Although these data suggest a predominant Th1 response to M. tuberculosis infection in the lungs, the majority of BAL-derived CD4(+) clones produced both IFN-gamma and IL-10 and the percentage of clones with this pattern of cytokine production was significantly higher in clones derived from BAL of active TB patients than from controls. Only rare clones derived from peripheral blood (PB)-derived CD45RO(+) CD4(+) T cells of both patients (nine cases) and controls (four cases) produced both IFN-gamma and IL-10; instead, the IL-10-producing clones derived from PB T cells most often also produced IL-4, displaying a typical Th2 phenotype. Higher average amounts of IFN-gamma and IL-10 were produced by BAL-derived CD8(+) clones of four active TB patients than of four controls, although the frequency of CD8(+) clones producing both IFN-gamma and IL-10 was lower than that of CD4(+) clones. The M. tuberculosis-specific BAL-derived T cell clones from three active TB patients were almost exclusively CD4(+) and produced consistently high levels of IFN-gamma often in association with IL-10, but very rarely with IL-4. Unlike the BAL-derived clones, the M. tuberculosis-specific clones derived from PB CD45RO(+) CD4(+) T cells of three different active TB patients and two healthy donors showed large individual variability in cytokine production as well as in the proportion of CD4(+), CD8(+), or TCR gamma/delta(+) clones. These results indicate the predominance of CD4(+) T cells producing both the proinflammatory cytokine IFN-gamma and the anti-inflammatory cytokine IL-10 in BAL of patients with active TB.     

Expression of CD40 and apoptosis related molecules in autoimmune thyroid diseases.

Apoptosis is responsible for the loss of thyrocytes in autoimmune thyroiditis. Recent investigations into the pathogenesis of apoptosis have revealed that the important roles of suicide molecules expression on both thyrocytes and cytotoxic T-lymphocytes. To study the mechanism of thyrocyte loss in various forms of thyroiditis, we evaluated in situ expression patterns of CD40, Fas, and Fas-L on thyrocytes and infiltrating inflammatory cells by immunohistochemical staining of thyroid samples obtained from 49 patients (Graves' disease, n=10: Hashimoto's thyroiditis, n=14; nonspecific lymphocytic thyroiditis, n=11; subacute granulomatous thyroiditis, n=11; normal, n=3). The role of cytotoxic T-lymphocytes was also evaluated by analyzing the expression of granzyme B along with their phenotypic characteristics. CD40 was not expressed on thyrocytes of normal controls while they showed a diffuse expression of Fas and a scattered focal expression of Fas-L. The plump thyrocytes proximal to the inflammatory infiltrates showed more intense expressions of these three molecules in various forms of thyroiditis and a close correlation was found between CD40 and Fas-L expression on thyrocytes. Unlike Fas, which was expressed on infiltrating lymphocytes in all groups, Fas-L was not expressed on infiltrating lymphocytes, except those in subacute granulomatous thyroiditis. Granzyme B expressing activated cytotoxic T-lymphocytes occupied a negligible proportion of CD8+ T-lymphocytes in various forms of thyroiditis, and no difference was found in terms of their proportions according to the type of thyroiditis. These results show the acquisition of CD40, Fas and Fas-L molecules on thyrocytes proximal to inflammatory cell aggregates and the negligible expression of granzyme B and Fas-L on the infiltrating lymphocytes, and suggest that Fas and Fas-L mediated apoptosis of thyrocytes (fratricide) may be more important than T cell-mediated cytotoxicity in various forms of thyroiditis.     

Enhanced production of gamma-interferon by thyroid-derived T cell clones from patients with Hashimoto''s thyroiditis.

T lymphocytes from thyroid infiltrate and peripheral blood (PB) of four patients with Hashimoto's thyroiditis (HT) were analysed at clonal level for their ability to secrete interleukin 2 (IL-2) and gamma-interferon (gamma-IFN). As controls, T cell clones from PB of four normal donors and from spleen of two trauma victims were used. While no abnormality was found in the capacity to produce IL-2, the proportion of gamma-IFN-producing (IFN-P) T cell clones derived from HT infiltrates was significantly higher (P less than 0.0005) than that of IFN-P clones derived from normal or patient PB. Most of CD4+ and CD8+ IFN-P clones from thyroid infiltrates, as well as a proportion of CD4+ PB-derived clones of patients with HT, released higher amounts of gamma-IFN than control clones. A relationship could be demonstrated between high gamma-IFN production and natural killer (NK) activity in T cell clones from thyroid and PB of HT patients. In fact, the percentage of IFN-P clones with NK potential (NK+) was remarkably higher (P less than 0.0005) in thyroid infiltrates than in normal spleen or PB. The proportion of IFN-P NK+ clones from patient PB was also significantly increased (P less than 0.02) but, unlike thyroid-derived clones in which the majority of IFN-P NK+ clones were CD8+, most PB-derived IFN-P NK+ clones from the same patients expressed the CD4+ phenotype. Almost all thyroid NK+ clones could be triggered to produce more gamma-IFN, while gamma-IFN synthesis by NK-negative thyroid clones was comparable to that of control clones. In view of the multiple effects ascribed to gamma-IFN in the cascade of events leading to immune responses, the abnormal potential to gamma-IFN secretion shown by intrathyroidal T lymphocytes may be of importance in the pathogenesis of autoimmune thyroiditis.     

Cytokines, thyroid autoantibody synthesis and thyroid cell survival in culture

In autoimmune thyroid disease lymphoid cells infiltrating the thyroid gland occur in conspicuous aggregates or as a diffusely distributed population invading the thyroid follicles. Consequently cytokines secreted by activated T cells or macrophages could influence neighbouring thyroid cells as well as other lymphocytes. We have investigated this possibility using recombinant cytokines. Thyroid cell survival was assessed in terms of mitochondrial dehydrogenase activity in monolayers exposed to tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 (IL-1 alpha and beta) and interleukin-2 (IL-2) in the presence or absence of thyroid-stimulating hormone (TSH). Neither TNF-alpha nor IL-2 affected thyroid cell survival, IFN-gamma was usually inhibitory and IL-1 alpha slightly enhanced cell survival in some experiments. However, the effects were small and variable and were not enhanced by potentially synergistic combinations of cytokines, longer periods of exposure, or different culture conditions. In contrast, IFN-gamma, IL-2 and TNF-alpha inhibited the ability of thyroid lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis to synthesize autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg). Comparison of lymphoid populations isolated by digestion and/or mechanical disaggregation indicated that a population of activated B cells, plasma cells and T cells, intimately associated with thyroid cells since they could only be extracted by digestion, was influenced by cytokines. Our studies suggest that in addition to its well-recognized ability to induce MHC class II antigens on thyroid cells, IFN-gamma may inhibit thyroid cell proliferation and TNF-alpha, IFN-gamma and IL-2 may down-regulate thyroid autoantibody synthesis.     

Peripheral blood lymphocytes of patients with common variable immunodeficiency (CVI) produce reduced levels of interleukin-4, interleukin-2 and interferon-gamma, but proliferate normally upon activation by mitogens.

Peripheral blood lymphocytes (PBL) of 11 patients with CVI produced reduced levels of interleukin-4 (IL-4) upon activation by mitogens as compared with those secreted by PBL of healthy donors. The interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production by PBL of a series of 15 patients with CVI was also reduced. Decreased levels of IL-4 or IL-2 and IFN-gamma production were not only observed after activation by phytohaemagglutinin (PHA) at concentrations of 10 and 1 micrograms/ml, but also after activation by concanavalin A (Con A, 10 micrograms/ml). Longitudinal studies indicated that this defective lymphokine production was consistent upon testing periods up to 5 months. No correlation between reduced IL-4, IL-2 or IFN-gamma production was observed. PBL of patients that produced reduced levels of one lymphokine generally secreted normal levels of the other two lymphokines. Despite the reduced synthesis of the T cell growth factors IL-2 and IL-4, the proliferative responses of the PBL of the patients were in the normal range, which is compatible with the finding that IL-2 and IL-4 have synergistic effects on lymphocyte proliferation, particularly when one of these lymphokines is present at suboptimal concentrations. Since IL-2, IL-4 and IFN-gamma can act as B cell growth and differentiation factors, our data suggest that the reduced synthesis of these lymphokines may contribute to the deficient immunoglobulin production in patients with CVI.     

Tumour necrosis factor-alpha synthesis by cerebrospinal-fluid-derived T cell clones from patients with multiple sclerosis.

T cell clones derived from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) were analysed for their ability to produce interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2) and interleukin-4 (IL-4). The CSF-T clones were compared for their ability to produce cytokines with autologous peripheral T clones and with liver-infiltrating T cell clones from patients with chronic active hepatitis. IL-4 production was also compared with that by peripheral T clones derived from atopic patients. All the CSF-T clones (both CD4+ and CD8+) produced large amounts of IFN-gamma and particularly of TNF-alpha. These cytokines were synthesized in significantly larger amounts by CSF T clones than by reference clones. Moreover, they were capable of secreting IL-2, but not IL-4. We conclude that the CSF-CD4+ T clones could constitute a subset with functional properties similar to those of T helper 1 (Th1)inflammatory cells of the mouse; and that the large amounts of TNF produced by CSF T cell clones strongly suggest a significant role for this cytokine in MS immunopathogenesis.