Neurofilament is an autoantigenic determinant in myasthenia gravis.

Intratumorous expression of a 153-kd protein (p153), which contains an acetylcholine receptor-like epitope, is the only tumor marker described to date that significantly associates with thymoma in paraneoplastic myasthenia gravis (MG). Here, we report that p153 is identical to the midsize neurofilament, as verified by immunohistochemistry, immunofluorescence, and western blot analysis. Furthermore, the acetylcholine receptor-like epitope of the midsize neurofilament (NF-M) was identified by peptide epitope mapping. We also show, using T-cell proliferation assays, a significantly increased response of intratumorous T cells to a recombinant midsize neurofilament fragment in thymoma patients with MG compared with MG patients with thymic follicular hyperplasia or thymoma patients without MG. The T cells of thymic follicular hyperplasia and thymoma patients without MG seem to be unresponsive to NF-M. In contrast, we found increased T-cell responses to recombinant acetylcholine receptor fragments in MG patients in general compared with non-MG patients. Increased T-cell responses to NF-M in patients with paraneoplastic MG might be the result of an abnormal positive selection of immature T cells within thymomas, caused by the expression of NF-M in neoplastic thymic epithelial cells. Our results offer further evidence that NF-M expression in thymomas is an autoantigenic determinant in MG.     

Increased circulation of T lymphocytes bearing surface thymosin alpha 1 in patients with myasthenia gravis: effect of thymectomy

We studied the interaction of the thymic hormone thymosin alpha 1 with peripheral blood B and T lymphocytes in patients with myasthenia gravis (MG), using antibodies against thymosin alpha 1 in an immunofluorescence technique. Eleven of 16 patients with symptomatic MG had an increased number of T lymphocytes bearing surface thymosin alpha 1 (T alpha 1); 5 patients with asymptomatic disease had normal levels of T alpha 1. In six young adults with symptomatic MG who subsequently responded to thymectomy, the number of T alpha 1 cells returned to normal 1 month after thymectomy. Because levels of T alpha 1 correlated with symptoms and thymosin alpha 1 specifically recruits helper T cells, our findings suggest that T alpha 1 may play an immunoregulatory role in the pathogenesis of MG. Determination of T alpha 1 levels may prove to be helpful in assessing residual thymic activity after thymectomy.     

胸腺切除对重症肌无力患者T淋巴细胞亚型的影响

目的：观察胸腺切除(Tx)术对重症肌无力(MG)病人的临床疗效及对T淋巴细胞亚型的影响。方法：用许氏评分法观察30例伴胸腺增生或胸腺瘤的MG患者的病情严重程度及Tx术后2个月的临床疗效;采用直接免疫荧光染色和流式细胞仪技术测定60名志愿健康者和30例伴胸腺增生或胸腺瘤的MG患者Tx术前及术后2个月T淋巴细胞亚型的变化。结果：伴胸腺增生或胸腺瘤的MG病人Tx术前外周血中CD4＋T淋巴细胞的百分率较正常人显著增多(P＜0．01),CD8＋T淋巴细胞的百分率较正常人显著减少(P＜0．01),CD4＋/CD8＋T细胞的比例明显增高(P＜0．01)。伴胸腺增生MG病人Tx术后随着临床症状的改善,CD8＋T淋巴细胞的百分率较术前显著升高(P＜0．05),CD4＋/CD8＋T细胞的比例较术前显著下降(P＜0．05)。伴胸腺瘤MG病人Tx术后随着临床症状的改善,CD4+T淋巴细胞的百分率较术前显著下降(P＜0．05),CD4＋/CD8＋T细胞的比例较术前显著下降(P＜0．05)。结论：重症肌无力患者T淋巴细胞亚型的测定既可以为MG免疫病理学的发病机理的研究提供实验依据,也能为Tx治疗MG提供一个客观的实验室指标,为判断疾病的转归提供实验依据。     

Thymic abnormalities in patients with myasthenia gravis

Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.     

Altered expression of Th1-type chemokine receptor CXCR3 on CD4+ T cells in myasthenia gravis patients

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.     

Studies on the thymus from patients with multiple sclerosis and myasthenia gravis

The thymus glands which were excised for therapy (myasthenia gravis; MG) or experimental therapy (multiple sclerosis; MS) were compared to thymic biopsies from patients undergoing cardiac surgery. There was no difference in the weight or total cells of MG and MS thymuses or of the cell density of control, of MG or MS glands. Only 1 of 25 MS thymuses was hyperplastic, as were 2 of 9 of the MG thymuses and none of the controls. Several differences were noted for thymic lymphocyte proliferation to mitogenes in MS patients and to antigens in MS and MG patients. Ms thymuses had a decreased stimulation index to antithymocyte globulin and to optimal concentrations of pokeweed mitogen. Myasthenia gravis thymuses showed a significantly increased stimulation of myelin basic protein. The % B and % T cell counts were normal for the MS patients. No differences were noted in the incidence of mixed lymphocyte reactions between thymocytes and peripheral lymphocytes in the three groups. Fresh thymic lymphocytes did not suppress concanavalin A stimulated lymphocyte proliferation. It is not known if the differences in lymphocyte proliferation between MS, MG, and control thymuses represent a primary or secondary change.     

Thymic lymphocyte subpopulations in myasthenia gravis

We compared the percentages of thymic mononuclear cells (TMC) that bind monoclonal antibodies to T-cell subpopulations in patients with myasthenia gravis (MG) and non-MG patients undergoing cardiac surgery (CS). There were no significant differences in percentages of OKT3+, OKT4+, OKT6+, or OKT8+ cells or the OKT4:OKT8 ratio. There was an increase in the percentage of Ia+ (immune response gene-associated antigen) TMC in MG compared with CS but no significant differences in B cells or phagocytic cells. The Ia+ cells could be abnormal B cells, activated T cells, or thymic dendritic cells.     

Evidence of enhanced recombinant interleukin-2 sensitivity in thymic lymphocytes from patients with myasthenia gravis: possible role in autoimmune pathogenesis

We evaluated the activation state of thymic lymphocytes in patients with myasthenia gravis (MG) by cytofluorographic analysis of CD25 expression and by testing their sensitivity to recombinant interleukin-2 (rIL-2) in the absence of any known previous stimulation. We detected no phenotypic signs of activation in fresh MG thymic lymphocyte suspensions, while functional signs of activation were reflected in a significantly higher sensitivity to rIL-2 in MG patients than in controls. The responses to rIL-2 were time- and dose-dependent, were inhibited by a blocking anti-IL-2 receptor antibody, and were associated with an increase in CD25+ T cells in both patients and controls. The T cells with functional signs of previous activation may represent autoreactive cells involved in the autoimmune process and confirm thymus gland hyperactivity in MG. These cells could result from primary autosensitization against the thymic acetylcholine receptor (AChR)-like molecule or from altered migration of peripheral activated cells into an abnormal thymic environment. Our results also provide a clue for understanding the effect of thymectomy in myasthenia gravis.     

Changes in lymphocyte subsets in myasthenia gravis: correlation with level of antibodies to acetylcholine receptor and age of patient.

We report a detailed analysis of the subsets of lymphocytes in patients with myasthenia gravis (MG). There was a slight, nonsignificant increase in the level of CD5+ B lymphocytes among MG patients as compared with normal controls. The proportion of CD5+ T cells in MG was similar to that in controls. However, whereas age had no effect on the level of these cells in normal individuals, a significant age-related decrease of these cells was present in MG patients. The proportion of double-positive CD4+CD8+ T cells was significantly increased in MG. The level of the CD29+CD4+ (helper-inducer) subset was significantly higher in MG patients than in controls. There was no correlation between the titer of autoantibodies to acetylcholine receptor and the level of either CD29+CD4+ T cells or CD5+ B cells among MG patients. The only T-cell subset that correlated with the autoantibody titer was the CD45RA+CD4+ (suppressor-inducer) subset of CD4+ T cells.     

Expression of OX40 and OX40 ligand (gp34) in the normal and myasthenic thymus

OBJECTIVES: To examine the expression of OX40, an activated memory T-cell marker, and its ligand (OX40L), a set of molecules for T-cell-B-cell interaction, and other lymphocyte activation markers in the thymuses of myasthenia gravis (MG) and controls. MATERIAL AND METHODS: We studied the expression of OX40, OX40L, IL-2Ralpha and HLA-DR in the thymic tissues of MG and controls using immunocytochemistry and flowcytometry. RESULTS: In both hyperplastic thymus of MG and control thymus, OX40+ cells were scattered mainly in the medulla with much fewer OX40L+ cells being distributed in the corticomedullary junctions. IL-2Ralpha and HLA-DR were expressed in the medulla at higher frequencies as compared with OX40 in controls as well as MG. In contrast, the numbers of OX40+ cells around the germinal centers (GC) were significantly greater than those of control thymuses, and some mononuclear cells in GC were OX40L+. A considerable number of OX40+ cells were seen in the thymic tissues adjacent to thymomas. OX40+ cells were CD4+ CD8- or CD4+ CD8+ and were mostly HLA-DR-. (The coexpression of OX40 and IL-2Ralpha on activated CD4+ T cells was previously reported.) CONCLUSION: OX40, expressed in a fraction of activated CD4+ T cells, may be upregulated in thymic tissues adjacent to GC and thymoma in MG, and OX40 may interact with OX40L in GC to enhance anti-acetylcholine receptor antibody production in MG.     

重症肌无力患者外周血T淋巴细胞亚群凋亡的研究

目的探讨外周血T淋巴细胞亚群凋亡在重症肌无力(MG)免疫发病机制中的作用及临床意义。方法采用流式细胞术结合免疫荧光抗体法测定了45例MG患者和40例正常对照组外周血CD4~ T淋巴细胞、CD8~ T淋巴细胞百分数及其凋亡状况,并对24例MG患者在应用糖皮质激素治疗后外周血T淋巴细胞亚群凋亡状况进行了观察。结果MG患者组外周血CD8~ T淋巴细胞百分率较正常对照组明显降低,CD4~ /CD8~ 比值较正常对照组明显升高：MG患者组外周血CD4~ T淋巴细胞凋亡程度较正常对照组明显降低；MG患者外周血CD4~ T淋巴细胞凋亡程度与MG类型、预后密切相关：应用糖皮质激素治疗后MG患者外周血CD4~ T淋巴细胞凋亡程度明显增强。结论MG患者存在T淋巴细胞亚群的分布异常及CD4~ T淋巴细胞凋亡功能障碍,其凋亡程度可能与MG类型、预后密切相关,糖皮质激素对MG患者外周血CD4~ T淋巴细胞凋亡缺陷具有纠正作用。     

Expression of Immune Molecules CD25 and CXCL13 Correlated with Clinical Severity of Myasthenia Gravis

Differential expressions of immune molecules have been shown in the thymi with pathological results, including myasthenia gravis (MG). CD25 is an activation marker expressed on T cells. CXCL13 mediates the homing and motility of B cells in secondary lymphoid tissues. Herein, we investigated the expressions of CD25 and CXCL13 in the thymi of thymic hyperplasia patients with MG or with non-MG. A total of 34 thymic hyperplasia patients with MG (20 generalized MG (GMG) and 14 ocular MG (OMG) and six thymic hyperplasia patients without MG were enrolled and analyzed using immunohistochemical staining and real-time polymerase chain reaction for CD25 and CXCL13. Our study demonstrated a higher expression of both CD25 and CXCL13 in hyperplastic thymi with OMG or GMG compared to those with non-MG. According to the immunohistochemical results, we observed that CD25 expression was significantly lower in atrophic thymi and non-MG hyperplastic thymi, compared with that in infant thymi (P?=?0.002 and 0.005, respectively). In contrast to CD25 expression, we did not observe differential expression of CXCL13 among three control groups. And a similar CD25 mRNA expression was found in real-time polymerase chain reaction (PCR) results. We observed that both hyperplastic thymi with OMG or GMG expressed significantly higher levels of CD25 than those with non-MG (P?=?0.007 and 0.001, respectively). And an increase of CD25 expression was observed in hyperplastic thymi with GMG compared to those with OMG (P?=?0.030). Similarly, CXCL13 expression was significantly higher in hyperplastic thymi with GMG or with OMG than those with non-MG (P?=?0.001 and 0.050, respectively). No significant CXCL13 expression difference was found between hyperplastic thymi with GMG and those with OMG (P?>?0.05). The real-time PCR results showed a similar tendency of CD25 mRNA expression among the thymi of non-MG, OMG, and GMG patients, but the difference did not reach significance (P?>?0.05). An obvious increased expression of CXCL13 was found in hyperplastic thymi with GMG patients, compared to those with non-MG and OMG patients (P?=?0.003 and 0.071, respectively). There was no difference found between hyperplastic thymi with non-MG and with OMG. Regression analysis showed a positive correlation between thymic CD25 level and MG symptom severity (F?=?28.240; P?=?0.000, r?=?0.523). Similarly, a positive correlation was found between thymic CXCL13 expression and MG disease severity (F?=?36.093; P?=?0.000, r?=?0.671). Taken together, our findings suggest CD25 and CXCL13 participate in the pathogenesis of MG and may influence the clinical symptoms of MG.     

重症肌无力胸腺单个核细胞白细胞介素-2、白细胞介素-10及其mRNA水平的变化

目的　研究重症肌无力 ( myasthenia gravis,MG)患者胸腺是否存在辅助性 T细胞 ( Th)亚群的免疫活性紊乱。方法　利用亲和层析法自人腓肠肌纯化获得乙酰胆碱受体 ( ACh R)并进行了鉴定 ,然后用其作为特异性抗原 ,经体外培养刺激 5例 MG患者胸腺和外周血单个核细胞 ,酶联免疫吸附分析 ( ELISA)法检测上清液中白细胞介素 -2 ( IL-2 )、白细胞介素 -1 0 ( IL-1 0 )水平 ,狭缝印迹杂交法检测 MG胸腺及外周血 IL-1 0 m RNA的表达。结果　MG胸腺和外周血经 ACh R刺激后 ,其上清液 IL-2水平略高于对照组 ( P>0 .0 5 ) ,经 ELISA法和狭缝印迹杂交法发现 MG外周血 IL-1 0及其 m RNA表达水平均略高于对照组 ( P>0 .0 5 ) ,胸腺则明显高于对照组( P<0 .0 5 )。结论　 MG发病过程中 IL-1 0的异常增高可能发生于转录或转录以上水平 ,其异常表达的机制有待于进一步研究。     

Antibodies to thymic epithelial cells in myasthenia gravis.

The presence of anti-thymus antibodies was investigated in the serum of 36 patients with myasthenia gravis (MG). Using an immunofluorescence technique on frozen thymic sections, we found 45% of patients sera reacting with normal or MG thymuses. Staining was confined to subcapsular and medullary keratin-positive epithelial cells. Thirty-five out of 36 sera from healthy controls and all 15 sera from patients presenting another autoimmune disorder were negative. Antibodies to thymic epithelial cells were almost exclusively detected in patients presenting thymic hyperplasia and did not disappear after thymectomy. They were not clearly associated with antiacetylcholine receptor antibody titer, nor with disease severity. Their strong association to thymic abnormalities highlights the role of the thymus in pathogenesis of MG. The reasons for the appearance of these antibodies, the structure they recognize on thymic epithelial cells and their possible etiological role are discussed.     

Enhanced proliferative response of myasthenic thymus cells in mixed lymphocyte reaction.

To determine the functional diversity of thymic lymphoid cells in patients with myasthenia gravis (MG), we evaluated mixed lymphocyte reactions (MLR) using thymus cells in 7 MG patients and 8 controls. In the MLR, we used thymus cells as responder cells and mitomycin C-treated peripheral non-T cells as stimulator cells. In an autologous MLR test, a low proliferative response was observed in both the MG patients and controls. In an allogeneic MLR test, in which thymus cells were co-cultured with allogeneic non-T cells, the thymus cells from MG patients showed an increased proliferative response to stimulator cells, whether they were from MG patients or the controls. However, thymus cells from the controls showed a low proliferative response to any allogeneic stimulator cells. The enhanced allo-reactivity of thymus cells from MG patients thus suggests that there is an increase in the number of functionally mature T lineage cells in the MG thymus.     

重症肌无力患者血清连接素抗体与临床的关系

目的 探讨重症肌无力（MG）患者血清连接素抗体（Titin—Ab）水平与病情及胸腺异常的关系,以及其对诊断和预后判断的价值。方法 应用酶联免疫吸附法（ELISA）检测MG患者（MG组）52例、非MG（其他神经系统疾病）患者（NMG组）18例、健康对照者（NC组）50名血清中Titin—Ab水平,并对其中10例进行胸腺手术的MG患者随访。结果 MG组Titin—Ab阳性率为36．5％,NMG组和NC组均为阴性,MG组显著高于NC组和NMG组（均P〈0．01）;以MG伴胸腺瘤（MGT）组阳性率最高（83．3％）,MG伴胸腺萎缩（MGA）次之（37．5％）,胸腺正常的MG组为23．0％,MG伴胸腺增生组为阴性;Titin．Ab诊断MGT特异性高于胸腺CT（P〈0．05）。Titin—Ab阳性MG患者抗体水平与肌无力程度呈显著正相关（r=0．562,P〈0．01）;对10例不同胸腺病理类型的MG患者手术前后Titin—Ab测定显示差异具有显著性（P〈0．05）。结论 Titin—Ab阳性多见于MGT和MGA者,诊断MGT的特异性高于CT;Titin—Ab对MG的诊断、病情及预后判断均有帮助。     

Myasthenia gravis with anti-acetylcholine receptor antibody or anti-muscle specific kinase antibody

Patients with myasthenia gravis (MG) are divided into 3 groups: anti-acetylcholine receptor antibody-positive MG (AChR MG), anti-muscle specific kinase antibody-positive MG (MuSK MG), and AChR-and MuSK-negative MG (double seronegative MG; double SNMG). A recent study on the detection of low-affinity antibodies binding to AChR showed the presence of AChR antibodies in about 70% of double SNMG patients. There is accumulating evidence that double SNMG patients are similar to AChR-MG patients with respect to clinical features and thymic pathology. Since most MG patients are thought to belong to the AChR-MG or MuSK-MG group of patients, this article reviews the pathophysiology, clinical features, and treatments in these 2 groups of MG patients. The pathophysiology of AChR-MG is closely related to the abnormal thymic pathology, such as thymic hyperplasia or presence of thymoma, and thy(mo)mectomy is recommended in patients with generalized AChR-MG. On the contrary, little thymic abnormality in patients with MuSK-MG discourages thymectomy; however, MuSK-MG patients do respond to thymectomy and therefore studies to define the indications of thymectomy in MuSK-MG patients are required. The responses to cholinesterase inhibitors are poor in patients with MuSK-MG, and these patients tend to show hyperactivity to the Tensilon test, such as fasciculation of facial muscles and stuffy sensation in the throat. The adverse responses to a small dose of intravenous edrophonium chloride injection may support the clinical diagnosis of MuSK-MG. Further, only small doses of acetylcholinesterase inhibitors are administered to patients with MuSK-MG in order to avoid cholinergic hyperactivity. In general, both types of MG patients respond well to treatments with immunosuppressants, including steroids, but some patients with MuSK-MG show persistent bulbar symptoms.     

Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.     

Influence of human myasthenia gravis thymus on the differentiation of human cord blood stem cells in SCID mice

The normal thymus contributes to T lymphocytes differentiation and induction of tolerance to self-antigens. Myasthenia gravis (MG) is characterized by abnormal thymic hyperplasia. To assess the potential influence of MG-thymus on the differentiation of T lymphocytes differentiation, we used the MG-thymus transplanted severe combined immunodeficiency (SCID) mice model to evaluate the human cord blood stem cells differentiation. Thymus fragments from MG patient and human cord blood stem cells were transplanted into SCID mice successively. SCID mice were observed to develop sustained human T lymphocytes and a functional anti-tumor immune. The levels of various T cell subsets in SCID mice with MG-thymus were different from that of control group. Among that, the frequency of CD4⁺CD25⁺ T cells was significant lower in SCID mice with MG-thymus. The deficiency of CD4⁺CD25⁺ T cells seens to contribute to the pathogenesis of MG.     

Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis.

Antibodies to muscle acetylcholine receptors, to other muscle antigens, and to some cytokines are found in the majority of patients with thymic tumors (thymomas) and myasthenia gravis (MG). The role of the tumor in initiating autoimmunity, however, is unclear; in particular, it is not known whether the thymoma exports mature and long-lived T cells, which could provide help for antibody production in the periphery. Here, we quantified recently exported thymic T cells using the approach of measuring episomal DNA fragments [T-cell receptor excision circles (TRECs)], generated by T-cell receptor gene rearrangement. Compared to values in healthy individuals (n = 10) or in patients with late-onset MG (n = 8), TREC levels were significantly raised in both the CD4+ and CD8+ peripheral blood compartments of patients with thymoma and MG (n = 14, p = 0.002 and p = 0.0004 compared to healthy controls) but only in the CD8+ compartment of the three patients with thymoma without MG (p = 0.4 and p = 0.01 for CD4+ and CD8+). TREC levels decreased following thymectomy to values similar to controls but were substantially raised in patients who had developed tumor recurrence (n = 6, p = 0.04 and p = 0.02 for CD4+ and CD8+); this was associated with increased antibodies to interferon-alpha and interleukin-12 in the one case studied serially. Collectively, these results support the hypothesis that the neoplastic thymoma tissue itself can generate and export mature, long-lived T cells and that these T cells reflect the thymic pathology and are likely to be related to the associated autoimmune diseases. The results also provide a new approach for early diagnosis of thymoma recurrence.