Antinuclear antibodies in scleroderma,mixed connective tissue disease and “primary” Raynaud's phenomenon

Summary The diversity of antibodies in patients with scleroderma, mixed connective tissue disease or primary Raynaud's phenomenon could be used as a laboratory aid in the clinical diagnosis. In serum samples of 75 patients we screened for antinuclear antibodies (HEp 2 cells), anti DNA, soluble nucleoprotein and extractable nuclear antigens (Sm, rRNP, Ul-nRNP, SSA/Ro, SSB/La and Scl-70). Distinctive antinuclear antibodies pattern was identified in each group of patients. This immunologic profile is valuable for clinical diagnosis and the preferential association of certain autoantibodies with some diseases and not with others, suggest an antigen-driven stimulus for its production.     

Autoimmunity to a 28-30 kD cell membrane DNA binding protein: occurrence in selected sera from patients with SLE and mixed connective tissue disease (MCTD).

Previous experiments have established the presence of a 30-kD DNA binding protein on the surface of human leukocytes. Herein we report that selected sera from patients with systemic lupus erythematosus (SLE) and MCTD are reactive with a 28-30 kD protein on immunoblots of peripheral blood mononuclear cells (PBMC) cell membrane preparations; the reactivity is abolished by prior incubation of the blot with DNA. Antibodies eluted from the 28-30 kD strip inhibited the binding of 3H. DNA to human PBMC. An immunomatrix of 28-30 kD reactive immunoglobulins was able to extract a 29-kD DNA binding protein from a PBMC cell membrane preparation. Flow cytometry experiments confirmed the cell surface IgG reactivity of sera with T lymphocytes. Additional experiments indicated that cell surface IgG binding was not due to antibodies binding to cell surface DNA, DNA anti-DNA immune complexes reacting with a DNA binding protein, anti-histone antibodies or anti-Sm antibodies. It is hypothesized that this autoimmune response could be one component of an idiotypic network involving anti-DNA antibodies.     

Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature

Summary The paper presents an autopsy case of mixed connective tissue disease (MCTD) with pulmonary hypertension (PH) and a review of literature. A 33-year-old woman with Raynaud's phenomenon and dyspnea of one year duration was diagnosed as having MCTD on the basis of a higher titer (1:163,840) of serum antibodies to the ribonucleoprotein (RNP). Cardiac catheterization showed complicating PH, confirmed an autopsy by the findings of concentric intimal cellular proliferation and typical plexiform lesions in the small arteries and arterioles of the lung, suggesting primary PH. Fatal PH with MCTD has been reported only 6 cases in literature including our case. All were young females, with histopathological findings consistent with plexogenic pulmonary arteriopathy in 5 cases and with recurrent pulmonary thromboembolism in the other. The aetiology of PH is still unknown, but it may be due to vasoconstriction evoked by the hyper-reactivity of the vessels.     

Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies — Novel tool for diagnostics and patient follow-up

Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes.     

Histopathological study of mixed connective tissue disease from 32 autopsy cases in Japan

Abstract

In order to identify the histological specificity of newly defined connective tissue disease, we examined 32 autopsy cases of mixed connective tissue disease (MCTD) which fulfilled the disease criteria proposed by the Japanese MCTD Committee. The age of the 32 cases ranged from 19 to 79 with an average age of 43 years. The male: female ratio was 3∶29. The duration of illness was 7.9 years on average. These tendencies were not so specific compared with other connective tissue diseases. In reference to the cause of death, pulmonary hypertension associated with severe pulmonary arterial lesions such as plexogenic arteriopathy and intimal thickening was found in 16 cases, which was 34% of all total autopsy cases. Totally pulmonary diseases including pulmonary hypertension, pulmonary fibrosis and interstitial pneumonitis amounted to half of all fatal cases. Following pulmonary disease, esophageal fibrosis, sialoadenitis and cardiac involvement succeeded. Although clinical signs such as dysphagia or hypomotility did not necessarily present before death, the frequency and severity of histological changes of the esophagus cannot be ignored. Accompanied with sicca syndrome, the salivary gland showed variable stages of inflammatory changes from slight lymphocytic infiltration in the periductal region to severe parenchymatous atrophy with severe fibrosis. Autopsy cases of MCTD disclosed myocardial damage in not a few cases, which were often accompanied with fibrosis, and these features were very similar to the those of esophageal lesions. On the other hand, involvement of the kidney, skin and muscle was very slight in MCTD compared with those of systemic lupus erythematosus, progressive systemic sclerosis and polymyositis/dermatomyositis. The kidney lesion was characterized by membranous glomerulonephritis. Skin continued to be scleroedematous in spite of long term illness. Muscle showed slight lymphocytic infiltration around small vessels and interstitium. In addition to serological and clinical features, histopathological study revealed specific features of MCTD different from other connective tissue diseases. In treatment and follow-up of the patients of MCTD, special care should be paid to the conditions of this disease which reflect the histological changes as presented here.     

Circulating lupus type anticoagulant and pulmonary hypertension associated with mixed connective tissue disease

Summary We report the case of a young woman, with mixed connective tissue disease (MCTD), associated with disabling pulmonary hypertension and presence of the lupus anticoagulant. The lupus anticoagulant, an antibody directed against phospholipid components, was linked in our patient to extensive thrombophlebitis and premature labor. Raynaud's phenomenon progressed towards finger necrosis in spite of optimal vasodilating treatment. The part played by the lupus anticoagulant in pulmonary hypertension remains to be established. Both these complications responded to prednisolone therapy, but the improvement was limited and short-lived.     

Derailed B cell homeostasis in patients with mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19 + CD27-IgD + CD38^high); (2) naive B cells (CD19 + CD27-IgD + CD38^low); (3) non-switched memory B cells (CD19 + CD27 + IgD+); (4) switched memory B cells (CD19 + CD27 + IgD-); (5) double negative (DN) memory B cells (CD19 + CD27-IgD-) and (6) plasma cells (CD19 + CD27^highIgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27^high B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.     

混合性结缔组织病30例临床分析

目的探讨混合性结缔组织病(MCTD)患者临床特点与病程的相关性。方法对明确诊断MCTD的30例住院病例进行了回顾性分析。将其分为两组A组病程＜5年，B组病程≥5年。结果MCTD首发症状主要为雷诺现象、关节痛/关节炎等，其临床表现A组雷诺现象发生率非常显著高于B组(P＜0．01)，而后者肺动脉高压/肺间质纤维化发生率显著增加(P＜0．05)。实验室指标中IgG、ESR异常发生率高，肾损(尿蛋白异常)发生率为26．7％。A组无一例死亡，而B组死亡率为25％。结论MCTD并非一良性疾病，随着病程延长，其重要脏器受损发生率增加且死亡率有增高趋势。     

Scleroderma renal crisis and concurrent isolated pulmonary hypertension in mixed connective tissue disease and overlap syndrome: report of two cases

We here report on scleroderma renal crisis (SRC) appearing concurrently with isolated pulmonary hypertension (IPHT), that is, pulmonary hypertension without interstitial lung disease with fibrosis, in a patient with mixed connective tissue disease (MCTD) and in one with overlap syndrome or undifferentiated connective tissue disease (UCTD). To the best of our knowledge there are only five previous reports on SRC in MCTD and UCTD. The unexpected appearance of SRC in the setting of concomitant IPHT and limited or absent scleroderma skin changes is discussed. Received: 26 January 2001 / Accepted: 13 July 2001