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Thymomas associated with pure red cell aplasia. Histologic and follow-up studies.

Seventeen cases of pure red cell aplasia (PRCA) with thymoma were studied clinically, histologically, and immunologically. Two cases were associated with myasthenia gravis (MG), and three with hypogammaglobulinemia. Coombs test and antinucleus antibody test were positive in five cases. All thymomas were spindle cell types, and the adjacent thymuses had no germinal center, but showed epithelial clusters frequently. All patients, except one whose tumor was unresectable, had thymo-thymomectomy. The operation was effective in six cases (37.5%), and the effects were not different between two operative procedures (simple and extended thymectomy). Myasthenic symptoms in two patients remitted after the operation, but effects on hypogammaglobulinemia were conincident with those on PRCA.

Agammaglobulinemia↗

Guanabenz and methyldopa on hypertension and cardiac performance.

In previous placebo-controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double-blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre-ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.

Adult↗

Autologous mixed lymphocyte reactions in NZB mice: analysis in recombinant inbred lines shows a T cell defect unrelated to autoantibody production.

The autologous mixed lymphocyte reaction (AMLR) has been examined in the AMLR-deficient strain, NZB, in C58 mice, which have normal AMLR responses, and in the (NZB x C58) recombinant inbred (NX8 RI) lines. Half of the NX8 RI lines had deficient AMLR and half were comparable in reactivity to the C58 parent strain. AMLR unresponsiveness did not correlate in the NX8 RI lines with H-2 or any other marker known to affect immune recognition. Non-T cells from H-2k NX8 RI lines which had deficient AMLR were able to stimulate an MLR when cultured with T cells of C58 origin. AMLR-positive H-2d lines responded to NZB stimulators, whereas NZB T cells did not respond to any of the H-2d NX8 RI lines but did exhibit strong alloreactivity. Thus, the AMLR defect in NZB mice is due to a T cell lesion. Furthermore, since AMLR deficiency in the NX8 RI lines did not correlate with a positive Coombs test or the production of naturally occurring thymocytotoxic antibody, we conclude that autoimmunity in NZB mice is a complex disease resulting from the inheritance of multiple independently segregating genes.

Animals↗

An unusual case of T-cell lymphoproliferative disorder.

A 54-year-old woman with epigastric pain had leukocytosis of 73,000/microliter consisting mainly of atypical lymphoid cells with convoluted and cleaved nuclei resembling Sézary cells; the bone marrow aspirate was nondiagnostic. Skin biopsy was unremarkable. The patient also had hypercalcemia and hemolysis with a positive direct Coombs' test, both of short duration. The arterial oxygen tension was decreased, but there was no demonstrable lung pathology. The patient subsequently developed rapidly enlarging lymphadenopathy. Lymph node biopsy was interpreted as "undifferentiated pleomorphic lymphoma." Immunologic functional studies revealed that the majority of the peripheral blood atypical lymphoid cells from involved lymph nodes formed rosettes with sheep erythrocytes. The lymphadenopathy regressed transiently after the administration of chemotherapy and the white blood cell count decreased from a maximum of 385,000/microliter to 3,500/microleter, at which point the arterial oxygen tension returned to normal. The unusual features of this patient are discussed in light of the known characteristics of the various types of T-cell lymphorpoliferative disorders.

Female↗

Dietary Platycladus orientalis seed oil suppresses anti-erythrocyte autoantibodies and prolongs survival of NZB mice.

Dietary fish oils rich in 20:5(5,8,11,14,17) and 22:6(4,7,10,13,16,19) are known to replace arachidonic acid [20:4(5,8,11,14)] and to improve the immunopathology of New Zealand mice. However, in humans, similar dietary strategies may be impractical because of the high levels of fish oils required. In contrast, we believe that beneficial effects in humans may be attainable using new exotic fatty acids. Toward this end, we have focused on 5,11,14-eicosatrienoic acid [5,11,14-ETA, 20:3(5,11,14)]. This fatty acid is structurally analogous to 20:4(5,8,11,14) but lacks the delta-8 double bond essential for conversion to eicosanoids. To examine our hypothesis, diets containing the oil of Platycladus orientalis containing 3% 5,11,14-ETA, a matched control oil, fish oil, or safflower oil were fed to NZB mice. There was a dramatic delay in both the onset and the titer of direct Coombs' tests in mice fed P. orientalis oil. These were directly reflected by the abundance of 5,11,14-ETA in serum lipids. Most striking was the accumulation of 5,11,14-ETA in serum and tissue phospholipids. Though constituting only 3% of dietary fatty acids, 5,11,14-ETA was the most abundant long chain polyunsaturated fatty acid in the serum phospholipids, suggesting that it very successfully competed with 20:4 as a constituent of membrane lipids. 5,11,14-ETA was incorporated into all tissue phospholipids examined except brain phosphatidyl inositol. Among tissues, liver showed the highest incorporation of 5,11,14-ETA into phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI), yet spleen PE had a higher quantity of ETA than other tissues. Lesser arachidonate in spleen PS, heart PC, and heart PI showed the evidence of replacement by 5,11,14-ETA. The data presented illustrates how new nutrition can modify autoimmune responses and emphasizes the need for further studies based on new nutritional strategies.

Anemia, Hemolytic↗

The contribution of I-Abm12 to phenotypic and functional alterations among T-cell subsets in NZB mice.

To further understand the contribution of I-A to the development of disease in murine lupus, we compared the incidence and/or titers of natural thymocytotoxic autoantibodies (NTAs), autoantibodies to red blood cells, gp70 immune complexes (gp70), antibodies to Sm, and rheumatoid factor in NZB (H-2d), NZB.H-2b and NZB.H-2bm12 mice. There were striking and significant differences among the three NZB strains in several of these parameters. NZB (H-2d) and NZB.H-2bm12 mice had a 100% incidence of NTA. In contrast, NZB.H-2b mice were found to have NTA in only 36% of animals at 8-10 months of age. Furthermore, the NTA titers of NZB.H-2bm12 mice were relatively low. There were also distinct differences between these strains with respect to the presence of antibodies to anti-erythrocytes (positive Coombs' test). NZB (H-2d) and NZB.H-2bm12 both had high titers of anti-erythrocyte autoantibodies (AEAs), whereas there was a delayed onset and lower titers in NZB.H-2b mice. Additionally, there was a dramatic increase in gp70 IC levels in NZB.H-2bm12 mice. In previous studies, NZB.H-2bm12 as well as NZB.H-2bm12 x NZB.H-2b F1 mice were found to produce high autoantibody titers to single-stranded (ss) and double-stranded (ds) DNA. Using unfractionated or fractionated splenic T cells (CD4+ CD8-, CD4- CD8+, or CD4-CD8-) from NZB.H-2b or NZB.H-2bm12 mice, we compared their relative abilities to cooperate with T-depleted splenocytes from NZB.H-2bm12 x NZB.H-2b F1 mice to produce antibodies to ss- and ds-DNA. Only T cells, including both CD4+ CD8- and CD4- CD8- populations, from NZB.H-2bm12 mice, were able to induce such autoantibody production among F1 splenocytes. Finally, marked alterations in splenic T cell subsets were found in NZB.H-2bm12 mice compared to NZB.H-2b mice, and to a lesser extent, in B6.C-H-2bm12 mice compared to C57BL/6 (H-2b) mice. These data further highlight the influence of I-A on autoimmunity and in particular the influence of the bm12 mutation on altering the natural history of disease expression in NZB mice.

Animals↗

Atypical antipsychotic-induced neutropenia in dogs.

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406. Neither size nor number of erythroid or myeloid CFUs differed between cultures containing control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 microg/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity.

Animals↗

Long-term follow-up study of children with chronic ITP.

A total of 126 children with chronic idiopathic thrombocytopenic purpura, including 35 splenectomized cases, were investigated in a long-term follow-up study, with regard to residual hematologic and immunologic abnormalities, complications and physical growth. Such hemorrhagic symptoms as petechiae, ecchymosis and epistaxis were still observed in about 22%-28% of the patients with a period of morbidity ranging from 3 to 15 years after onset. Residual thrombocytopenia below 150,000/microliters was found in 62% of patients within 5 years, 59% within 5 to 9 years and 57% within 10-14 years after onset. Other abnormalities were mild anemia, low serum level of IgA or IgM, positive antinuclear antibody, rheumatoid factor, and positive Coombs test in a small number of patients. Increased platelet-associated IgG was still obtained in patients with subnormal platelet counts whose morbid periods were 6 to 27 years after onset. Investigation of the patients by questionnaire revealed such complications as obesity, striae atrophicae, abdominal pain, headache, cataract, Perthes' disease, and cardiac complication in some patients. No apparent disturbances except for obesity were observed in their physical growth.

Autoimmune Diseases↗

Late anaemia in infants with rhesus haemolytic disease treated with intensive phototherapy.

The purpose of the present study was to determine the incidence of late anaemia in infants with rhesus haemolytic disease (RHD) who had received intensive phototherapy. Sixty infants with RHD and with strongly positive direct Coombs' tests who had received intensive phototherapy (blue double light) were followed as out-patients with regard to development of late anaemia. Fifteen (25%) infants developed moderate anaemia and 5 (8%) severe anaemia, one of the latter requiring a blood transfusion. The incidence of late anaemia was equal in "non-exchanged" infants and those who required exchange transfusion. The former developed anaemia significantly earlier than the latter, and in both groups the declining Hb level caused a marked reticulocyte response which was equal in both groups. This response may explain the low incidence of anaemia in both the "non-exchanged" and "exchanged" infants. From the present study and previous investigations it can be concluded that phototherapy, especially intensive phototherapy, is of great value in the treatment of rhesus haemolytic disease.

Anemia, Neonatal↗

Comparative study of metoprolol and alpha-methyldopa in untreated essential hypertension.

The hypotensive actions of metoprolol and alpha-methyldopa have been compared in 37 men with previously untreated essential hypertension; 36 belonged to stage 1 and 1 to stage 2 of the WHO classification. After four weeks of placebo treatment the patients were randomly allocated to treatment with either of the two drugs. Treatment was started with metoprolol 75 mg daily or alpha-methyldopa 375 mg and was doubled after eight weeks. Satisfactory blood pressure control was defined as systolic blood pressure below 160 mm Hg and diastolic below 95 mm Hg. The patients were examined every four weeks and in those with unsatisfactory control the dose was gradually increased up to a maximum daily dose of metoprolol 450 mg or alpha-methyldopa 2250 mg. The trial lasted for 24 weeks after randomization. Five patients dropped out of the study. After six months, satisfactory blood pressure control was recorded in 16 out of 17 patients and 14 out of 15 patients treated with metoprolol and alpha-methyldopa, respectively. The average reduction in blood pressure produced by the two drugs was comparable. One patient in the alpha-methyldopa group developed drug exanthema and two patients a positive Coombs' test. Other side effects were few and did not differ between the two compounds.

Blood Pressure↗

[Immunoblastic lymphadenopathy--malignant neoplasia or hyperimmune reaction? (author's transl)].

Six patients have been observed which exhibited the features of the so called immunoblastic lymphadenopathy. The histological and clinical findings allow to distinguish the disease from both the malignant lymphomas and other forms of benign pseudolymphomas. The most important clinical features are severe general symptoms, generalised lymphadenopathy, hepatosplenomegaly, skin rash and a variety of abnormal reactions in the B-cell system such as hypergammaglobulinaemia, a transient positive Coombs test and the appearance of plasma cells in the peripheral blood. Evidence for a neoplastic nature of the disease is lacking. Nevertheless, the course of the disease may be progressive and fatal, but spontaneous remissions and subsequent relapses have also been essential part of the therapeutic strategy. Immunosupressants such as corticosteroids may have a positive effect in cases with immunological complications.

Adult↗

[Summary].

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Autoantibodies↗

Hemolytic anemia provoked by recombinant alpha-interferon.

A 30-year-old female with chronic hepatitis C treated with recombinant alpha-interferon developed serious hemolytic anemia after receiving 10 million units a day for 4 weeks. The results of Coombs' tests were negative before and after interferon therapy. The hemolytic anemia gradually improved after the withdrawal of recombinant alpha-interferon and the administration of methyl-prednisolone. The clinical course suggested that the recombinant alpha-interferon had provoked the hemolytic anemia.

Adult↗

Acute hemolysis associated with hepatitis A.

A 62-yr-old woman, admitted to Mitsui Memorial Hospital with complaints of jaundice, general malaise and anorexia, was diagnosed as acute hepatitis A by positive IgM anti-HA. On the 13th hospital day, indirect hyperbilirubinemia (total bilirubin 57 mg/dl, indirect bilirubin 38.5 mg/dl) and splenomegaly were noted. Hemoglobin concentration decreased to 8.4 g/dl and reticulocytes increased to 6%. Bone marrow showed hyperplastic marrow with erythroid hyperplasia. Coombs test was negative. After administration of prednisolone 40 mg daily for 30 days, hemoglobin concentration increased to 11.9 g/dl and total bilirubin was decreased to 0.4 mg/dl. The liver biopsy specimen obtained on the 62nd day, revealed recovery stage of acute hepatitis. Jaundice with increased indirect bilirubin, anemia with reticulocytosis, elevated plasma hemoglobin concentration and predominance of LDH1 were indicative of hemolysis. The enzyme activities in the red blood cells, which were taken 1 year after the onset, were within normal limits. Scanning electron microscopy of the red cells showed no significant abnormalities in their shape and the nature of the surface.

Anemia, Hemolytic↗

Two further examples of IgG thimerosal-dependent antibodies and their serological characteristics.

Two further examples of IgG thimerosal-dependent antibodies have been found by routine immunohematological tests carried out in our laboratory. Both antibodies fixed the complement and had no apparent blood group specificity. Their reactivity was inhibited by adding thimerosal to the serum prior to the addition of red blood cells. If cross matching is performed accordingly, thimerosal-dependent antibodies should not any longer represent a blood bank problem.

ABO Blood-Group System↗