Defect of a complement receptor 3 epitope in a patient with systemic lupus erythematosus.

Complement receptor 3 (CR3) is expressed on cells of the reticuloendothelial system and involved in the clearance of immune complexes. In this article a patient with a deficiency of the C3bi binding site of this receptor is described. Clinically this patient exhibited predominantly cutaneous manifestations of a systemic lupus erythematosus with an immune vasculitis and panniculitis. The deficiency of the CR3 epitope was demonstrated using flow cytometry. The functional relevance of this defect was demonstrated in a rosetting assay with C3bi-loaded erythrocytes. C3bi binding was found to be significantly decreased. Furthermore, there was an impairment of phagocytosis of opsonized Escherichia coli. The CR3 defect is not due to an autoantibody but is assumed to have a genetic basis. These data suggest that the defect of the CR3 may be involved in the pathogenesis of the immune vasculitis in this patient.

The interferon-induced Mx-homologous protein in people with symptomatic HIV-1 infection.

Twenty-six people with symptomatic HIV-1 infection were screened for the presence of interferon (IFN) alpha and IFN alpha antibodies in their sera and the presence of the IFN-induced intracellular Mx-homologous protein in their peripheral blood leukocytes. Eleven people had measurable IFN alpha levels ranging from 1 to 40 IU/ml. None of the sera tested was positive for IFN alpha binding or IFN alpha neutralizing antibodies in the assays employed. Twenty-five of the 26 people had significant levels of the Mx-homologous protein in their peripheral mononuclear cells. The Mx concentrations varied from 0.3 to 6 U/ml in the people studied. IFN alpha-positive people had significantly higher levels of the Mx homolog than IFN alpha-negative people (P less than 0.03). Furthermore, the Mx homolog content in Walter-Reed class 2 people was significantly lower than in Walter-Reed class 5/6 people (P less than 0.01). Our results suggest that the IFN system is activated in more than 90% of the people with lymphadenopathy-associated syndrome, AIDS-related complex and AIDS. Since acid-labile IFN alpha can induce the Mx homolog in vitro endogenously produced IFN alpha seems likely to be responsible for the high Mx homolog levels detected.

Correlation of the antiproliferative effect and the Mx-homologous protein induction by IFN in patients with malignant melanoma.

The human interferon-induced intracellular protein homologous to the murine Mx-protein has recently been identified by means of a specific monoclonal antibody. Three of six melanoma cell lines elicited this intracellular human Mx-homolog upon incubation with IFN-alpha or IFN-gamma, yet all six melanoma cell lines tested were susceptible to the antiproliferative effect of IFN-alpha and IFN-gamma. Compared per antiviral unit, IFN-gamma had weaker Mx-inducing but stronger antiproliferative activity than IFN-alpha. These data suggest that the IFN-induced Mx-homologous protein is not involved in the antiproliferative action of IFN on malignant melanoma cell lines. Furthermore, 51 patients with advanced malignant melanoma were treated thrice weekly with 10 x 10(6) IU rIFN-alpha-2b and 6 x 10(6) nIFN-alpha, respectively. Nine of the 51 patients experienced systemic objective tumor responses (3 complete response, 6 partial response), but had Mx concentrations in their mononuclear cells equal to the Mx levels of non-responders during IFN-alpha therapy. Therefore, the level of Mx-homologous protein induced during IFN therapy is not a predictive marker for an antitumor response in malignant melanoma.

Positron emission tomography in neuropsychiatric lupus erythematosus.

We performed positron emission tomography (PET) using 18F-labeled 2-F-2-deoxyglucose in 13 patients with systemic lupus erythematosus (SLE). Ten of them had clinical signs of central nervous system involvement (NP-SLE). All patients with neurologic symptoms showed pathologic changes on PET, always in accordance with the clinical state. Three patients without neuropsychiatric manifestations had normal PETs. Computed tomography of the brain and magnetic resonance imaging proved to be less sensitive to both presence and localization of CNS lesions. We conclude that the combination of PET and MRI constitutes the most useful diagnostic procedure for NP-SLE.

Prognostic value of clinical, laboratory, and histological characteristics in multiple myeloma: improved definition of risk groups.

Follow-up data of 320 multiple myeloma (MM) patients entering the German Myeloma Treatment Group (GMTG) trial MM01 were analysed for factors predicting overall (OAS) and tumour related survival (TRS). Response to primary induction chemotherapy was relevant for prognosis if a limit of 25% tumour cell mass (TCM) reduction was used to separate responders from non-responders. Furthermore, TCM, histological grading of myeloma cells, degree of bone marrow infiltration, haemoglobin, platelet counts, calcium, creatinine, albumin, beta 2M, and Bence Jones proteinuria correlated to both OAS and TRS. Age was relevant for OAS only. The multivariate analysis revealed histological grading, TCM and platelets as the most reliable prognostic factors. Based on these data the Durie/Salmon classification could be improved by defining poor prognosis patients (50% TRS: 16 months) characterised by pretreatment platelets of < or = 150,000 and/or poorly differentiated myeloma cell morphology. Patients lacking both risk factors displayed 50% survival times of 46 months in stage III and 88 months in stage II.

A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma. A prospective trial of the German Myeloma Treatment Group.

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Pyridinium cross-links in multiple myeloma: correlation with clinical parameters and use for monitoring of intravenous clodronate therapy--a pilot study of the German Myeloma Treatment Group (GMTG).

The relevance of quantitative determinations of urinary deoxypyridinolines (DPY) and pyridinolines (PY), and of serum type I collagen carboxyterminal cross-linked telopeptides (ICTP), has been evaluated for patient monitoring in multiple myeloma (MM). In 178 untreated MM patients, a clear correlation was found between ICTP concentrations, bone destructions and serum calcium levels. Furthermore, serum ICTP, urinary DPY and PY concentrations were estimated before and during treatment in a further 33 MM patients randomly allocated to four groups receiving intravenous melphalan/prednisone (MivP) chemotherapy alone, or MivP in combination with three different doses of i.v. clodronate. 1800 mg of i.v. clodronate combined monthly with MivP induced a rapid and sustained reduction in bone resorption parameters to the normal range, a result not obtained with either MivP alone, or with a lower clodronate dose. While confirming the relevance of determining pyridinium cross-links for estimating bone resorption in MM, our data indicate that measurements of these parameters could be useful for dose finding and monitoring of bisphosphonate therapy.

High incidence of monoclonal immunoglobulins in patients after liver or heart transplantation.

Sera from 56 recipients of liver or heart transplants were investigated for monoclonal immunoglobulins (mIg) by immunofixation electrophoresis (IFE) at different times during 4 years after transplantation. Transient, changing, or stable mIgs were found in 18 patients. A significantly increased mIg incidence was observed in heart Tx patients, patients over 40 years of age, and those receiving azathioprine or antithymocyte globulin in addition to prednisolone and cyclosporine as immunosuppressive treatment. No correlations could be found between the presence of mIg and the number of rejection episodes or intercurrent infections. Such serum mIg represent monoclones of at least 1 x 10(9) cells of B lymphocyte lineage that apparently proliferate without adequate suppressive control. Since immunosuppressed allograft recipients are at risk of developing B cell lymphomas, such monoclones may be regarded as prelymphomas necessitating a careful follow-up in these patients.

Crossreacting idiotypes of kappa-monoclonal immunoglobulins M in sera of patients with Waldenström's macroglobulinemia.

Seventeen anti-idiotypic antisera (anti-Id) were prepared against kappa-monoclonal IgM from patients with Waldenström's macroglobulinemia. Their reactivity against homologous and heterologous IgM was tested using an ELISA. Crossreacting idiotypes were only found in two out of 289 investigated antigen-antibody reactions. One anti-Id IgG crossreacted with determinants on polyclonal IgM. These rare crossreactions were observed in Waldenström's macroglobulinemia patients with and without polyneuropathy. The scarcity of common idiotypes on different monoclonal IgM does, however, not constitute a decisive argument against common or related antibody specificities of such monoclonal IgM.

MHC gene products and anticardiolipin antibodies in systemic lupus erythematosus results of a multicenter study. SLE Study Group.

Anticardiolipin antibodies (aCL) and HLA-DR antigens were determined in 314 central European patients with systemic lupus erythematosus (SLE). Both HLA-DR4 and DR7 were increased in aCL-positive patients, and aCL were significantly associated with DRw53. The association between DRw53 and aCL was also apparent in those 17 patients with SLE and the anticardiolipin syndrome. There was no association between aCL and HLA-DQ or C4 alleles in SLE.

Immunological characterization of mononuclear cells and morphological findings in patients with mammary carcinoma.

Mononuclear cells from peripheral blood and draining lymph nodes of 40 patients with invasive mammary carcinoma were examined for various immunological cell surface markers including surface membrane immunoglobulins and rosetting properties (E, EA, EAC). No significant relationship could be established to anyone of the following criteria for which the literature reports varying prognostic values: Clinical staging of the disease , histological tumor type, grading, nuclear differentiation, round cell infiltration, perivenous infiltration, sinus histiocytosis, and lymph node reaction patterns (lymphocyte predominance, germinal center predominance, lymphocyte depletion, unstimulated nodes). From the reported results it is concluded that the analysis of lymphocyte cell surface markers in mammary carcinoma is not a suitable parameter for supporting the existence of specific or unspecific anti-tumor immune reactions which may be suspected from certain histological reaction patterns.

Resting energy expenditure and weight loss in human immunodeficiency virus-infected patients.

Resting energy expenditure (REE) and body composition were investigated in 60 clinically stable patients with human immunodeficiency virus (HIV) infection varying with respect to immune impairment. REEs differed significantly from predicted values (> or < 10% of the Harris-Benedict [HB] equation) in 40% of patients. Seven percent of patients showed markedly increased REE (> +20% of HB prediction), whereas REE was decreased in 13% (< -10%). Increased REE was found during all clinical stages of the disease (Walter Reed [WR] 2 through 6) and was not strictly associated with the degree of immune impairment, presence of diarrhea or Kaposi's sarcoma, nutritional state, or anamnestic wasting. Twenty-seven patients were evaluated for a mean period of 319 days; 11 lost more than 5% of their initial body weight during the observation period. Weight-losing patients were normometabolic before but showed a significantly increased REE (+7% of predicted values or +8% when compared with previous measurements) during weight loss. The degree of deviation from estimated REE was strongly associated with the degree of weight loss. We summarize that increased REE is not a constant feature of HIV infection. It is not associated with clinical and laboratory parameters of immune deficiency, but may occur during weight loss. Thus increased REE represents an inadequate adaptation to malnutrition and contributes to wasting.

Effect of increased protein intake and nutritional status on whole-body protein metabolism of AIDS patients with weight loss.

The aim of this study was to investigate nutritional status and protein metabolism during total parenteral nutrition (TPN) in AIDS patients with weight loss. Six patients on treatment for AIDS-associated complications were investigated and reviewed TPN that supplied energy equivalent to 1.5 times the resting energy expenditure (REE). Amino acid (AA) supply increased from 0.6 g/kg body weight (BW)/d on days 1 to 3 and 1.2 on days 4 to 6 to 1.8 on days 7 to 9. Nonprotein energy was given as equicaloric amounts of glucose and fat emulsion. There were repeated measurements of nitrogen balance and whole-body protein turnover (WBPT) using a bolus 15N-glycine method on the morning of days 3, 6, and 9. Principal findings were as follows: (1) increasing the supply of AAs significantly improves nitrogen balance in AIDS patients; (2) there is no simple linear effect of increasing amounts of AAs on WBPT in AIDS patients; (3) WBPT is high and variable in these patients; and (4) mean WBPT of each patient is significantly correlated with body cell mass (BCM) as a proportion of BW (P < .001, r = .92). We conclude that poor nutritional status in AIDS patients with weight loss is associated with high WBPT. However, these patients can attain at least transiently positive nitrogen balance with sufficient protein intake, predominantly through an increase in whole-body protein synthesis (WBPS).

Detection of Ureaplasma urealyticum in urine of patients with systemic lupus erythematosus and healthy individuals by culture and polymerase chain reaction.

A method was developed to detect Ureaplasma urealyticum in urine by the polymerase chain reaction (PCR). A 457-bp fragment of the urease gene of U. urealyticum was amplified by PCR. Before PCR, components disturbing the amplification had to be reduced. This was possible by diluting the urine 1 in 10 with distilled water and by the extraction of the U. urealyticum DNA. Urine specimens from 41 patients with systemic lupus erythematosus (SLE) and 21 healthy individuals were treated by the dilution method and investigated by PCR for U. urealyticum DNA. The results were compared with those obtained by culture and the detection rates of PCR and culture were found to be identical. Also there was no difference in the detection rates of U. urealyticum from urine of SLE patients and healthy individuals; 10 (24.4%) of the 41 urine specimens from SLE patients and five (23.8%) of the 21 urine specimens from healthy individuals gave positive results for U. urealyticum. The results of this study do not indicate a decisive role for U. urealyticum in SLE.

Cytostatic drug sensitivity test for human multiple myeloma, measuring monoclonal immunoglobulin produced by bone marrow cells in vitro.

An in vitro cytostatic drug sensitivity test for human multiple myeloma has been developed, predicting differences in sensitivity of the individual tumor to various anticancer drugs. Bone marrow preparations containing the tumor cells were incubated with cytostatic drugs and cultured for 10 days. Using an enzyme-linked immunosorbent assay we measured tumor products--monoclonal immunoglobulin and beta 2-microglobulin--in the culture supernatants. The reduction of these products in vitro due to the drugs administered was compared with the patients' further clinical course during treatment with different standard cytostatic drug regimens. We found a predictive value of more than 80% for this easily performed test.

Immune complexes in multiple sclerosis: relation to clinical pattern.

Using a C1q binding test, circulating immune complexes (IC) were detected in 33.3% of sera from 138 patients and in 19.4% of 124 spinal fluid samples from patients with multiple sclerosis. Most often they occur in sera alone. As a rule their detectable amount is small in sera as well as in spinal fluids. IC were observed with equal frequency during acute exacerbations and in stable phases of the disease. In patients with early MS of less than 3 months duration, IC were detected only rarely, whereas their frequency increased up to 50% in patients with longer standing disease. Immunosuppressive therapy has no influence on IC formation. Patients with immune complexes exhibited a more rapid clinical deterioration if compared as a group with IC-negativ ones. No correlations were found between immune complex formation and the CSF-IgG index or the rate of pleocytosis in spinal fluids. Neither the complement factors C3, C4, C3A nor total hemolytic complement activities (CH50) in serum were significantly decreased in patients with IC formation in serum as compared with the IC-negative group. The results demonstrate that IC formation probably is of no importance in the pathogenesis of multiple sclerosis.

Reactivity of sera and isolated monoclonal IgM from patients with Waldenström's macroglobulinaemia with peripheral nerve myelin.

Sera of 23 patients with Waldenström's macroglobulinaemia and six monoclonal IgM paraproteins, which had been isolated from these sera, were examined for reactivity against peripheral nerve tissue. Of these 23 patients, 12 had clinical signs of peripheral polyneuropathy (PN). Using an indirect immunofluorescence method, all sera and monoclonal IgM preparations reacted with peripheral nerve structures, displaying a distinct granular fluorescence pattern with anti-IgM sera. The Waldenström sera reacted mainly with structures at the border of the myelin sheath, as well as between myelin and axon, and occasionally with the axon itself. There was no difference between sera of patients with PN and those without. Negative results were obtained in a complement fixation assay. Of the 23 sera, 15 reacted in an antibody-dependent lymphocyte-mediated cytotoxicity reaction (ADLC) with peripheral nerve myelin, and to a much lesser extent with myelin basic protein from CNS. Five of the six isolated monoclonal IgM preparations also gave positive ADLC reactions. These results constitute additional evidence for an immunological mechanism in the pathogenesis of PN in Waldenström's macroglobulinaemia.

Positron emission tomography and magnetic resonance imaging for cerebral involvement in patients with systemic lupus erythematosus.

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI. Antineuronal antibodies were determined to investigate their putative role in CNS involvement in SLE. Twenty patients had distinct neurological (17) and/or psychiatric (3) symptoms. Ten patients had pronounced cognitive impairment. Neurological and cognitive deficits were thus found to be unrelated disorders in SLE. Global glucose utilisation of SLE patients did not differ significantly from that of normal controls, nor were differences found between SLE patients with or without neurological or cognitive abnormalities. On MRI of the brain, the number and size of white matter lesions correlated with the presence of neurological deficits but were unrelated to the severity of cognitive impairment. Within the normal range, lower global glucose utilisation tended towards lower values with increasing number and size of white matter lesions. Patients with lesions larger than 8 mm also showed distinctly increased IgG anticardiolipin antibody titres, whereas measuring antineuronal antibodies did not reveal any relation to the variables investigated. We conclude that the demonstration of CNS lesions by MRI can contribute confirmatory evidence for CNS involvement in SLE, but PET or the presence of antineuronal antibodies adds little if any information beyond that obtained by clinical examination, neuropsychological testing, and MRI.

Home enteral nutrition in patients with Acquired Immunodeficiency Syndrome.

UNLABELLED: 14 patients in advanced stages of HIV infection (1 ARC, 13 AIDS; sex: 1 female, 13 male; age 37.8 +/- 6.3 years; body mass index (BMI): 17.4 +/- 2.4 kg/m(2)) were followed prospectively while receiving home enteral nutrition (observation period: 62 +/- 75 days). Artificial nutrition was indicated because of severe weight loss (9-38 kg within 6-48 months, n = 7) or cerebral toxoplasmosis with eating and swallowing disorders (n = 7). In all patients a defined formula diet (175 +/- 17.7 kJ/kg body weight) was administered through an endoscopically placed gastrostomy tube (PEG). Home enteral nutrition was well tolerated by all patients and no significant PEG-related complications occurred. Enteral nutrition resulted in significant increases in body weight (p < 0.005), body cell mass (BCM, p < 0.05), total body fat (TBF, p < 0.005), serum albumin concentration (p < 0.05), and serum total iron-binding capacity (transferrin, p < 0.01). CONCLUSION: Home enteral nutrition via PEG is safe and well tolerated in patients with advanced HIV-related immunodeficiency and is capable of improving nutritional state including BCM.

Weight gain and increased concentrations of receptor proteins for tumor necrosis factor after patients with symptomatic HIV infection received fortified nutrition support.

OBJECTIVE: To determine whether certain nutrients and dietary factors act as modulators of the immune system and improve the nutritional status of immunocompromised patients. DESIGN: Controlled, double-blind, crossover phase trials of the effects of a fortified formula in patients infected with the human immunodeficiency virus (HIV). Patients consumed a control formula for 4 months and a study formula for 4 months. SUBJECTS: Ten men with symptomatic HIV infection who were following stable medication regimens and had no malignancies, mycobacteriosis, or additional virus infection requiring systemic treatment. INTERVENTION: Formula fortified with alpha-linolenic acid (1.8 g/day), arginine (7.8 g/day), and RNA (0.75 g/day) and a standard formula. MAIN OUTCOME MEASURES: Nutritional status determined by anthropometric, bioelectrical, biochemical, and dietary assessment; energy expenditure determined by indirect calorimetry; disease progression; CD4 lymphocyte counts; HIV p24 antigen plasma concentrations; tumor necrosis factor (TNF) receptor proteins; and compliance control parameters. STATISTICAL ANALYSES PERFORMED: Student's t tests for paired and unpaired data. RESULTS: Fortified nutrition resulted in a weight gain (+ 2.9 kg/4 months vs -0.5 kg/4 months with the control formula, P < .05), an incorporation of eicosaenoic acid into erythrocyte cell membranes (+ 47% of baseline values, P < .05), and increased plasma arginine concentrations (96.8 +/- 45.1 vs 51.8 +/- 20.9 mumol/L, P < .01). The serum concentrations of the soluble tumor necrosis factor receptor (sTNFR) proteins increased during the study period (sTNFR 55 = + 0.23 vs -0.40 ng/mL, P < .001; sTNFR 75 = + 0.90 vs -0.36 ng/mL, P < .01), whereas no changes in CD4+ lymphocyte counts were observed. CONCLUSION: Increasing dietary intakes of n-3 polyunsaturated fatty acids, L-arginine, and RNA increased body weight, possibly by modulating the negative effects of TNF.