Soluble CD27 induces IgG production through activation of antigen-primed B cells.

OBJECTIVES: High levels of soluble CD27 (sCD27), a marker of immune activation, are found in several infectious [including human immunodeficiency virus type-I (HIV-1)] and autoimmune diseases; however, a direct biological effect of sCD27 on B cells has not been established. The aim of this study was to investigate whether sCD27, by binding to CD70, can induce immunoglobulin G (IgG) production from B cells. METHODS: B cells from healthy and HIV-1-infected individuals were cultured with recombinant human sCD27 (rhsCD27), and IgG production was measured. The role of rhsCD27 in inducing the expression of transcription factors involved in plasma cell differentiation was evaluated. Furthermore, we investigated the impact of different cytokines on the modulation of CD70 expression on B cells and the relationship between levels of IgG and sCD27 in serum from healthy and HIV-1-infected individuals. RESULTS: We demonstrated that rhsCD27 induced IgG production from antigen-primed (CD27+) B cells. This effect was mediated by rhsCD27 binding to CD70 on B cells leading to activation of Blimp-1 and XBP-1, transcription factors associated with plasma cell differentiation. We found a significant correlation between levels of serum sCD27 and IgG in HIV-1-infected individuals and healthy controls. CONCLUSIONS: sCD27 may act to enhance immunoglobulin production and differentiation of activated memory or recently antigen-experienced B cells, thus providing an activation signal to antigen-experienced B cells. This mechanism may operate during autoimmune and chronic infectious diseases, situations in which continuous immune activation leads to upregulation of CD70 expression and increased sCD27 cleavage.

Impairment of short-term memory and Korsakoff syndrome are common in AIDS patients with cytomegalovirus encephalitis.

BACKGROUND AND PURPOSE: The diagnosis of cytomegalovirus encephalitis (CMV-E) in AIDS patients is challenging as other illnesses may obscure the symptoms. Here, we characterize the clinical symptoms of CMV-E and link them to post-mortem findings. Patients and methods In 254 homosexual men with AIDS, followed from HIV diagnosis to death before the antiretroviral combination therapy era, CMV-E was suspected in 93 cases. All were CMV-positive in blood. Neurological examination, including cognitive testing was performed in 34 of them within 6 months before death. CMV-E was diagnosed by CMV-PCR in cerebrospinal fluid (n = 24) or by post-mortem (n = 24). RESULTS: The majority complained of forgetfulness (91%), balance difficulties (85%) and impotence (85%). Impaired short-term memory was present in 29 patients. It was extreme in 17, justifying the diagnosis of Korsakoff's syndrome. This was often associated with infectious CMV in blood (P = 0.01). Brainstem symptoms were found in 19 patients. Post-mortem examination often revealed ventriculoencephalitis. CMV was found primarily around the ventricles and in other structures, described in Korsakoff's syndrome. CONCLUSION: The location of CMV in the brain corresponded well to the clinical findings, demonstrating the close relationship between the neurological symptoms and the neuroanatomical lesions.

Clostridium perfringens septicemia and acute leukemia.

Three cases of fatal clostridial septicemia in patients with acute leukemia are described. Predisposing factors and treatment are discussed. Clostridium septicemia should always be suspected when a patient with neutropenia suddenly develops diffuse abdominal pain, fever, and tachycardia over 120/min. The importance of early treatment with penicillin or another adequate antibiotic is discussed.

Myxoedema in a case of acute myeloid leukaemia.

A 42-year-old woman developed myxoedema during the course of acute myeloid leukaemia. The possible association with cytostatic treatment, especially thioguanine, and the role of levothyroxine for the growth of the leukaemic cell mass are discussed.

C-reactive protein levels in HIV complicated by opportunistic infections and infections with common bacterial pathogens.

In order to determine the pattern of C-reactive protein (CRP) concentrations in HIV-infected patients with various other infections, we conducted a prospective study (for the period 1990-91) of all HIV-seropositive patients hospitalized with fever and a retrospective study (for the period 1990-95) of all patients infected with Mycobacterium avium complex (MAC) and Pneumocystis carinii pneumonia (PCP). Samples from blood, cerebrospinal fluid and sites with clinical signs of infection were obtained for bacteriological culture. Polymerase chain reaction (PCR) determination was performed for cytomegalovirus in blood and CSF. Patients with opportunistic infections had a significantly lower increase in CRP concentration than patients infected with common bacterial pathogens. Patients with PCP and mycobacterial infections had a distinct CRP response after the onset of therapy. Lack of CRP increase at diagnosis of MAC infection was associated with a shorter survival and normalization of CRP after MAC therapy with a significantly longer survival.

CRP concentration in a patient with acute leukaemia and bone marrow infarction.

A patient with acute lymphoblastic leukaemia, CRP increase and bone marrow infarction is described. Bone marrow infarction must be suspected in a patient with leukaemia, skeletal pain, fever and CRP increase.

C-reactive protein during chemotherapy for acute leukemia with special reference to non-infective causes of fever.

C-reactive protein, CRP, was followed longitudinally in 41 patients being treated for acute leukemia. It was analysed by a rapid (2-h) immunochemical assay in a laser-nephelometer. The cytostatic treatment given either intravenously or intrathecally did not cause any CRP increase with the exception of 7% of the treatment courses, given to 3 patients, and neither did transfusion reactions. The patients had altogether 117 febrile episodes. During 44 episodes with evidence of bacterial or fungal infection, CRP increased above the reference value (90 mg l-1). The same observation was made during 37 febrile episodes with clinically probable infections. CRP remained within the reference value when fever was caused by virus infections or occurring for unknown reasons.

C-reactive protein-immunoglobulin complexes in two patients with macroglobulinemia.

Two patients with macroglobulinemia, one with a monoclonal IgA and the other with a monoclonal IgM, are described. In connection with cytostatic treatment and infection both patients got very high CRP-concentrations as measured by laser nephelometry. These seemed to be caused by C-reactive protein immunoglobulin complex formation as determined by immunofixation.

Four immunochemical methods for measuring C-reactive protein in plasma compared.

Four immunochemical methods for measuring C-reactive protein (CRP) in plasma were compared: radial immunodiffusion (RID), electroimmunoassay (EIA), immunoturbidimetry (IT), and laser nephelometry (LN). Close agreement was found between RID and EIA (EIA = 0.96 RID + 7.7 mg/L, r = 0.977, n = 100), IT and EIA (EIA = 1.11 IT - 15.8 mg/L, r = 0.951, n = 100), IT and RID (RID = 1.10 IT - 11.5 mg/L r = 0.959, n = 94). In initial studies in 1983, LN showed good agreement with RID (LN = 0.98 RID + 11.9 mg/L, r = 0.973, n = 60). Since then, normal CRP values measured by LN have tended to increase and, at the time of the present study (1986), LN agreed poorly with other methods. The reason for this change is obscure. Having excluded the possibility of enzymatic degradation of CRP, we conclude that instrumentation problems are involved, and therefore we no longer use this method.

CMV PCR in leucocytes as an early marker for the development of CMV disease in AIDS patients.

The relationship between cytomegalovirus (CMV) DNA in leucocytes and CMV disease in AIDS patients was sought. In 195 HIV-1 infected, mostly AIDS patients, CMV nPCR was performed in 477 peripheral EDTA blood samples which were collected also for CD4 cell counts (403), classic (410) and rapid virus isolation (270), and antigenemia tests (190). Most patients who died were autopsied. Immunohistopathology for CMV was performed. The first 43 patients were classified clinically according to having (A) verified organ involvement of CMV (15), (B) suspected CMV disease due to symptoms (4), or no CMV-associated disease (24). CMV-DNA was detected in the majority of samples (66%) and patients (68%). In contrast, CMV in the samples was detected in only 16% by classical and 11% by rapid isolation and in 8.4% by the antigenemia test. Acquisition of CMV DNA in leucocytes became more common as the CD4 cell counts fell. Detection of CMV DNA was significantly associated with CMV-associated symptoms and later mortality. In conclusion, CMV PCR of DNA in leucocytes is a sensitive and early marker of CMV disease in HIV-infected AIDS patients. It might be a marker to be added to CD4 cell counts for initiation of preemptive therapy.

Surgical treatment of cytomegalovirus enterocolitis in severe human immunodeficiency virus infection. Report of eight cases.

PURPOSE: The aim of this study was to describe our experiences of surgical removal of inflamed bowel in cytomegalovirus enterocolitis. METHODS: Eight homosexual males with a mean age of 41 years (range, 29-59 years) and a mean CD4 count of 21 x 10(6)/l (1-60 x 10(6)/l) with advanced human immunodeficiency virus infection and severe cytomegalovirus enterocolitis were treated with ileocecal resection (4 patients) or right-sided hemicolectomy (4 patients). Symptoms were lower abdominal pain, severe diarrhea, fever, and weight loss, unrelieved by anticytomegalovirus therapy. Radiologic examination showed that ulcerative inflammation was limited to the right colon and terminal ileum. Microscopic examination confirmed the cytomegalovirus enterocolitis. Intermittent cytomegalovirus treatment, usually with foscarnet for 10 to 14 days every 4 to 6 weeks was given postoperatively. RESULTS: Two minor postoperative complications occurred: a lesser wound infection and a moderate bleeding from the abdominal wound edges. One patient died after three weeks because of gastrointestinal bleeding from an ulcerating Kaposi's sarcoma lesion and another patient died from unrelated causes three weeks after discharge from the hospital. The remaining 6 patients experienced complete or partial palliation of the abdominal symptoms for a mean of 14 months (range, 5-35 months) until death or the end of observation time. One patient is still alive two years after the operation. The overall mean survival was 12 months (range, 0.5-35 months). Recurrent or persistent symptoms and/or signs of cytomegalovirus enterocolitis occurred in four patients after a mean of seven months. CONCLUSION: Resection of inflamed bowel combined with postoperative anticytomegalovirus treatment leads to excellent palliation and a relatively favorable survival in AIDS patients with cytomegalovirus enterocolitis.

Low frequency of plasma nerve-growth factor detection is associated with death of memory B lymphocytes in HIV-1 infection.

Nerve growth factor (NGF) regulates B cell activation and differentiation and is an autocrine survival factor for memory B lymphocytes. We have reported recently that the number of memory B cells is reduced during HIV-1 infection. In this study we evaluated whether alteration in the NGF supply was involved in memory B cell loss in HIV-1-infected subjects. High rate of cell death in vitro was observed in memory B cells from HIV-1-infected individuals compared to uninfected donors (26.2 +/- 2.5%versus 7.9 +/- 1.4%, P < 0.001). The increased expression of Fas on memory B cells from infected subjects did not enhance the susceptibility of the cells to Fas-mediated apoptosis in vitro. The frequency of NGF detection in plasma from HIV-1-infected subjects was significantly lower than in healthy donors (33.6%versus 63.6%, P < 0.001). Also, the median plasma NGF in HIV-1-infected individuals was significantly lower than in uninfected controls (5 versus 14 pg/ml, respectively, P < 0.01). Interestingly, the plasma NGF level was correlated directly 1 to the percentage of memory B cells (P < 0.05). HIV-1-infected subjects with a low number of peripheral memory B cells had a reduced incidence of plasmatic NGF (7.4%) compared to patients with a normal level of memory B cells (37%, P < 0.01). Moreover, the addition of recombinant NGF (1 micro g/ml) to cultures of purified B cells reduced cell death of memory B cells from HIV-1-infected subjects from 24.04 +/- 3.0% to 17.4 +/- 1.3% (P < 0.01). HIV-1-infected individuals also carried higher levels of natural anti-NGF autoantibodies compared to uninfected subjects. In conclusion, we found that memory B cells from HIV-1-infected individuals are primed for cell death. Our study suggests an association between low frequency of plasma NGF detection and the increased cell death of memory B lymphocytes observed during HIV-1 infection. Low levels of NGF in plasma may be due to reduced supply or to NGF binding to natural anti-NGF autoantibodies.