Nodular glomerulopathy associated with nonamyloidotic kappa light chain deposits and excess immunoglobulin light chain synthesis

A nodular glomerulopathy characterized by mesangial deposits of monoclonal kappa light chains was detected by immunofluorescence in a renal biopsy from a patient with proteinuria and hypertension. These nodules lacked the tinctorial and morphologic features of amyloid. Ultrastructurally, the nodules contained electron-dense granular deposits as well as fibrils in parallel arrangement. The fibrils measured 110-140 A in diameter. They were consistent in size with amyloid fibrils. However, they differed in lacking the randomly oriented network of typical amyloid fibrils and more closely resembled fibrils intrinsic to mesangial matrix. The patient had no bone marrow or X-ray evidence of myeloma and no evidence of free monoclonal light chains in serum or concentrated urines. Biosynthetic studies of the patient's bone marrow cells demonstrated unbalanced immunoglobulin synthesis with excess production of monoclonal kappa light chains. These observations suggest that the observed glomerulopathy results from direct deposition of monoclonal light chains. Deposits with kappa light chain determinants have been found in 7 other patients with similar nodular glomerulopathies, 4 of whom had diagnosed clinical myeloma. The lesion of nonamyloidotic nodular glomerulopathy previously described in 19 patients, nor examined by immunopathologic techniques or not shown to contain light chain determinants, may have a similar pathogenesis.     

Chromosome mapping of cell membrane antigens expressed on activated B cells

Hybrids formed by fusion of either human acute lymphoblastic or chronic lymphocytic leukemia cells and the mouse myeloma P3.X63.Ag8/653 have been used to show that the expression of two cell surface antigens, Bp37 and p76, associated with B cell activation and detected by the monoclonal antibodies BB1 and BB2, respectively, segregate with human chromosomes 12 and 19, respectively. Another antigen expressed on activated B cells (p24) also maps to chromosome 12 (Katz et al., Eur. J. Immunol. 1984. 13: 1008) which is of interest in the light of the frequent involvement of this chromosome in certain B cell leukemias and lymphomas.     

Immunization of rabbits with a modified vaccinia Ankara recombinant virus bearing the HIV envelope antigen on its outer membrane

Modified vaccinia virus Ankara (MVA) is a highly attenuated strain of vaccinia virus, which propagates efficiently in chicken embryo fibroblasts but fails to complete its growth cycle in many types of mammalian cells. We constructed a recombinant virus MVA/EK5, which has a chimeric gene encoding for the extracellular domain of the HIV envelope protein fused to the cytoplasmic and transmembrane domain of the B5R protein of vaccinia virus. The fused HIV envelope antigen was expressed in the African green monkey kidney BS-C-1 cells infected with the recombinant virus. This virus, which had been grown in chicken embryo fibroblasts, induced in rabbits antibodies against the HIV envelope antigen, in addition to those against poxvirus.     

Rapid activation of glycogen synthase and protein phosphatase in human skeletal muscle after isometric contraction requires an intact circulation

The effects of isometric contraction (66% of maximal force) and recovery on glycogen synthase fractional activity (GSF) in human skeletal muscle have been studied. Biopsies were taken from the quadriceps femoris muscle at rest, at fatigue and 5 min postexercise on two occasions: after one of the contractions, the circulation to the thigh was occluded during the 5 min recovery (OCC), and after the other contraction, the circulation was intact (control, CON). During CON, GSF decreased from (mean ± SE) 0.34±0.05 at rest to 0.24±0.02 at fatigue and then increased to 0.74±0.04 at 5 min postexercise; corresponding values for OCC were 0.37±0.04, 0.25±0.04 and 0.48±0.05 (P<0.001 vs. CON for 5 min postexercise only). Compared with the value at fatigue, protein phosphatase activity (PP) increased by 79±16% during CON recovery (P<0.01), whereas no change was observed during OCC recovery. Uridine diphosphate glucose increased by approximately 2.5-fold at fatigue, remained elevated during OCC recovery, but reverted to the preexercise level during CON recovery (P<0.001 vs. OCC recovery). Glucose 6-P increased approximately 5-fold at fatigue and was higher at 5 min postexercise in OCC vs. CON recovery (8.6±1.5 vs. 4.1±0.9 mmol/kg dry wt; P<0.01). It is concluded that the rapid increase in GSF after intense exercise with an intact circulation may be at least partly attributed to an increase in the specific activity of PP. The increase in GSF during recovery in OCC may be at least partly attributed to the high glucose 6-P content in vivo, which enhances the substrate suitability of GS for PP. Thus, separate mechanisms exist for the activation of PP and GS during recovery from intense short term exercise.     

IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients

Intravenous immunoglobulin (IVIg) is used to treat a number of immune-deficiencies and autoimmune diseases. It has been shown that IVIg contains anti-idiotypic antibodies, which explains its immunomodulatory action.In murine models, recent investigations have demonstrated that IVIg can prevent and reduce the affliction by systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and scleroderma. Relevant disease-specific fractions of IVIg were able to reproduce and even enhance the therapeutic effect in a murine model.IVIg treatment before tumor resection in rodents inoculated with melanoma and sarcoma cells dramatically improved the cure rate (50%) in comparison to the control group (0%).In patients affected by SLE, several clinical manifestations responded to IVIg treatment including serositis, hematological manifestations, treatment-resistant nephritis and central nervous system involvement. Similarly, in women with recurrent fetal loss due to APS, IVIg was able to diminish the abortion rate. Vasculitides such as Churg-Strauss' and Wegener's and skin fibrosis in patients affected by scleroderma improved after IVIg treatment. In agreement with in vitro investigations, prolonged survival has been noted in cancer patients treated with IVIg.We suggest that in the presence of a steroid and immunosuppressive-resistant autoimmune disease, IVIg is a rational and safe choice.     

Failure of the H2 antagonist cimetidine to reverse parasite antigen-specific lymphocyte unresponsiveness in experimental filariasis.

Using sera from 75 healthy donors, 68 rheumatoid arthritis (RA) patients, and 85 tuberculosis (TB) patients, we have examined the level of antibody of the three major classes binding to seven mycobacterial species, and to three control antigens. The major findings are that IgM binding to mycobacteria is reduced in RA patients who have HLA-DR7 (P = 0.008 for M. tuberculosis antigen), and that IgA binding to mycobacteria is reduced in RA patients who have HLA-DR2 (P = 0.007 for M. tuberculosis; P = 0.0004 for M. nonchromogenicum). These associations were not seen in TB, and were restricted to these antibody isotypes. We believe this is the first report of isotype specific Class II MHC-associated regulation of antibody levels in man. A possible interpretation of our data is that patients bearing these haplotypes are recognizing suppressor epitopes common to all the mycobacterial species tested. Since DR2 and DR7 have recently been shown to be associated with a significantly reduced risk of RA, our findings are compatible with the view that changes in immune responsiveness to mycobacterial antigens, or to autoantigens which cross-react with them, are relevant to RA.     

gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo

We report that gp49B1, a mast cell membrane receptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIM), constitutively inhibits mast cell activation-secretion induced by stem cell factor (SCF), a tissue-derived cytokine that also regulates mast cell development. The intradermal injection of SCF into the ears of gp49B1 null (gp49B(-/-)) mice elicited approximately 4- and 2.5-fold more degranulating mast cells and tissue swelling caused by edema, respectively, than in gp49B(+/+) mice. SCF did not induce tissue swelling in mast cell-deficient mice, and the responsiveness of gp49B(-/-) mice to mast cell-associated amine and lipid mediators was unaltered. When gp49B(+/+) and gp49B(-/-) mice were pretreated with antagonists of the amines, SCF-induced tissue swelling was reduced by >90% and 60%, respectively, and it was reduced by >90% in both genotypes when a cysteinyl leukotriene receptor antagonist was also provided. Hence, the dominant contribution of secretory granule amines to SCF-induced tissue swelling is the result of gp49B1-mediated inhibition of the production of cysteinyl leukotrienes by mast cells. Our findings also provide the first example of an ITIM-bearing receptor that constitutively suppresses inflammation generated in vivo independently of the adaptive immune response by a receptor that signals through intrinsic tyrosine kinase activity rather than immunoreceptor tyrosine-based activation motifs.     

Inhalation anesthetic-induced neuroinvasion by an attenuated strain of West Nile virus in mice

There are contradictory reports regarding the effects of inhalation anesthetics on the immune system. Measurable immune responses have been studied in vitro, but little is known about the in vivo effects in the intact organism. We used an attenuated, non-neuroinvasive, nonlethal strain of the encephalitic West Nile virus, termed WN-25, which can become lethal in combination with environmental stressors, to study possible modulatory immune effects of inhalation anesthetics in mice. Both single short-term exposure and repeated exposure to halothane and nitrous oxide were studied. Exposure to 30% CO2 served as a positive control. Mortality, brain invasion, spleen weight, and antiviral antibodies served as the experimental endpoints. Halothane and nitrous oxide led to viral brain invasion, increased mortality, and suppressed immune response in a concentration- and time-dependent manner. Repeated exposures had a cumulative effect. Assessment of the stability of the viral attenuation did not demonstrate any alteration in the character of the virus, suggesting an increased access to the brain by inhalation anesthetics that led to the fatal encephalitis. These findings may be of special concern to populations at risk, such as operating room staff and patients undergoing general anesthesia in endemic areas of encephalitic virus species, in which subclinical infection may develop into an overt disease.     

Impact of depressive symptoms on adult asthma outcomes.

BACKGROUND: Psychological disorders, including depression, are common in adults with asthma. Although depression is treatable, its impact on longitudinal asthma outcomes is not clear. OBJECTIVE: To elucidate the impact of depressive symptoms on patient-centered outcomes and emergency health care use in adults with asthma. METHODS: We conducted a prospective cohort study of 743 adults with asthma who were recruited after hospitalization for asthma. Depressive symptoms were defined as having a score of 16 or more on the Center for Epidemiologic Studies Depression Scale. We examined the impact of depressive symptoms on patient-centered outcomes (validated severity-of-asthma score, Marks Asthma Quality of Life Questionnaire, and 12-Item Short-Form Health Survey physical component summary score) and on future emergency health care use for asthma ascertained from computerized databases. RESULTS: The prevalence of depressive symptoms was 18% (95% confidence interval [CI], 15%-21%) among adults with asthma. Depressive symptoms were associated with greater severity-of-asthma scores after controlling for age, sex, race/ ethnicity, educational attainment, and cigarette smoking (mean score increment, 2.6 points; 95% CI, 1.8-3.4 points). Furthermore, depressive symptoms were associated with poorer asthma-specific quality of life (mean score increment, 19.9 points; 95% CI, 17.7-22.1 points) and poorer physical health status (mean score decrement, 3.7 points; 95% CI, 1.5-5.8 points). Depressive symptoms were associated with a greater longitudinal risk of hospitalization for asthma (hazard ratio, 1.34; 95% CI, 0.98-1.84). After controlling for differences in preventive care for asthma, the relationship was stronger (hazard ratio, 1.45; 95% CI, 1.05-2.0). CONCLUSION: Depressive symptoms are common in adults with asthma and are associated with poorer health outcomes, including greater asthma severity and risk of hospitalization for asthma.     

Identified serotonergic neurons in the Tritonia swim CPG activate both ionotropic and metabotropic receptors

Although G-protein-coupled (metabotropic) receptors are known to modulate the production of motor patterns, evidence from the escape swim central pattern generator (CPG) of the nudibranch mollusk, Tritonia diomedea, suggests that they might also participate in the generation of the motor pattern itself. The dorsal swim interneurons (DSIs), identified serotonergic neurons intrinsic to the Tritonia swim CPG, evoke dual component synaptic potentials onto other CPG neurons and premotor interneurons. Both the fast and slow components were previously shown to be due to serotonin (5-HT) acting at distinct postsynaptic receptors. We find that blocking or facilitating metabotropic receptors in a postsynaptic premotor interneuron differentially affects the fast and slow synaptic responses to DSI stimulation. Blocking G-protein activation by iontophoretically injecting the GDP-analogue guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S) did not significantly affect the DSI-evoked fast excitatory postsynaptic potential (EPSP) but decreased the amplitude of the slow component more than 50%. Injection of the GTP analogues guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) and 5'-guanylyl-imidodiphosphate, to prolong G-protein activation, had mixed effects on the fast component but increased the amplitude and duration of the slow component of the DSI-evoked response and, with repeated DSI stimulation, led to a persistent depolarization. These results indicate that the fast component of the biphasic synaptic potential evoked by a serotonergic CPG neuron onto premotor interneurons is mediated by ionotropic receptors (5-HT-gated ion channels), whereas the slow component is mediated by G-protein-coupled receptors. A similar synaptic activation of metabotropic receptors might also be found within the CPG itself, where it could exert a direct influence onto motor pattern generation.