Mandakolathur R. Murali, M.D.

Specialty: Allergy

Massachusetts General Hospital

WAC 6-626
15 Parkman Street
Boston, MA 02114


The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.

Thakur, B. K., D. M. Bernardi, et al. (1998). "Invasive cutaneous aspergillosis complicating immunosuppressive therapy for recalcitrant pemphigus vulgaris." J Am Acad Dermatol 38(3): 488-90.

Thakur, B. K., M. R. Murali, et al. (1998). "Hypereosinophilia and markedly elevated immunoglobulin E in a 3-year-old child." Ann Allergy Asthma Immunol 80(5): 371-6.

Murali, R., J. H. Wolfe, et al. (1998). "Altered levels of urokinase on monocytes and in serum of children with AIDS; effects on lymphocyte activation and surface marker expression." J Leukoc Biol 64(2): 198-202.

Urokinase (UK) type plasminogen activator is a serine protease produced by activated human monocytes. Despite the well-documented roles played by UK in cell-mediated immunity in healthy humans, the roles played by UK in the derangements of cell-mediated immune responses observed in HIV disease remain largely undefined. In these studies the numbers of peripheral blood lymphocytes and monocytes bearing surface UK (UK+) as well as serum levels of UK (flow microfluorimetry and ELISA, respectively) were determined in children with AIDS and in healthy HIV-negative children. The effects of exogenous UK on lymphocyte activation (cell cycle analysis using living cells) and surface marker (CD3, CD4, CD8, and CD19) expression (flow microfluorimetry using fixed cells) were also studied. Data are expressed as percent total cells. Numbers of UK+ lymphocytes in children with AIDS were similar to those observed in healthy children. In contrast, numbers of UK+ peripheral blood monocytes were dramatically decreased (> 70%) in the children with AIDS. However, serum levels of UK were increased (nearly threefold) in these children. When lymphocytes from these children were cultured with soluble UK, numbers of cells in S phase of cell cycle appeared suppressed. Incubation of fixed lymphocytes from either a child with AIDS or from a healthy child with exogenous UK appeared to increase numbers of cells expressing CD3. Incubation with UK had no effect on expression of any other surface marker (CD4, CD8, or CD19) using cells from the child with AIDS. In contrast, incubation with UK appeared to decrease (fivefold) numbers of cells expressing CD19 and increase numbers of cells expressing CD4 and CD8 only when fixed lymphocytes from a healthy HIV-negative child were used. The results suggest important roles for UK in regulation of lymphocyte surface markers in general and in CD3- and CD19-dependent lymphocyte activation pathways specifically. Furthermore, these studies add to a widening body of evidence implicating UK dysregulation in the pathogenesis of HIV disease and may point to pharmacological opportunities involving UK to delay or prevent progression of HIV infection into full-blown AIDS.

Thakur, B. K. and M. R. Murali (1995). "EMLA cream-induced allergic contact dermatitis: a role for prilocaine as an immunogen." J Allergy Clin Immunol 95(3): 776-8.

Auci, D. L., G. Kleiner, et al. (1993). "Cytokine-induced suppression and potentiation of hapten-specific immediate hypersensitivity responses." Immunol Invest 22(3): 205-18.

The ability of subcutaneously (s.c.) injected cytokines (IL-4, IL-5, IL-6, IFN alpha, IFN gamma, GMCSF) to regulate the induction of hapten-specific immediate hypersensitivity (IH) responses was studied in BPO-KLH (benzylpenicilloyl-keyhole limpet hemocyanin) sensitized BALB/c mice at the peak of a hapten-specific IgE antibody forming cell (AFC) response. To induce IH responses, mice were injected in the right pinna with either BPO-BSA (benzylpenicilloyl-bovine serum albumin), BPO-KLH (0.01-1.0 micrograms/ml) or mcAb anti-IgE (0.001 - 1.0 micrograms/ml); and in the left pinna with an equal volume of saline (0.05 ml). Pinnae were measured 5 min to 4 hr later using a micrometer caliper. Treatment of mice with IL-4 or IFN gamma dramatically suppressed the induction of IH responses in dose dependent fashion. In contrast, treatment of mice with IL-6 and IFN alpha increased these responses in dose dependent fashion, while GMCSF and IL-5 had no effect. The suppression obtained with IL-4 and IFN gamma, and the increases seen with IL-6 and IFN alpha, were transient since these cytokines, as well as GMCSF and IL-5, had no effect on IH responses elicited 21 days after the peak of BPO-specific IgE AFC responses. The data suggest that cytokine mediated effects on IH responses occur via changes in serum levels of BPO-specific IgG1 or IgE, through direct or indirect effects of cytokines on mast cells or other cell types, or by affecting the ability of BPO-specific homocytotropic antibodies to bind to mast cell surfaces.

Karve, M. M., M. R. Murali, et al. (1992). "Rapid evolution of cardiac tamponade due to bacterial pericarditis in two patients with HIV-1 infection." Chest 101(5): 1461-3.

We describe two HIV-seropositive patients with acute pneumococcal empyema and pericarditis. Cardiac tamponade evolved rapidly in each patient and was reversed with prompt surgical intervention. In each case, immunologic abnormalities were detected which could have facilitated local spread of infection and progression to tamponade. Pericarditis, an otherwise rare manifestation of pneumococcal infection in the antibiotic era, should be anticipated in HIV-seropositive patients with pneumococcal empyema.

Auci, D. L., H. G. Durkin, et al. (1992). "Dysregulated proteolysis in AIDS." Immunol Invest 21(4): 305-19.

Plasmin activity induced by different concentrations of added urokinase (UK) in serum from 20 patients with AIDS (P) and 10 healthy control (HC) subjects was measured using the fibrin plate assay. 125I-fibrin coated 24 well plates were exposed to UK (0.34-6.8 ng/ml) or to trypsin (T) (2.5 micrograms/ml) in the presence of serum (10%) from P or HC. Control wells were exposed to either T or tris buffer (pH 8.1) alone. Volumes were adjusted to 1 ml with buffer and after 1 hr at 37 degrees C, radioactivity (cpm) released into the medium was determined using a gamma counter. Data are expressed as % plasmin activity or as % inhibition of plasmin activity. All sera from HC totally abrogated (greater than 98%) the plasmin activating ability of UK (1.7 ng/ml). In contrast, sera from approximately 50% of P were less able to inhibit plasmin activation (to 26%). The inability of P sera to inhibit plasmin activation was specific since P and HC sera were equally capable of inhibiting T. Mixing experiments using P and HC sera demonstrated that P sera did not block the ability of HC sera to inhibit plasmin activation. The inhibitory activity of HC and active P sera eluted in the void volume of a spehadex G100 column (MW greater than 100,000 daltons) and is acid sensitive, however HC sera also contains an acid stable inhibitor(s) of plasmin activation not detected in P sera. These data suggest dysregulation of UK dependent proteolysis may be associated with AIDS.

Auci, D. L., S. M. Chice, et al. (1992). "Constitutive production of PAI-II and increased surface expression of GM1 ganglioside by peripheral blood monocytes from patients with AIDS: evidence of monocyte activation in vivo." J Leukoc Biol 52(3): 282-6.

To characterize the activation state of monocytes during human immunodeficiency virus (HIV) infection, peripheral blood monocytes (PBMs) from patients with acquired immunodeficiency syndrome (n = 10) and from healthy controls (n = 10) were cultured for 4 days. Monocyte culture supernatant (MCS) was collected daily, and levels of urokinase (UK) inhibitor PAI-II, a product of activated monocytes, released into MCS were determined (fibrin plate assay). To examine the activation state of PBMs independently, expression of GM1 ganglioside on PBMs from patients with AIDS (n = 9), patients with AIDS-related complex (ARC) (n = 8), HIV+ asymptomatic patients (n = 6), and HIV- healthy controls (n = 11) was determined (flow cytometry; living cells in suspension). Data are expressed as percent inhibition of UK, or as percent total cells. Patients' MCS collected on days 1-4 of culture contained similar levels of PAI-II because it inhibited UK in similar fashion (70-90%). In contrast, MCS from healthy controls, collected after 2 days, had decreased ability to inhibit UK (15-50%) and thus contained lower levels of PAI-II. Monocyte activation, measured by increased expression of GM1 ganglioside on PBM surfaces, directly correlated with the progression of HIV infection into the development of AIDS, since the order of magnitude of GM1 ganglioside expression on PBMs was AIDS greater than ARC greater than HIV+ asymptomatic = healthy controls. Our data indicate that PBMs from patients with AIDS are constitutively activated and suggest that activation directly correlates with disease progression.

Platanias, L. C., D. Paiusco, et al. (1989). "Thrombotic thrombocytopenic purpura as the first manifestation of human immunodeficiency virus infection." Am J Med 87(6): 699-700.

Durkin, H. G., D. L. Auci, et al. (1989). "Control of IgE responses." Clin Immunol Immunopathol 50(1 Pt 2): S52-72.

Peyer's patches (PP) in germ-free rats (GF) and in the hyper-IgE syndrome patient (HIES) differ from their conventional rat (C) and healthy human (HH) counterparts in that GF rats contained fewer (two-fold) PP and none was detected in HIES. Existing PP in GF rats had reduced cellularity (three-fold) and different B and T cell subsets: high numbers of IgE-bearing (sIgE+) B cells (approximately 15% of total cells), one-half of which also expressed sIgA, were present in GF rat PP while none was detected in C rat PP (less than 1%). GF rat PP also contained elevated numbers of sIgA+ cells and decreased sIgM+ cells, with elevated numbers of sThy 1+ RT 7.1+ Ig- T cells (suppressor phenotype) and reduced sThy 1- RT 7.1+ Ig- T cells (helper phenotype). The cellular composition of GF rat PP was converted to that resembling a C rat within 18 hr after (a) use of standard (unautoclaved) chow; (b) feeding with certain bacteria or "working" bacterial cell wall components (BCWC) and synthetic derivatives, murein, MTP-PE, and norMDP, but not with LPS, core lipid A, or lipoprotein; BCWC had no effect if injected intravenously; or (c) thymectomy. Each procedure resulted in (i) elimination of sIgE+ B cells and normalization of the other isotypes, and (ii) loss of T suppressor cells and normalization of T helper cells. After treatments, no sIgE+ cells were detected in bone marrow (BM), thymus, other lymphoid organs, or blood. PP were not detected in HIES, although they were present in HH (approximately 10/individual). P blood contained two distinct sIgE+ B cell subpopulations, the apparent source of which was mesenteric lymph node (MLN), the only organ in which high numbers of these cells (35%) (five nodes examined) were detected; far fewer IgE+ cells were found in spleen (less than 5%), and none was detected in BM, thymus, other LN, or appendix, which was virtually acellular. Virtually no IgE secreting plasma cells were detected in MLN, spleen, appendix, other lymphoid organs, or in gut lamina propria. IgE+ B cells in MLN were not detected in follicles (classical B cell areas); instead, they were found in high numbers in the thymus-dependent area and in medulla. Most follicles (greater than 98%) in MLN and spleen contained intercellular IgE complexed to bacterial antigen and/or CD23 (IgE-binding factor? antigen?), but contained no germinal centers.(ABSTRACT TRUNCATED AT 400 WORDS)

Ross, J. M., M. R. Murali, et al. (1984). "Anaphylaxis and immunologic insulin resistance in a diabetic woman with ketoacidosis." Diabetes Care 7(3): 276-9.

A diabetic woman presented with diabetic ketoacidosis after demonstrating immediate-type hypersensitivity to heterologous insulin. She had had interrupted insulin therapy in the past. Insulin requirements during the course of treatment for the acidosis suggested marked resistance, with 50,000 U of insulin needed in the first 36 h. Anaphylaxis requiring intubation and emergency treatment developed after intravenous purified pork insulin was administered. Elevated titers of insulin-specific IgG (441.6 U/L serum) demonstrated immunologic insulin resistance. Positive intradermal skin tests for beef and pork insulins and detection of insulin-specific IgE by RAST assay revealed concurrent immediate-type allergy. A review of the literature revealed the unique occurrence in this patient of simultaneous ketoacidosis, insulin allergy, anaphylaxis, and immunologic resistance. Interrupted insulin therapy in susceptible individuals remains a potential danger, even with the availability of purified insulin preparations.

Thiruvengadam, K. V., K. Arunachalam, et al. (1972). "Pulmonary alveolar microlithiasis in a family." J Assoc Physicians India 20(9): 707-12.