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PubMed1987

Molecular regulation of phagocyte function. Evidence for involvement of a guanosine triphosphate-binding protein in opsonin-mediated phagocytosis by monocytes.

Although many functions of phagocytes are known to be regulated by guanosine triphosphate (GTP)-binding proteins, phagocytosis itself has not been considered one of these. However, previous studies have examined only unstimulated neutrophil phagocytosis. Motivated by our previous work, which showed that stimulated neutrophil phagocytosis is regulated by GTP-binding proteins (H. D. Gresham, M. G. Peters, and E. J. Brown. 1986. J. Cell Biol. 103:215a), we have examined the effect of pertussis toxin (PT) on monocyte receptor-mediated phagocytosis. PT inhibited unstimulated and fibronectin-stimulated IgG-mediated phagocytosis and also inhibited C3b-mediated phagocytosis stimulated by fibronectin or phorbol dibutyrate. Cholera toxin (CT) had no effect on unstimulated or stimulated phagocytosis mediated by IgG or C3b. PT inhibition of phagocytosis was not mediated via increases in cellular cAMP levels or by inhibition of the respiratory burst. Inhibition of phagocytosis did not result from decreased numbers of plasma membrane opsonin receptors nor decreased ability to bind opsonized targets. Although phorbol ester-stimulated phagocytosis was inhibited by PT, ligand-independent internalization of CR1 stimulated by phorbol dibutyrate proceeded normally in PT-intoxicated cells. We conclude that a PT-sensitive GTP-binding protein does regulate phagocytic function in monocytes. This protein operates on a molecular mechanism specific to the process of ingestion in both unstimulated monocytes and in cells stimulated to increase phagocytosis. Because unstimulated neutrophil phagocytosis is unaffected by PT or CT, and stimulated neutrophil phagocytosis is inhibited by both PT and CT, our data also demonstrate that monocytes and neutrophils have distinct mechanisms for regulation of phagocytic function.

Catalase↗
PubMed1983

Electrophoretic isolation of a membrane-bound NADPH oxidase from guinea-pig polymorphonuclear leukocytes.

Electrophoretic isolation of a membrane-bound NADPH oxidase of guinea-pig polymorphonuclear leukocytes was attempted with the O2- -generating membranes of cells unstimulated or stimulated with C3b-zymosan or sodium dodecyl sulfate, and also with the phagosomes isolated from the phorbol myristate acetate-coated latex particle-phagocytosing cells. When these vesicles were subjected to discontinuous polyacrylamide gel electrophoresis in the presence of Triton X-100 and then assayed for NADPH-Nitroblue tetrazolium reducing activity, the activity was detected by the appearance of a single, blue band of the reduced dye on the gel, independent of the source of vesicles. In addition, the enzyme was able to generate O2- and its activity was significantly augmented with the homologous liver microsomal cytochrome b5. Its activity was heat-labile and inactivated by N-ethylmaleimide and p-chloromercuribenzene sulfonate. The enzyme, with an apparent molecular weight of 150 000, in the phagosomes was easily susceptible to limited proteolysis by trypsin and formed an active fragment with a molecular weight of 70 000, accompanying the loss of O2- -generating activity of the vesicles.

Animals↗
PubMed1993

A novel ELISA assay for the detection of C3 nephritic factor.

We have developed an ELISA procedure for the detection of C3 nephritic factor (C3NeF), in which wells are coated with a fixed concentration of 2 micrograms C3b per well, and subsequently reacted with B and D. The presence of increasing concentrations of NiCl2 showed a NiCl2 concentration-dependent generation of C3bBb and very little solid-phase bound C3bBb was generated with MgCl2. The formation of solid-phase C3bBb in the presence of an optimal concentration of 1 mM NiCl2, was time-dependent and plateau values were reached after 30 min at 37 degrees C. IgG purified from the serum of a patient with membranoproliferative glomerulonephritis (MPGN) type II containing C3NeF stabilizing activity was bound to the C3bBb generated on microwells in a dose-dependent manner whereas normal IgG exhibited only minor reactivity. C3NeF activity was measured using the ELISA method in patients with MPGN type II (n = 15) and other diseases (n = 17) and in normal controls (n = 15). Most of the patients with MPGN type II exhibited positive C3NeF at various levels, while two of the disease controls showed only slight reactivities. C3NeF titers measured by this new ELISA procedure correlated well with previously described hemolytic assays (r = 0.617, p < 0.01).

Complement C3 Nephritic Factor↗
PubMed2003

F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins.

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Animals↗
PubMed1986

Loss of complement receptor type 1 (CR1) on ageing of erythrocytes. Studies of proteolytic release of the receptor.

Complement receptor type 1 (CR1) is a glycoprotein of Mr about 250 000 present on erythrocytes and other cell types. CR1 acts as a cofactor in the factor I-mediated breakdown of complement fragment C3b to form iC3b. Using an assay of cofactor activity, a wide variation in mean CR1 levels between erythrocytes from individual donors is observed. CR1 levels also decrease on ageing of erythrocytes in vivo, and again the rate of loss is widely variable between individuals. However, variable loss of CR1 during ageing of erythrocytes is likely to make only a minor contribution to the observed variation in mean CR1 levels. CR1 is very sensitive to proteolysis, and random proteolytic removal of CR1 from erythrocytes is likely to be an important factor in loss of CR1 on ageing of red cells in vivo. In vitro, mild trypsin treatment, plasmin or thrombin digestion of erythrocytes results in the loss of the factor I cofactor activity from the cell surface, and appearance of this activity in the supernatant. We conclude that an active fragment of CR1 is released from the cell surface on proteolysis. Subsequent prolonged trypsin treatment destroys most of the activity of this fragment. Proteolytic removal of CR1 from red cells may account not only for loss on ageing of cells, but also for the acquired CR1 deficiencies observed by others in systemic lupus erythematosus.

Erythrocyte Aging↗
PubMed1984

Inhibition of macrophage C3b-mediated ingestion by syphilitic hamster T cell-enriched fractions.

Macrophages are important for host defense against syphilitic infection. Our results show that C3b-mediated ingestion (C3bMI), a characteristic of activated macrophages, was inhibited in vitro by nonadherent cells from hamsters infected with Treponema pallidum subspecies endemicum. When macrophage target cells from normal, syphilitic, or lipopolysaccharide-treated animals were co-cultured with nonadherent cells derived from normal or syphilitic hamsters, noticeable differences were detected. Nonadherent syphilitic cells significantly suppressed macrophage C3bMI, whereas normal nonadherent cells displayed little or no suppressive activity. In general, macrophage C3bMI was reduced by nonadherent cells obtained throughout the course of syphilitic infection, although it eventually began to recover. The syphilitic nonadherent cells with maximum suppressive effect were those obtained from hamsters infected for 3 to 6 wk. The addition of treponemal antigens additionally inhibited C3bMI. The inhibitory effect of syphilitic nonadherent cells on either lipopolysaccharide-treated or syphilitic macrophages was sustained even when the nonadherent cells were removed from the cultures, and the effect continued for at least 72 hr thereafter. Fractionation of syphilitic nonadherent cell populations by two independent methods produced T cell-enriched preparations with significantly more suppressive activity than non-T cell-enriched preparations. These observations may account for the chronicity of syphilitic infection.

Adult↗
PubMedDate not supplied

[Secretion of membrane-bound serine proteinases by polymorphonuclear leukocytes during adhesion to various types of receptor-dependent and receptor-independent sorbents].

A high level of the membrane-bound proteinase (LMP) secretion by human polymorphonuclear leukocytes (up to 680 nmol/min/ml with N-benzoyl-L-arg-EE as a substrate) was shown during the cell adhesion to receptor-dependent (immobilized aggregates of IgG and C3b) and receptor-independent (DEAE-Sephadex and polymethyl methacrylate) absorbents. Incubation medium contained 6.10(6) cells/ml. The rate of secretion reached the maximal level during 15 min although its level was already high to the 5 min of C3b- and hydrophobic surface-induced activation (491 +/- 55 and 382 nmol/min, respectively). The high level of LMP secretion coincided with the peak of luminol-dependent chemoluminescence during the receptor-dependent adhesion, but did not correlate with a low level of luminescence in the receptor-independent adhesion. Localization of LMP in latent form in neutrophil membrane was shown earlier; the enzyme activation may occur due to effect of polycationic molecules of bovine tissue proteinase inhibitor of Kunitz type, protamine sulfate, alkaline fraction of ampholines. The enzyme (with BAEE as a substrate) was identified as serine proteinase of the trypsin-like type which activated Hageman factor (the XII factor of clotting system) and demonstrated the kininogenase activity. Only slight elastase-like activity was detected after incubation of neutrophils with all the adsorbents studied (0-2 nmol/min/ml with MeOSucAlaAlaProValpNA as a substrate). Chymotrypsin-like activity achieved maximum only by 30 min of activation with all the types of adsorbents (up to 270 nmol/min/ml with N-benzoyl-Tyr-EE as a substrate); this suggests impairment of azurophilic granules and appearance of cathepsin G.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Phagocytosis of aged human neutrophils by macrophages is mediated by a novel "charge-sensitive" recognition mechanism.

The removal of neutrophils and their histotoxic contents from the inflamed site is a prerequisite for resolution of tissue injury, and a point at which factors critical to the pathogenesis of chronic inflammation may act. Engulfment of intact, senescent neutrophils by macrophages represents an important neutrophil disposal process. In this study the mechanism by which human monocyte-derived macrophages (M phi) recognized and ingested human neutrophils that had been aged in culture was studied using an in vitro phagocytic assay. Inhibition of M phi receptors for Ig Fc and the opsonic complement fragments C3b and iC3b with MAbs to M phi FcR, CR1, CR3, and CR4 had no effect on recognition, and the pattern of inhibition observed when polyanions were included in the medium at 1 mg/ml was different from that reported for the M phi receptor for protein advanced glycosylation end products (AGE), indicating a recognition mechanism different from those proposed for M phi phagocytosis of senescent erythrocytes. Furthermore, although aging neutrophils undergo programmed cell death (or apoptosis), which is directly related to recognition by M phi, the pattern of inhibition observed with monosaccharides was different from that reported to inhibit the binding of apoptotic mouse thymocytes to isologous M phi. By contrast, evidence was obtained for a novel recognition mechanism inhibitable by cationic sugars and amino acids in a charge-dependent fashion, and directly modulated by pH but not affected by inhibitors of the mannose-6-phosphate, sheep erythrocyte, mannosyl-fucosyl, asialoglycoprotein, and scavenger receptors of the macrophage. These observations suggest that hydrogen ions and charged molecules may modulate M phi uptake of senescent neutrophils at inflamed sites, and that recognition itself may involve charged structures on the cells.

Acetylglucosamine↗
PubMed1990

Nonsteroidal antiinflammatory agents inhibit upregulation of CD11b, CD11c, and CD35 in neutrophils stimulated by formyl-methionine-leucine-phenylalanine.

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit PMN aggregation, chemotaxis, degranulation, and superoxide anion production stimulated by synthetic formyl peptides. Many of these functions are dependent upon receptors for the complement components C3b and iC3b (CD35 and CD11b, respectively), or the adherence molecules CD11b and CD11c. Using flow cytometry and specific monoclonal antibodies, we studied the effects of the NSAID piroxicam and indomethacin on the upregulation of these cell surface proteins on PMNs stimulated with FMLP, C5a, or ionomycin. Incubation of PMNs at 37 degrees C increased the expression of all three of these surface proteins. A further increase was induced by stimulation with FMLP, C5a, or ionomycin. Both piroxicam and indomethacin inhibited FMLP-induced upregulation of CD11b, CD11c, and CD35, but neither drug affected the upregulation of these surface molecules induced by C5a or ionomycin. Furthermore, piroxicam had no effect on 37 degrees C-induced upregulation of any of the surface proteins, while indomethacin showed no effect on 37 degrees C-induced CD11b upregulation but suppressed CD11c and CD35 upregulation. Inhibition of surface protein upregulation by FMLP was not due to inhibition of FMLP binding to PMNs. We conclude that piroxicam and indomethacin inhibit FMLP receptor-mediated upregulation of CD11b, CD11c, and CD35 in PMNs, but have no effect on the upregulation of these molecules by ionomycin or C5a. These data suggest that piroxicam and indomethacin interfere with postreceptor signaling events specific to PMN stimulation by FMLP.

Adult↗
PubMed1997

Altered expression of IgG and complement receptors indicates a significant role of phagocytes in atopic dermatitis.

BACKGROUND: Strict dietary precautions against allergic sensitization may benefit a group of predisposed children. OBJECTIVE: To develop new strategies for identifying these children, a better understanding of the processes that initiate sensitization and regulate and perpetuate the inflammatory response is needed. METHODS: We measured the expression of the receptors for the constant (Fc) region of IgG (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) and that for the complement fragments C3b and C3bi (CR1 and CR3) in neutrophils and monocytes from 39 children with atopic dermatitis, 17 disease control patients with acute infections, and 17 healthy control subjects. The capacity of phagocytes to produce reactive oxygen species was also determined. To find the best way of discriminating the patients with atopic dermatitis from control subjects, a stepwise logistic binary regression model was made. RESULTS: The stepwise logistic regression analysis was based on differences in individual receptor expression between the study groups. Because acute infections strongly affected receptor expression in both neutrophils and monocytes, to avoid diagnostic bias, children with acute infections were excluded from the analysis. The combination of the receptors CR1 in neutrophils and Fc gamma RI and Fc gamma RII in monocytes was the best indicator of atopic dermatitis. A significant correlation between the expression of CR1 in neutrophils and in monocytes, as well as reactive oxygen species production of phagocytes, and the severity of the eczema was detected. CONCLUSIONS: These results suggest that a distinct receptor profile of phagocytic cells can be characterized in patients with atopic dermatitis, providing a new direction to the search for early identification of children predisposed to allergic sensitization.

Causality↗
PubMed1994

Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass.

Plasma concentrations of the complement activation products C3b, iC3b, and C3c; the terminal C5b-9 complement complex; and the granulocyte proteins calprotectin, myeloperoxidase, and lactoferrin were assessed in two groups of patients undergoing aortocoronary bypass procedures. In 10 patients operated on, the bypass circuits were coated by the Carmeda Bio-Active Surface and systemic heparinization was reduced to 1.5 mg/kg; in another 10, the systems were uncoated and the dosage of systemic heparinization was 4 mg/kg. In both groups, significant complement activation was observed after the onset of cardiopulmonary bypass, but the maximum levels of C3b, iC3b, and C3c and the terminal C5b-9 complement complex were significantly lower in the heparin-coated group. In both groups, a significant increase in calprotectin, myeloperoxidase, and lactoferrin release was observed by the end of operation. The maximum myeloperoxidase levels were significantly lower in the heparin-coated group than those in the uncoated group (p = 0.03). There was a correlation of borderline significance between the formation of terminal C5b-9 complement complex and lactoferrin release, as well as between the formation of terminal C5b-9 complement complex and myeloperoxidase release (p = 0.05). The postoperative blood loss did not differ significantly between the two groups. We conclude that coating by end point-attached and functionally active heparin allows a significant reduction in the amount of systemic heparinization, and significantly reduces complement and granulocyte activation.

Aged↗
PubMed2001

Identification of a site on mannan-binding lectin critical for enhancement of phagocytosis.

Mannan-binding lectin (MBL) constitutes an important part of the human innate immune defense system. It has been shown to mediate the activation of complement upon binding to specific microbial carbohydrate motifs, to directly opsonize organisms, and to enhance the phagocytosis of targets suboptimally opsonized with IgG or complement components C3b or C4b. This enhancement of phagocytic activity induced by MBL and other molecules that contain a collagen-like region contiguous with a pattern recognition domain is mediated by a 126,000 M(r) surface glycoprotein, designated C1qR(P). Although it has been known that the collagen-like domain of these "defense collagens" contains the interaction site(s) that triggers this enhancement of uptake, the specific interaction site has not been identified. To address this issue, wild type and mutant MBL constructs were generated, inserted into baculovirus, expressed in Sf9 cells, and the recombinant MBL (rMBL) proteins purified by mannan affinity chromatography. The effect of wild type and mutant rMBL on the phagocytosis of targets suboptimally opsonized with IgG or with IgM and C4b by human peripheral blood monocytes was then assessed. Two mutants, one of which has five GXY triplets deleted below the kink region of MBL and the other one having only two of the GXY triplets deleted below the kink, failed to enhance phagocytosis, suggesting the importance of the specific sequence GEKGEP in stimulating phagocytic activity. Similar sequences were detected in other defense collagens, implicating the consensus motif GE(K/Q/R)GEP as critical in mediating the enhancement of phagocytosis through C1qR(P.) Clarification of specific ligand-C1qR(P) interactions should facilitate the investigation of the signal transduction processes involved in the cell activation, as well as provide the basis for the design of specific modulators of the functions mediated by this receptor.

Amino Acid Sequence↗
PubMed1999

The role of a single N-linked glycosylation site for a functional epitope of herpes simplex virus type 1 envelope glycoprotein gC.

A monoclonal antibody, B1C1, binding to an epitope of antigenic site II of the herpes simplex virus type 1 (HSV-1) glycoprotein gC-1, is a potent inhibitor of two important biological functions of gC-1: its binding to cell surface heparan sulfate and its binding to the receptor for complement factor C3b. Here, we have analyzed a B1C1-resistant HSV-1 variant (HSV-12762/B1C1B4.2), obtained after passage of wild type HSV-1 (HSV-12762) in the presence of high concentrations of B1C1. The transport of newly synthesized mutant gC-1 to the cell surface was comparable to that of wild type glycoprotein, but no binding of surface-associated mutant gC-1 to B1C1 was detected. However, mutant and wild type gC-1 bound equally well to other site II Mabs. Attachment of wild type but not mutant virus was inhibited by B1C1. Sequencing of the mutant gC-1 gene revealed only one nucleotide change, resulting in replacement of Thr150 by an Ile, in turn destroying an N-glycosylation site at Asn148. Loss of one complex type N-linked glycan was confirmed by endoglycosidase digestion and subsequent SDS-polyacrylamide gel electrophoresis. Circular dichroism analysis of purified gC-1 from cells infected with mutant or wild type virus did not reveal any difference in secondary structure between mutant and wild type gC-1. It was not possible to obtain a B1C1-resistant phenotype by nucleotide-directed mutagenesis of gC-1 where Asn148 was changed to a glutamine. These data demonstrated that the threonine of the glycosylation site and not the N-linked glycan in itself was essential for B1C1 binding

Amino Acid Sequence↗
PubMed1987

Prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes treated with C3b or bacterial lipopolysaccharide.

C3b or lipopolysaccharide treatment of human peripheral blood monocytes in culture stimulates an early release of thromboxane B2 and a delayed release of prostaglandin E into culture supernatants. Immunoreactive thromboxane B2 release is maximal from 2-8 h, whereas prostaglandin E release is maximal from 16-24 h after stimulation of monocytes in culture. We further examined this process by comparing the time course of labelled prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes which were pulse or continuously labelled with [3H]arachidonic acid and [14C]eicosatrienoic acid. The release of labelled eicosanoids was compared with the release of immunoreactive prostaglandin E and thromboxane B2. The time course of prostaglandin E2 release was virtually identical to the release of prostaglandin E1 in all culture supernatants regardless of labelling conditions. However, release of immunoreactive prostaglandin E paralleled the release of labelled prostaglandin E1 and E2 only for continuously labelled cultures. The release of labelled prostaglandin E1 and E2 from pulse labelled cultures paralleled the release of thromboxane B2 and not immunoreactive prostaglandin. In contrast, labelled and immunoreactive thromboxane B2, quantitated in the same culture supernatants, demonstrated similar release patterns regardless of labelling conditions. These findings indicate that the differential pattern of prostaglandin E and thromboxane B2 release from human monocytes is not related to a time-dependent shift in the release of prostaglandin E1 relative to prostaglandin E2. Because thromboxane B2 and prostaglandin E2 are produced through cyclooxygenase mediated conversion of arachidonic acid, these results further suggest that prostaglandin E2 and thromboxane B2 are independently metabolized in human monocyte populations.

Alprostadil↗
PubMed1994

Involvement of the pertussis toxin-sensitive GTP-binding protein in regulation of expression and function of granulocyte complement receptor type 1 and type 3.

Human polymorphonuclear leukocytes (PMN) express receptors for complement (C) C3b and C3bi termed CR1 and CR3, respectively. The addition of PMA or fMLP to PMN enhances the capacity of these receptors to promote binding of C3b- and C3bi-coated erythrocytes. fMLP-dependent increase of the binding of these ligand-coated erythrocytes was completely abolished by prior exposure of the PMN to pertussis toxin (IAP). GTP-binding protein (Gi alpha) was ADP-ribosylated and dysfunctional by this treatment. On the other hand, PMA-dependent binding of these ligands, as well as control binding, was inhibited only slightly, if at all, by the IAP treatment. The levels of C receptor expression on cell surface were determined by flow cytometry using monoclonal antibody against CR1 and those against the alpha and beta chains of CR3 (CR3 is composed of alpha and beta chain). Upon exposure of PMN to the chemotactic factor or PMA, or upon incubation of the cells at 37 degrees C, the surface expression of CR1 and CR3 alpha was increased. IAP also blocked an fMLP-induced increase of CR1 and CR3 alpha, but did not block the temperature- or PMA-dependent increase of these receptors. Opsonized zymosan (SOZ), another ligand for CR3, also led to an increase of both CR1 and CR3 alpha. Neither PMA nor SOZ brought about an increase of the surface expression of CR3 beta, but fMLP caused a slight increase of CR3 beta in an IAP-sensitive manner. Based on the IAP-sensitivity of the receptor expression, therefore, it appears that at least two separate mechanisms are operative in the control of C receptors. In addition, the alpha and beta chains of CR3 are regulated independently. The present data offer evidence suggesting that C receptor functions are in part regulated through a GTP-binding protein via modulation of their surface expression.

Adenosine Diphosphate Ribose↗
PubMed1995

Immunopathogenesis of inflammatory myopathies.

Immune-mediated mechanisms appear to play a primary role in the pathogenesis of polymyositis (PM) and dermatomyositis (DM). The serum of patients with active DM has high levels of circulating complement fragments C3b, C4b, and C5b-9 membranolytic attack complex (MAC) and demonstrates a very high C3 uptake in an vitro assay system. The MAC and the immune complex-specific C3bNEO fragment are deposited on the endomysial capillaries early in the disease and lead sequentially to loss of capillaries, muscle ischemia, muscle fiber necrosis, and perifascicular atrophy. In contrast, in PM the muscle fiber injury is initiated by sensitized CD8+ cytotoxic T cells that recognize heretofore unknown and probably endogenous muscle antigens in the context of major histocompatibility complex (MHC) class I expression. A restricted (oligoclonal) pattern of T-cell receptor with prominence of Va1, Vb6, and Vb15 genes is noted within the endomysial infiltrates suggesting that the T-cell response is antigen driven. In both PM and DM, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 are upregulated in the endomysial endothelial cells and function as ligands for the leukocyte integrins leukocyte function-associated antigen (LFA)-1 and very late activating antigen (VLA)-4, allowing activated lymphocytes to adhere to the endothelial cells and migrate to the muscle fibers. Among viruses, only the retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV)-1 have been convincingly shown to trigger PM, which is mediated by nonviral-specific, cytotoxic CD8+ cells. The treatment of inflammatory myopathies remains empirical. Many patients respond to steroids to some degree and for some period of time. Azathioprine, methotrexate, cyclosporine, cyclophosphamide, and plasmapheresis can be of mild to moderate benefit. High-dose intravenous immunoglobulin (IVIg) is a promising therapeutic modality for some patients resistant to therapies. In a controlled study, IVIg was effective in DM not only in improving the clinical symptoms but also in reversing the underlying immunopathology. The role of IVIg in PM and IBM is under study in control trials.

Atrophy↗
PubMed1996

Mechanism of suppression of cell-mediated immunity by measles virus.

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.

Antibodies, Monoclonal↗
PubMed1998

Complement activation in sudden deafness.

OBJECTIVE: To test whether complement activation is associated with sudden deafness. DESIGN: Plasma samples obtained from patients in the acute phase of sudden deafness were analyzed for complement activation measured by C3bc levels and terminal complement complex. Comparisons were made with plasma samples from healthy controls. PATIENTS: Twenty-five adult patients with unilateral sudden deafness. The criteria for inclusion were symptoms of hearing loss for not longer than 14 days and a hearing loss of 35 dB or more measured at entry. RESULTS: Levels of C3bc were higher in patients compared with controls (P<.001). There were no differences in the formation of terminal complement complex in patients and controls. CONCLUSIONS: The elevated levels of C3bc in patients with sudden deafness indicate an activation of the first part of the complement cascade and therefore suspected inflammatory causes. Measurements of C3bc levels might identify patients with sudden deafness who would benefit from treatment with anti-inflammatory drugs.

Adult↗