Immunology Today December 1983 A u t o i m m u n e tissue d a m a g e

Humoral or cellular effector mechanisms? from Hubert Kolb and Klaus Toyka Human autoimmune diseases have long been regarded as the sole consequence of autoantibody production, often with concomitant immune complex formation. More recent evidence indicates that T lymphocytes and macrophages may play an important role in damaging target tissues. In July, invited participants discussed in the Diisseldorf Autoimmunity Workshop 1983" the evidence for the dominance of humoral or cellular effector mechanisms in the various human autoimmune diseases.

Classically, human autoimmunity is attributed to the action of autoantibodies and immune complexes, often via activation of the cytolytic and inflammatory potential of the complement system. The few examples of cell-mediated autoimmunity, like experimental allergic encephalomyelitis (EAE) or experimental allergic orchitis (EAO), were regarded as less typical and confined to animal models. The case for antibody-based damaging reactions in most autoimmune diseases rests on passive transfer experiments: serum or immunoglobulin fractions from patients with myasthenia gravis, autoimmune thyroiditis, immune complex glomerulonephritis, autoimmune hemolytic anemia, aplastic anemia (some), idiopathic thrombocytopenic purpura, and, more recently, myeloma polyneuropathy (U. A. Besinger, Munich), pemphigus vulgaris and the Lambert-Eaton myasthenic syndrome have all been shown to induce in recipient animals clinical symptoms resembling the respective human disease. Workshop participants demonstrated passive transfer by serum immunoglobulins of acute and chronic polyneuritis (A. Sumner, Philadelphia; K. V. Toyka, D/isseldor0, galactocerebrosideinduced experimental allergic neuritis (EAN) (Sumner and A. Asbury, Philadelphia) and EAE (H. Lassmann, Vienna). * The workshop was organized by H. Kolb, K. V. Toyka and W. Wechsler, and was supported by the Deutsche Forschungsgemeinschaft, SFB 200.

Surprisingly, the blood-nerve barrier allows human IgG to penetrate into the interstitial space (the endoneurium) of nerve fibers in the recipient animals while it is relatively tight to autologous IgG in man and animals (U. G. Liebert, Wfirzburg). IgG antibodies may therefore reach the nerve targets in cross-

species experiments (G. Schwendemann, Diisseldort). This is important when passive transfer experiments with anti-nerve antibodies are carried out. In the human immunoneuropathies the antigens are unknown with the exception of a newly discovered subgroup of dysproteinemic polyneuropathy with monoclonal antibodies to the myelinassociated glyeoprotein (A. Steck, Lausanne). The exact pathogenic role of these monoclonals is under study. IgG from recently diagnosed type-1 diabetics, when transferred to mice, impairs the insulin response by 0-islet cells to glucose stimulus1 although no significant islet cell damage or inflammation is apparent (H. Kolb, D/.isseldorf and Toyka). In many passive transfer experiments it has not been ruled out that other serum factors (for example T-lymphocyte Continued on p. 333

Immunoepidemiology helps to unravel the mysteries of dengue haemorrhagic fever from Tikki Pang It is now nearly 20 years since a strong correlation was noted in Thailand between secondary immune responses and severe dengue syndromes. It is currently thought that 'enhancing' antibodies, in an individual undergoing a second infection with a different serotype of dengue virus, promotes viral replication in monocytes which then become the targets of an immune elimination response (possibly T-cell mediated). The monocytes then release various chemical mediators which produce the symptoms of shock and haemorrhage seen in dengue haemorrhagic fever (DHF). Much new knowledge has been gained in recent years especially from immunoepidemiological and immunological studies, and these were discussed at a recent meeting*.

A major question has always been: what sequences of dengue infections result in enhanced severity of disease? N. Sangkawibha (Bangkok) described results from an elegant long-term epidemiological study of Thai children where careful pre- and post-epidemic parameters were determined for a wide variety of factors. The data from the study suggest that risk factors for DHF *Held in Kuala Lumpur, Malaysia, on 1 - 3 September 1983.

(and the associated dengue shock syndrome, DSS) are secondary infections with dengue-2 virus which follow primary infections with dengue- 1, dengue-3 and dengue-4 (in descending order of risk). All patients who had DHF/DSS had secondary antibody responses and only dengue-2 viruses were recovered from these patients. As part of the same study, S. B. Halstead (Honolulu) reported that for sequential dengue Continued on p. 334

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334 provoking autoimmune reactions was another mechanism pertinent to the discussion of dominant effector mechanisms (D. Bitter-Suermann, Mainz). Clinicians want to know which effector mechanism is dominant in the progressive, relapsing phase of the disease in order to devise suitable therapy. With the advent of T-cell-directed immunosuppressants such as cyclosporine and macrophage or lymphocyte subsetImmunoepidemiology- Contd. from p. 331 infections there exists an 'original antigenic sin' antibody response which was used to identify the initial dengue infections in hospitalized DHF/DSS cases. An independent study performed by D. S. Burke and colleagues (Bangkok) also suggests that pre-existing antibody is an important factor in the pathogenesis of D H F due to dengue-2 and also dengue-4 virus in Thai children. Halstead also gave an unofficial report of the major dengue outbreak in Cuba in 1981 (116 143 cases with 10 000 cases of DHF/DSS - the first time D H F had been documented outside South-east Asia) and at the same time pointed out the potential threat of D H F in parts of the world where dengue viruses circulate but which, as yet, do not have cases of DHF/DSS. The Cuban data also suggest a large predominance of secondary infections among DHF patients, with a possible dengue-1 followed by dengue-2 sequence responsible for severe disease. Another interesting feature of this outbreak is the marked under-representation of black children among DHF/DSS cases. It should also be noted, however, that data presented from recent outbreaks in Malaysia and Indonesia suggest that dengue-3 virus can also be associated with severe DHF/DSS in children undergoing a second infection. Immunological studies have also provided additional insights into pathogenetic mechanisms at the cellular level. J. S. M. Peiris (Peradeniya, Sri Lanka) and M. J. Cardosa (Oxford) described the antibody enhancement phenomenon, suggesting that complement receptors on the surface of monocytes, in addition to Fc receptors, may play a role in promoting entry of virus. Halstead, in collaboration with E. A. Henchal, M. K. Gentry and others (Washington, DC), also reported preliminary results on the use of monoclonal antibodies as reagents to study the mechanisms of enhancement and the distribution of enhancing epitopes. Seven dengue-2 strains were studied for antibody-dependent enhancement in a mouse macrophage line (P388-D1), using a panel of five monoclonal antibodies to dengue-2. The

Immunology Today, voL 4, No. 12, 1983

specific monoclonal antibodies it should eventually be possible to perform depletion experiments which block selectively immune effector mechanisms of choice (P.J. Grob, Ziirich). This type of experiment may finally help to determine the dominant effector mechanism in the various autoimmune diseases and lead to immunotherapy which is more specific and more efficient than today's generalized immunosuppression.

Hubert Kolb is in the Diabetes-Forschungsinstitut and Klaus V. Toyka is in the Neurologische Universitaetsklinik, D-4OOODilsseldooe l, FR G.

results indicate a heterogeneity of infection enhancement in that two dengue-2 strains were enhanced by only three monoclonal antibodies, two by four antibodies, and three by all five antibodies. S. Hotta (Kobe) showed that macrophages activated by a variety of agents also effectively support dengue virus replication. In an important study of fatal cases of DHF/DSS, S. Yoksan and N. Bhamarapravati (Bangkok) reported that dengue viral antigen could be localized in the mononuclear phagocytic cells of several reticuloendothelial organs at the time of death. These cells are the Kuppfer cells of the liver, sinusoidal lining cells in the spleen, lymph nodes and the thymic cortex, and the alveolar macrophages of the lung. In studies of experimental dengue infection of mice, T. Pang (Kuala Lumpur) detailed various parameters of the T-cell response to dengue virus infection; the response (as measured by a delayed-type hypersensitivity, D T H , assay) was mediated by both Ly-1 ÷ and Ly-2 ÷ T cells, was enhanced by T-cell adjuvants, was influenced by the route of immunization, and was genetically restricted by the H - 2 complex. U. G. Chaturvedi (Lucknow, India), also working with mice, showed that dengue virus infection induces splenic T lymphocytes to produce a cytotoxic factor which induces macrophages to produce a cytotoxin (CF2). These two factors are then thought to result in depressed and altered macrophage functions in the infected animal. However, the relevance of studies carried out in mice to the human disease is unclear although they may serve as a means to standardize new investigative techniques which may ultimately be applied to studies in man. Y. C. Chan (Kent Ridge, Singapore) proposed a hypothesis postulating that dengue virus strains infecting humans differ in the content of sialic acid in their envelopes and that this plays a central role in the pathogenesis of DHF; viruses which replicate in mosquitoes (in contrast to those which replicate in vertebrate cells) are thought to contain sialie acid, and persons infected with this virus are at greater risk of contracting

DHF/DSS as a result of the virus directly activating the alternative complement pathway. The renewed interest in the probable role of complement in the pathogenesis of D H F was also reflected in a paper presented by V. Churdboonchart (Bangkok) who used crossed immunoelectrophoresis to measure C3 and C3 split products (C3SP) in DHF/DSS cases. She reported that in severe DSS and in fatal cases, the native C3 level was lowest and the C3SP level highest. In an in-vitro study, she also showed that dengue viral antigens activate complement through the alternative pathway while dengue antigenantibody complexes seem to depend mainly on the classical pathway. In addition to the obviously important role played by the host immune response in disease production, the role of the virus should also be considered. Henchal has prepared monoclonal antibodies against all four dengue serotypes in an attempt to define more clearly the structure and biological function of antigenic determinants on the surface of dengue virions. Most studies were performed with dengue-2 virus and the specificities and spatial arrangements of the monoclonal antibodies (Mabs) were determined by haemagglutination inhibition, plaque-reduction neutralization, immunofluorescence and also competitive binding assays. Biological activities of the Mabs were determined by antibody enhancement assays in macrophage cell lines and mouse protection assays. Using this approach he defined four 'linkage groups' or domains in which the Mab-binding sites or epitopes are organized on the surface of the dengue virions. These specific antigenic regions were shown to play functional roles in viral pathogenesis and immune protection. Further studies examining the interaction of antibodies directed against unique regions on dengue antigens will, it is hoped, lead to a greater understanding of the molecular basis of DHF pathogenesis.

References 1 Svcnningsen,A., Dyrbcrg, T., Ceding, I. et al. J. Clin. Endocn'nol. Maab. (in press) 2 Yarom, Y., Naparstek, Y., Lev-Ram, V. et al. (1983) Nature (London) 303, 246-247

Vaccine development Bhamarapravati described the development of a live attenuated vaccine

Immunoepidemiology helps to unravel the mysteries of dengue haemorrhagic fever.

It is now nearly 20 years since a strong correlation was noted in Thailand between secondary immune responses and severe dengue syndromes. It is curre...
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