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The lysis of cells by complement requires only the terminal components C5, C6, C7, C8 and C9 and is initiated by the cleavage of C5 to C5b. Sequential addition of C6, C7, C8, and C9 to C5b leads to the formation of the membrane attack complex (MAC)' which, when inserted into the lipid bilayer, can form transmembrane pores (1-5). It is well known that when complement of one species is activated on homologous erythrocytes, lysis is much less efficient than when it is activated on other species of cell, and even among different heterologous cell species the lytic efficiency may be very different. It has long been known that the basis of this variable lytic efficiency is found, at least in part, at the C8 and/or C9 step (6-9). More recently, specific membrane proteins have been described that appear to protect cells from homologous complement . The first of these to be described was the decayaccelerating factor (DAF), a membrane protein of -70 kD molecular mass (10). This protein interferes with the assembly of the C3 converting enzymes both of the classical and alternative pathway (10, 11) and therefore it has only indirect effects on the cell lytic mechanism. A further membrane protein that does restrict homologous lysis, and that has been described both as the C8-binding protein (C8bp) (7, 12) and as homologous restriction factor (HRF) (13), has also been isolated . It seems likely that both these descriptions apply to a single protein of 65 kD molecular mass. In addition, a 55/65-kD MAC-inhibiting protein (MIP) with the capacity to bind C8 and C9 has been identified both on human erythrocyte membranes and in normal human serum (14). The relationship ofthis to HRF/C8bp is not yet clear. Both DAF and HRF/C8bp are bound on cell membranes by a glycolipid anchor (15, 16) and can be eluted from the cell membrane, at least in part, by phosphatidylinositol-specific phospholipase C. These proteins also have the capacity when they are isolated from

No abstract

The main features of the protein structure are two antiparallel beta-sheets (a central one with three strands and another with two), a short helix that packs against the three-stranded beta-sheet, and a carboxy-terminal region that, although lacking regular secondary structure, is well defined and packs against the three-stranded beta-sheet, on the opposite face to the helix. We have used the structure, in combination with existing biochemical data, to identify residues that may be involved in C8 binding.

The World Bank is publishing nine volumes of Disease Control Priorities, 3rd edition (DCP3) between 2015 and 2018. Volume 9, Improving Health and Reducing Poverty, summarises the main messages from all the volumes and contains cross-cutting analyses. This Review draws on all nine volumes to convey conclusions. The analysis in DCP3 is built around 21 essential packages that were developed in the nine volumes. Each essential package addresses the concerns of a major professional community (eg, child health or surgery) and contains a mix of intersectoral policies and health-sector interventions. 71 intersectoral prevention policies were identified in total, 29 of which are priorities for early introduction. Interventions within the health sector were grouped onto five platforms (population based, community level, health centre, first-level hospital, and referral hospital). DCP3 defines a model concept of essential universal health coverage (EUHC) with 218 interventions that provides a starting point for country-specific analysis of priorities. Assuming steady-state implementation by 2030, EUHC in lower-middle-income countries would reduce premature deaths by an estimated 4·2 million per year. Estimated total costs prove substantial: about 9·1% of (current) gross national income (GNI) in low-income countries and 5·2% of GNI in lower-middle-income countries. Financing provision of continuing intervention against chronic conditions accounts for about half of estimated incremental costs. For lower-middle-income countries, the mortality reduction from implementing the EUHC can only reach about half the mortality reduction in non-communicable diseases called for by the Sustainable Development Goals. Full achievement will require increased investment or sustained intersectoral action, and actions by finance ministries to tax smoking and polluting emissions and to reduce or eliminate (often large) subsidies on fossil fuels appear of central importance. DCP3 is intended to be a model starting point for analyses at the country level, but country-specific cost structures, epidemiological needs, and national priorities will generally lead to definitions of EUHC that differ from country to country and from the model in this Review. DCP3 is particularly relevant as achievement of EUHC relies increasingly on greater domestic finance, with global developmental assistance in health focusing more on global public goods. In addition to assessing effects on mortality, DCP3 looked at outcomes of EUHC not encompassed by the disability-adjusted life-year metric and related cost-effectiveness analyses. The other objectives included financial protection (potentially better provided upstream by keeping people out of the hospital rather than downstream by paying their hospital bills for them), stillbirths averted, palliative care, contraception, and child physical and intellectual growth. The first 1000 days after conception are highly important for child development, but the next 7000 days are likewise important and often neglected.

The administration of the immunosuppressive humanized monoclonal antibody CAMPATH 1-H, which recognizes CD52 on lymphocytes and monocytes, is associated with a first-dose cytokine-release syndrome involving TNF ␣ , IFN ␥ , and IL-6 clinically. In vitro models have been used to establish the cellular source and mechanism responsible for cytokine release, demonstrating that cytokine release is isotype dependent, with the rat IgG2b and human IgG1 isotype inducing the highest levels of cytokine release, which was inhibited with antibody to CD16, the low affinity

The binding of the iC3b receptor (CR3) to unopsonized zymosan was shown to result from CR3 attachment to cell wall ß-glucans. A specificity of neutrophil responses for ß-glucan was first suggested by a comparison of yeast (Saccharomyces cerevisiae) cell wall components for stimulation of a neutrophil superoxide burst. Neutrophils responded poorly to heat-killed yeast, but gave increasingly better responses to cell wall polysaccharides devoid of proteins (zymosan) and nearly pure ß-glucan particles derived from zymosan. Zymosan triggered a burst that was 29% as great as that stimulated by phorbol myristate acetate (PMA), and ß-glucan particles stimulated a burst that was 72% as great as that produced by PMA. Phagocytic responses to yeast were also inhibited by soluble glucans but not by soluble mannans. Three types of experiments demonstrated a role for CR3 in these responses. First, neutrophil ingestion of either yeast or yeast-derived ß-glucan particles was blocked by monoclonal anti-CR3, fluid-phase iC3b, or soluble ß-glucan from barley. Monocyte ingestion of ß-glucan particles was also blocked by anti-CR3, but not by anti-CRi or anti-C3. Second, the neutrophil superoxide burst response to either zymosan or ß-glucan particles was blocked by anti-CR3 or fluid-phase iC3b, and was completely absent with neutrophils from 3 patients with an inherited deficiency of CR3. Third, CR3 was isolated from solubilized neutrophils by affinity chromatography on ß-glucan-Sepharose.

This study shows that immunotherapy shifted cytokine responses to allergen from a TH-2 to a TH-1 dominant pattern, suggesting direct effects on T cells. How these cytokine changes relate to clinical desensitization is not clear. In the longer term they would result in an isotype switch from IgE to IgG. Early changes in cytokine or chemokine production might downregulate mast cell or basophil reactivity and explain the rapid desensitization in rush VIT.