Mark Walport

Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.

Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.

Grand challenges in global mental health

A consortium of researchers, advocates and clinicians announces here research priorities for improving the lives of people with mental illness around the world, and calls for urgent action and investment.

Arthritis Critically Dependent on Innate Immune System Players

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, similar to rheumatoid arthritis. Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.

Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity

Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP–/– mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.

Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Removal of cells dying by apoptosis is essential to normal development, maintenance of tissue homeostasis, and resolution of inflammation. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are high abundance pulmonary collectins recently implicated in apoptotic cell clearance in vitro. Other collectins, such as mannose-binding lectin and the collectin-like C1q, have been shown to bind to apoptotic cells and drive ingestion through interaction with calreticulin and CD91 on the phagocyte in vitro. However, only C1q has been shown to enhance apoptotic cell uptake in vivo. We sought to determine the relative importance of SP-A, SP-D, and C1q in pulmonary clearance of apoptotic cells using knockout and overexpressing mice, and to determine the role of calreticulin and CD91 in this process. SP-A, SP-D, and C1q all enhanced apoptotic cell ingestion by resident murine and human alveolar macrophages in vitro. However, only SP-D altered apoptotic cell clearance from the naive murine lung, suggesting that SP-D plays a particularly important role in vivo. Similar to C1q and mannose-binding lectin, SP-A and SP-D bound to apoptotic cells in a localized, patchy pattern and drove apoptotic cell ingestion by phagocytes through a mechanism dependent on calreticulin and CD91. These results suggest that the entire collectin family of innate immune proteins (including C1q) works through a common receptor complex to enhance removal of apoptotic cells, and that collectins are integral, organ-specific components of the clearance machinery.

Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility.

The families of 29 patients with systemic lupus erythematosus and 42 normal subjects were studied to determine the inheritance of the HLA-A, B, C, and DR antigens and also the complement polymorphisms for C2, C4A, C4B, and Bf, which are encoded in the same region of the sixth chromosome. Null (silent) alleles for C4A, C4B, or C2 were found in 24 of the 29 (83%) patients compared with 18 of the 42 (43%) normal controls. HLA-DR3 was present in 20 (69%) of the patients and seven out of 39 (18%) of the normal controls. There was strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B. The data did not permit the relative contributions of DR3 and null factors of C4A and C4B as genetic risk factors to be distinguished. The known association of systemic lupus erythematosus with uncommon inherited and acquired deficiencies of complement components suggests, however, that the presence of null alleles for C4A and C4B, as well as C2, found in most of the patients, is relevant to their genetic susceptibility to this disease.

Complement facilitates early prion pathogenesis

New-variant Creutzfeldt–Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-γ receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-γ receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody–antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4

1 The ability of intradermally injected leukotrienes C4 (LTC4), LTD4 and LTB4 to produce inflammatory changes in human skin alone and in combination with prostaglandin E2 (PGE2) has been investigated. 2 LTC4 and D4 (0.012–0.38 nmol) caused dose‐related erythema and wealing. No evidence of synergism between PGE2 and LTC4 or LTD4 was detected, although only single dose combinations were studied. 3 LTB4 (0.15–1.5 nmol) caused areas of induration which persisted for more than 4 h and which showed perivascular neutrophil infiltrates on histological examination. Only slight synergism between PGE2 and LTB4 was found. 4 It was concluded that these pro‐inflammatory properties of LTC4, LTD4 and LTB4 are consistent with their proposed roles as mediators of inflammation in the skin and other tissues.

C1q, autoimmunity and apoptosis.

Deficiency of classical pathway complement components displays a hierarchical association with the development of systemic lupus erythematosus (SLE). Individuals with deficiency of C1q, the first component of the classical pathway of activation, have the highest prevalence of SLE and the most severe manifestations of the disease. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes SLE. Complement proteins are deposited in inflamed tissues causing consumption of complement. In addition, autoantibodies to C1q develop as part of the autoantibody response. Understanding how C1q deficiency results in the autoimmune phenotype of SLE may provide valuable clues to the role of the complement system in the maintenance of immune tolerance. In this review firstly we discuss the relationship between C1q deficiency and/or consumption and lupus. Secondly, we consider the links between apoptosis and complement. Finally we review the lessons we have learned from a murine model of C1q deficiency discussing the experimental evidence in support of the hypothesis that C1q may critically influence the immune response to self-antigens contained within the surface blebs generated by apoptotic cells.