Kenneth B. M. Reid

C1q: Structure, function, and receptors

C1q is the first subcomponent of the C1 complex of the classical pathway of complement activation. Several functions have been assigned to C1q, which include antibody-dependent and independent immune functions, and are considered to be mediated by C1q receptors present on the effector cell surface. There remains some uncertainty about the identities of the receptors that mediate C1q functions. Some of the previously described C1q receptor molecules, such as gC1qR and cC1qR, now appear to have less of a role in C1q functions than in functions unrelated to C1q. The problem of identifying receptor proteins with complementary binding sites for C1q has been compounded by the highly charged nature of the different domains in C1q. Although newer candidate receptors like C1qR(p) and CR1 have emerged, full analysis of the C1q-C1q receptor interactions is still at an early stage. In view of the diverse functions that C1q is considered to perform, it has been speculated that several C1q-binding proteins may act in concert, as a C1q receptor complex, to bring about C1q mediated functions. Some major advances have been made in last few years. Experiments with gene targeted homozygous C1q-deficient mice have suggested a role for C1q in modulation of the humoral immune response, and also in protection against development of autoimmunity. The recently described crystal structure of Acrp-30, which is a serum protein secreted from adipocytes, has revealed a new C1q/TNF superfamily of proteins. Although the members of this superfamily may have diverse functions, there may be a common theme in their phylogeny and modular organisation of their distinctive globular domains.

ISLET AMYLOID FORMED FROM DIABETES-ASSOCIATED PEPTIDE MAY BE PATHOGENIC IN TYPE-2 DIABETES

Pancreatic islet amyloid deposits were found in 22 of 24 type-2 diabetic subjects (aged 48-68 years) and were not present in 10 age-matched controls. A novel peptide, 37 aminoacids long, termed diabetes-associated peptide (DAP), has been identified in amyloid-containing pancreatic extracts from 3 type-2 diabetic patients but not in extracts from 6 non-diabetic subjects. DAP has major homology with calcitonin-gene related peptide (CGRP) and the islet amyloid of all 22 diabetics showed CGRP immunoreactivity. The immunoreactivity was inhibited by preabsorption of three different CGRP antisera either with CGRP carboxyterminal peptide 28-37 or with extracted DAP. Both diabetic and non-diabetic subjects had CGRP/DAP immunoreactivity in islet B-cells. Electron microscopy of islets containing amyloid indicated fibrillar amyloid between the endocrine cells and capillaries, usually penetrating into deep invaginations of the plasma membrane of the B-cells. These results suggest that islet amyloid contains DAP, which may originate from B-cells. Accumulation of amyloid in islets is likely to impair islet function and may be a causal factor in the development of type-2 diabetes.

Structure-function relationships of the complement components

The primary amino acid sequences of the 20 complement components and control proteins, found in plasma, and of many of the cell-surface molecules associated with the control of the complement system are known from recent cDNA cloning studies. This has indicated that most of these proteins contain a number of well-defined domains of 40-80 amino acids: between two and 30 domains of one type are found in some of the proteins, while others show a mosaic structure composed of more than three different types of domain. The same types of domain are found in a growing number of non-complement proteins such as blood clotting factors and certain cell adhesion molecules. The main purpose of a recent meeting was to assess and correlate the data emerging from structure comparison and prediction techniques and from functional and physicochemical studies of isolated domains and whole proteins.

Collectins and ficolins: sugar pattern recognition molecules of the mammalian innate immune system

Collectins and ficolins represent two important groups of pattern recognition molecules, which bind to oligosaccharide structures on the surface of microorganisms, leading to the killing of bound microbes through complement activation and phagocytosis. Collectins and ficolins bear no significant sequence homology except for the presence of collagen-like sequences over the N-terminal halves of the polypeptides that enable the assembly of these molecules into oligomeric structures. Collectins and ficolins both contain lectin activities within the C-terminal halves of their polypeptides, the C-type carbohydrate recognition domain (CRDs) and fibrinogen beta/gamma (homology) (FBG) domain, respectively. These domains form trimeric clusters at the ends of the collagen triple helices emanating from a central hub, where the N-terminal ends of the polypeptides merge. The collectins and ficolins seem to have evolved to recognize the surface sugar codes of microbes and their binding, to these arrays of cell surface carbohydrate molecules, targets the microbe for subsequent clearance by phagocytic cells.

Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis

Pulmonary alveolar proteinosis was first described by Rosen et al in 1958.1 It is an unusual diffuse lung disease characterised by the accumulation of large amounts of a phospholipoproteinaceous material in the alveoli. It has a variable clinical presentation and course. Most cases are primary but occasionally the condition is secondary to other conditions or inhalation of chemicals. Whole lung lavage remains the most effective treatment and the overall prognosis is good. Surfactant homeostasis is abnormal and animal experiments suggest that this may relate, in some instances at least, to defects in GM-CSF signalling. There are at least two congenital forms of the disease and several different animal models suggesting that pulmonary alveolar proteinosis is unlikely to be a single disease entity and more likely to represent a clinical syndrome. Pulmonary alveolar proteinosis is a rare lung disease and accurate estimates of incidence are not available. Current estimates suggest an incidence of one in two million people. The series reported in the literature suggest a male preponderance (male:female ratio 3:1).1-11 Peak onset is in the third or fourth decade of life with over 80% of reported cases occurring in this age group.1-9 However, there are reports of the disease occurring in neonates,12 children,13-15 and the elderly.11 ### CLINICAL PRESENTATION Dyspnoea is the most common presenting symptom. It usually occurs on moderate exertion but in a few patients occurs at rest.1-11 Cough is the other common symptom. These symptoms are often trivial and some patients do not present until they develop a supervening infection. This may explain the acute onset of symptoms and fever observed in some patients. A low grade fever may also occur as a consequence of pulmonary alveolar proteinosis in the absence of secondary infection.6 Physical examination is often normal and inspiratory crackles …

Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disorder caused by an opportunistic fungal pathogen, Aspergillus fumigatus (AFU:). Lung surfactant proteins SP-A and SP-D can interact with the glycosylated antigens and allergens of AFU:, inhibit specific IgE binding to these allergens, and block histamine release from sensitized basophils. We have now examined the therapeutic effect of exogenous administration of human SP-A, SP-D, and a recombinant fragment of SP-D (rSP-D), in a murine model of pulmonary hypersensitivity induced by AFU: antigens and allergens, which resembles human ABPA immunologically. The ABPA mice exhibited high levels of AFU:-specific IgG and IgE, blood eosinophilia, extensive infiltration of lymphocytes and eosinophils in the lung sections, and a Th2 cytokine response. Treatment with SP-A, SP-D, and rSP-D lowered blood eosinophilia, pulmonary infiltration, and specific Ab levels considerably, which persisted up to 4 days in the SP-A-treated ABPA mice, and up to 16 days in the SP-D- or rSP-D-treated ABPA mice. The levels of IL-2, IL-4, and IL-5 were decreased, while the level of IFN-gamma was raised in the splenic supernatants of the treated mice, indicating a marked shift from Th2 to Th1 response. These results clearly implicate pulmonary SP-A and SP-D in the modulation of allergic reactions.

Structures and functions associated with the group of mammalian lectins containing collagen‐like sequences

The number of proteins found in body fluids and at cell surfaces, which are known to display carbohydrate‐binding properties, continues to increase rapidly. In these proteins, in addition to a domain associated with lectin properties, one or more, non‐lectin domains are present. It is possible that binding of sugar residues by the lectin domain may be important in triggering a variety of recognition and clearance mechanisms via the non‐lectin domains. The group of lectins containing collagen‐like sequences may provide some insight into structure/function relationships of the different domains in view of the well defined structures already available for several of these molecules.

Properdin, the terminal complement components, thrombospondin and the circumsporozoite protein of malaria parasites contain similar sequence motifs.

Properdin is a plasma glycoprotein which stabilizes the C3bnBb¯ enzyme complex of the alternative pathway of the complement system1,2. Unlike the classical pathway, which is initiated by interaction of C1q with the Fc regions of IgG or IgM antibodies in immune complexes, the alternative pathway can be directly activated via binding of C3b to surfaces of foreign organisms3,4. The stabilized C3bnBbP¯ complex activates components C3 and C5 resulting in opsonization of foreign material (via C3b) and assembly of the membrane attack complex (via C5b) on target cells. Therefore properdin greatly enhances complement-mediated clearance and inactivation mechanisms in both natural and acquired resistance to infection1,4. This paper shows that the primary amino acid sequence of properdin is composed mainly of six repeating motifs, each of ∼60 amino acids, and that similar sequences are found in thrombospondin5, the circumsporozoite protein of malaria parasites6–8 and regions of the membrane-attack components of complement9. These similarities may provide insight into the mechanisms by which parasites avoid host defences mediated by complement.

Mechanisms of anti-influenza activity of surfactant proteins A and D: comparison with serum collectins

The present study provides the first direct comparison of anti-influenza A virus (IAV) activities of the collectins surfactant protein (SP) A and SP-D, mannose-binding lectin (MBL), and conglutinin. SP-D, MBL, and conglutinin inhibited IAV hemagglutination activity with a greater potency than and by a distinct mechanism from SP-A. Although isolated trimeric SP-D carbohydrate recognition domains inhibited hemagglutination activity, preparations of SP-D also containing the collagen domain and NH2 terminus caused greater inhibition. In contrast to SP-A (or nonmultimerized SP-D), absence of the N-linked attachment did not effect interactions of multimerized SP-D with IAV. SP-D, SP-A, and conglutinin caused viral precipitation through formation of massive viral aggregates, whereas MBL formed aggregates of smaller size that did not precipitate. All of the collectins enhanced IAV binding to neutrophils; however, in the case of MBL, this effect was modest compared with the binding enhancement induced by SP-D or conglutinin. These studies clarify the structural requirements for viral inhibition by SP-D and reveal significant differences in the mechanisms of anti-IAV activity among the collectins.

Complement system proteins which interact with C3b or C4b A superfamily of structurally related proteins

Recent cDNA sequencing data has allowed the prediction of the entire amino acid sequences of complement components factor B and C2, the complement control proteins factor H and C4b-binding protein and a partial sequence for the Cab/C4b receptor CR1. These proteins all contain internal repeating units of approximately 60 amino acids, each repeating unit having a characteristic framework of highly conserved residues. The N-terminal Ba and CA portions of factor B and C2 both contain 3 repeating units and the chains of C4b-binding protein and factor H contain 8 and 20 repeating units, respectively, while the precise number of units in CR1 is not known yet. These structurally homologous complement proteins are also functionally related as they all interact with C3b and C4b during activation of the cascade. The repeating units also occur in the functionally unrelated proteins subcomponent C1r, β2-glycoprotein 1, blood clotting factor XIII and interleukin-2 receptor. In this review Ken Reid and his colleagues propose that this could be a general feature of a superfamily of structurally related proteins.