Colin M. Fitzsimmons

C-Reactive Protein Frequently Colocalizes With the Terminal Complement Complex in the Intima of Early Atherosclerotic Lesions of Human Coronary Arteries

There is increasing evidence that complement activation may play a role in atherogenesis. Complement proteins have been demonstrated to be present in early atherosclerotic lesions of animals and humans, and cholesterol-induced atherosclerotic lesion formation is reduced in complement-deficient animals. Potential complement activators in atherosclerotic lesions are now a subject matter of debate. C-reactive protein (CRP) is an acute-phase protein that is involved in inflammatory processes in numerous ways. It binds to lipoproteins and activates the complement system via the classic pathway. In this study we have investigated early atherosclerotic lesions of human coronary arteries by means of immunohistochemical staining. We demonstrate here that CRP deposits in the arterial wall in early atherosclerotic lesions with 2 predominant manifestations. First, there is a diffuse rather than a focal deposition in the deep fibroelastic layer and in the fibromuscular layer of the intima adjacent to the media. In this location, CRP frequently colocalizes with the terminal complement complex. Second, the majority of foam cells below the endothelium show positive staining for CRP. In this location, no colocalization with the terminal complement proteins can be observed. Our data suggest that CRP may promote atherosclerotic lesion formation by activating the complement system and being involved in foam cell formation.

Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses

Soluble egg antigens of the parasitic helminth Schistosoma mansoni (S. mansoni egg antigen [SEA]) induce strong Th2 responses both in vitro and in vivo. However, the specific molecules that prime the development of Th2 responses have not been identified. We report that omega-1, a glycoprotein which is secreted from S. mansoni eggs and present in SEA, is capable of conditioning human monocyte-derived dendritic cells in vitro to drive T helper 2 (Th2) polarization with similar characteristics as whole SEA. Furthermore, using IL-4 dual reporter mice, we show that both natural and recombinant omega-1 alone are sufficient to generate Th2 responses in vivo, even in the absence of IL-4R signaling. Finally, omega-1–depleted SEA displays an impaired capacity for Th2 priming in vitro, but not in vivo, suggesting the existence of additional factors within SEA that can compensate for the omega-1–mediated effects. Collectively, we identify omega-1, a single component of SEA, as a potent inducer of Th2 responses.

Processes in atherogenesis: complement activation

The complement system consists of a complex group of plasma proteins, which, on activation, lead to a cascade of interactions culminating in the production of a variety of pro-inflammatory molecules. The system also contains cellular receptors for complement fragments produced during activation and regulatory molecules. It is part of the innate immune system representing humoral defence, but in certain circumstances may itself contribute to disease. In the formation of atherosclerotic lesions, there are two outstanding cellular phenomena, monocyte recruitment, with subsequent development of lipid-filled foam cells and smooth muscle cell activation. Subendothelial deposition of low density lipoprotein appears to be an important stimulus in these events and substantial evidence suggests that complement activation may be a link between lipoprotein deposition and subsequent lesion development.

Complement-Induced Release of Monocyte Chemotactic Protein-1 From Human Smooth Muscle Cells A Possible Initiating Event in Atherosclerotic Lesion Formation

Increasing evidence suggests that complement activation might represent an important mechanism in early atherogenesis. Thus, complement components, in particular the membrane attack complex (MAC) C5b-9(m), have been isolated from human atherosclerotic lesions. Furthermore, complement activation is known to occur in atherosclerotic lesions induced in experimental animals, and the severity of cholesterol-induced plaques is markedly reduced in complement-deficient animals. During atherogenesis monocytes are recruited into the arterial wall, and a potent chemoattractant for monocytes, monocyte chemotactic protein-1 (MCP-1), is expressed by vascular smooth muscle cells (SMCs). We hypothesized that generation of MACs on SMCs during the activation of complement might lead to the release of MCP-1 and hence to monocyte recruitment. In this study, MACs were generated on human SMCs in vitro by sequential addition of the purified complement components C5b6, C7, C8, and C9. This supernatant of the culture was chemotactic for freshly isolated peripheral blood monocytes in a modified Boyden chamber. The chemotactic activity of the supernatant was abolished by anti-MCP-1 blocking antibodies but not by an isotype-matched antibody against an irrelevant antigen. The release of chemotactic activity was dependent on the dose of MAC formed on SMCs and was demonstrated within 10 minutes of exposure of the cells. The data support the hypothesis that complement-mediated release of MCP-1 from SMCs might be important in the recruitment of monocytes into the developing atherosclerotic lesion and could be an important initiating event in atherogenesis.

Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised-controlled trial results

To cite this article: Mpairwe H, Webb EL, Muhangi L, Ndibazza J, Akishule D, Nampijja M, Ngom‐wegi S, Tumusime J, Jones FM, Fitzsimmons C, Dunne DW, Muwanga M, Rodrigues LC, Elliott AM. Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised‐controlled trial results. Pediatr Allergy Immunol 2011; 22: 305–312.

Influence of Exposure History on the Immunology and Development of Resistance to Human Schistosomiasis Mansoni

Background Previous studies suggest that humans can acquire immunity to reinfection with schistosomes, most probably due to immunologic mechanisms acquired after exposure to dying schistosome worms. Methodology/Principal Findings We followed longitudinally two cohorts of adult males occupationally exposed to Schistosoma mansoni by washing cars (120 men) or harvesting sand (53 men) in Lake Victoria. Men were treated with praziquantel each time S. mansoni infection was detected. In car washers, a significant increase in resistance to reinfection, as measured by the number of cars washed between cure and reinfection, was observed after the car washers had experienced, on average, seven cures. In the car washers who developed resistance, the level of schistosome-specific IgE increased between baseline and the time at which development of resistance was first evidenced. In the sand harvesters, a significant increase in resistance, as measured by the number of days worked in the lake between cure and reinfection, was observed after only two cures. History of exposure to S. mansoni differed between the two cohorts, with the majority of sand harvesters being lifelong residents of a village endemic for S. mansoni and the majority of car washers having little exposure to the lake before they began washing cars. Immune responses at study entry were indicative of more recent infections in car washers and more chronic infections in sand harvesters. Conclusions/Significance Resistance to reinfection with S. mansoni can be acquired or augmented by adults after multiple rounds of reinfection and cure, but the rate at which resistance is acquired by this means depends on immunologic status and history of exposure to S. mansoni infection.

Factors Affecting Human IgE and IgG Responses to Allergen-Like Schistosoma mansoni Antigens: Molecular Structure and Patterns of in vivo Exposure

Background: The human IgE response is associated with allergy and with host defence against parasitic worms. A response to Sm22.6, the dominant IgE antigen in adult Schistosoma mansoni worms, correlates with resistance to re-infection after treatment. Sm22.6 is one of a family of EF-hand containing parasite proteins with sequence similarity to dynein light chain (DLC) and with major non-parasite allergens. Here we compare human IgE and IgG responses to other family members, Sm20.8 and Sm21.7, as well as to SmDLC1, relating these to antigen structure and expression in parasite life stages. Methods: Recombinant antigens were used in ELISA to measure antibody isotype responses in 177 cases from an endemic area, before and 7 weeks after treatment. Parasite antigen expression was assessed by RT-PCR and Western blotting. Results: Levels of antibodies to Sm22.6 and Sm20.8 (but not to Sm21.7 or SmDLC1) showed posttreatment increases in all but young children. Many produced IgE to Sm22.6 and Sm20.8 (2 EF-hands), few to Sm21.7 (1 EF-hand) or SmDLC1 (no EF-hands). Sm21.7 was expressed in cercariae, adults and eggs, Sm22.6 and Sm20.8 were concentrated in the adult. Conclusions: These studies suggest that IgE antigens Sm22.6 and Sm20.8 are only released to boost antibodies when adult worms die, whilst Sm21.7 and SmDLC1 are released constantly from eggs dying in host tissue. IgE responses to these allergen-like molecules may be influenced by patterns of exposure and the number of EF-hand motifs.

Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity.

The Th2 immune response, culminating in eosinophilia and IgE production, is not only characteristic of allergy but also of infection by parasitic worms (helminths). Anti-parasite IgE has been associated with immunity against a range of helminth infections and many believe that IgE and its receptors evolved to help counter metazoan parasites. Allergens (IgE-antigens) are present in only a small minority of protein families and known IgE targets in helminths belong to these same families (e.g., EF-hand proteins, tropomyosin, and PR-1 proteins). During some helminth infection, especially with the well adapted hookworm, the Th2 response is moderated by parasite-expressed molecules. This has been associated with reduced allergy in helminth endemic areas and worm infection or products have been proposed as treatments for allergic conditions. However, some infections (especially Ascaris) are associated with increased allergy and this has been linked to cross-reactivity between worm proteins (e.g., tropomyosins) and highly similar molecules in dust-mites and insects. The overlap between allergy and helminth infection is best illustrated in Anisakis simplex, a nematode that when consumed in under-cooked fish can be both an infective helminth and a food allergen. Nearly 20 molecular allergens have been isolated from this species, including tropomyosin (Ani s 3) and the EF-hand protein, Ani s troponin. In this review, we highlight aspects of the biology and biochemistry of helminths that may have influenced the evolution of the IgE response. We compare dominant IgE-antigens in worms with clinically important environmental allergens and suggest that arrays of such molecules will provide important information on anti-worm immunity as well as allergy.

Human IgE response to the Schistosoma haematobium 22.6 kDa antigen.

In Schistosoma mansoni and S. japonicum infection, the 22·6 kDa tegumental antigens Sm22·6 and Sj22·6 are principal targets for the human IgE response, and levels of IgE to Sm22·6 have been correlated with resistance to re‐infection after chemotherapy. S. haematobium is arguably a more important species in terms of human infection, and in this report we describe for the first time the molecular characterization of a cDNA from S. haematobium (Sh22·6) that is closely homologous to Sm22·6 and Sj22·6. As a member of the tegument‐associated antigen family, Sh22·6 possesses EF‐hand domains and regions homologous to the dynein light chain domains. We have expressed recombinant Sh22·6 and studied the IgE responses to the antigen in a group of 99 infected individuals (68 children and 31 adults) from an endemic area of Gabon who donated blood before and 5 weeks after praziquantel treatment. IgE to Sh22·6 was detected by ELISA in 18 subjects (18%), and in the majority of responders levels rose between pre‐ and post‐treatment. Interestingly, the proportion of adults expressing IgE to Sh22·6 was 35·5%, significantly higher than the 10·3% seen in children. IgE from at least 10 of the 18 ELISA responders recognized Sh22·6 on Western blots of adult worm extract and recombinant antigen. These results demonstrate that like related molecules in other species, Sh22·6 is a target for the human IgE response. The data also indicate that changes in the IgE response occur with age or with progressive exposure to key antigens.

Survival of the fittest: allergology or parasitology?

Allergologists have long recognized that only a small fraction of the environmental and food proteins that we are exposed to give rise to IgE responses. This has raised the intriguing and important question: What makes an allergen an allergen? Many protein allergens have close homologs in metazoan parasites, and as helminth genome information grows, it appears increasingly clear that not only are the immune mechanisms of allergy and anti-helminth immunity closely related, but so are the helminth and allergen proteins that induce them. This suggests that at least part of the secret of what allows some proteins to be allergens may actually lie in the long co-evolutionary relationship between worms and their vertebrate (and latterly human) hosts.