G. Richard Olds

Identification of the Schistosoma japonicum 22.6–kDa Antigen as a Major Target of the Human IgE Response: Similarity of IgE–Binding Epitopes to Allergen Peptides

Human resistance to reinfection with Schistosoma mansoni and Schistosoma haematobium correlates with elevated IgE titers against worm antigens (soluble worm antigen preparation, SWAP). In S. mansoni infection, low levels of reinfection following chemotherapy are associated with the recognition of a cloned tegumental protein Sm22.6. Because of potential species–specific differences in resistance to schistosomes, we attempted to identify Schistosoma japonicum antigens recognized by human IgE. Following a survey of 176 infected individuals in Leyte, Philippines, we show that IgE antibodies from the majority of older, high–IgE/SWAP responders recognize antigens in the 22 (Sj22)–, 45–, 78– and 97–kDa range in SWAP. Limited IgE cross–reactivity between Sj22 and Sm22 was observed following a comparison of Filipino IgE responses to these antigens. The antigen was cloned from an adult S. japonicum λ–ZAP cDNA library (Mindoro strain) by immunoscreening with pooled high–titer IgE antisera and a rabbit anti–Sj22 polyclonal antibody. The deduced amino acid sequence of the identified cDNA clone, MJ–1, showed significant homology to Sm22.6 (74%) and Sj22.6 (99%). Although the molecular sequence of Sj22.6 has already been reported, this is the first demonstration of its recognition by human IgE, thereby strengthening its potential as a vaccine candidate. Using an overlapping peptide approach, four IgE–binding epitopes were identified in Sj22.6, two of which exhibited similarities to known IgE–binding epitopes from codfish (Gad c 1) and β–lactoglobulin–related allergens. These findings suggest that allergy and protective immunity to helminth infection may be linked by the structural similarities of epitopes recognized by human IgE.

Paramyosin: a candidate vaccine antigen against Schistosoma japonicum.

Paramyosin, a 97 kDa myofibrillar protein, is a candidate vaccine antigen for prevention of infection with the human parasite Schistosoma mansoni. To determine if paramyosin would also induce protection against Schistosoma japonicum, paramyosin was biochemically purified from S. japonicum adult worms. SDS‐PAGE demonstrated a single protein with a molecular weight of 97 kDa. In four separate experiments, vaccination of mice with S. japonicum paramyosin without adjuvant induced significant resistance (62%–86%, P < 0.001) against cercarial challenge as compared to controls. These data suggest that S. japonicum paramyosin may represent a candidate vaccine for immunization against schistosomiasis japonica.

Administration of Praziquantel to pregnant and lactating women

Praziquantel (PZQ) is the safest of all anti-helminthics and now forms the backbone for all national control programs against schistosomiasis (Med. Res. Rev. 3 (1983) 147-200; Bull. WHO 57 (1979) 767-771; Wegner, D.H.G, Therapeutic Drugs (1991), Churchill Livingstone; Adv. Intern. Med. 32 (1987) 193-206; Drugs 42 (1991) 379-405; Pharmac. Ther. 68 (1995) 35-85; Ann. Intern. Med. 110 (1989) 290-296). Despite its lack of known toxicity, the drug was not tested on pregnant or lactating women prior to release. It is currently listed as Pregnancy Category B by the US FDA, which is a drug presumed safe based in animal studies. Unfortunately, this has been interpreted by most national control programs and WHO (1998) to exclude lactating and pregnant women from treatment. In fact, some experts advocate excluding adolescent girls from mass treatment campaigns over this issue. As a result, a large number of women living in endemic countries are currently left untreated or have treatment significantly delayed. A review of the current known toxicology of PZQ, combined with over two decades of clinical experience with this drug, suggest very low potential for adverse effects on either the mother or her unborn child. In contrast, significant animal and human data are presented in this review that suggest both the pregnant woman and her unborn fetus suffer morbid sequella from schistosomiasis. A double-blind placebo-controlled trial that could resolve this issue would require a very large and expensive study and in light of the above facts might not now be ethically appropriate. The author concludes that pregnant women should be treated with PZQ, that women of childbearing age should be included in all mass treatment programs and that lactating women are not systematically excluded from treatment.

Morbidity due to schistosomiasis japonica in the People's Republic of China

Transmission and morbidity induced by Schistosoma japonicum were evaluated in 825 individuals undergoing periodic treatment with praziquantel on Jishan island, Jiangxi Providence, in the Peoples Republic of China. Eggs of S. japonicum were found in the stools of 39.4% of the population; 70% of those infected were less than 20 years of age. Hepatomegaly greater than 3 cm in the midsternal line was detected by physical examination and ultrasonography in 75% and 90% of individuals, respectively, regardless of infection status. Symmers clay pipe-stem fibrosis of the liver was detected by ultrasonography in 20% of all individuals. Hepatitis B surface antigen and antibody to hepatitis C were found in 11% and less than 1% of the population, respectively. Our study suggests that, despite intermittent chemotherapy, morbidity due to S. japonicum is still a significant problem in China.

Schistosomiasis japonica on Jishan Island, Jiangxi Province, People's Republic of China: persistence of hepatic fibrosis after reduction of the prevalence of infection with age

Hepatic fibrosis due to schistosomiasis japonica was examined by ultrasonography in a cross-sectional community study of 825 individuals on Jishan Island, Jiangxi Province, China. The prevalence of active infection was 39.4% with peak infection in the 10-19.9 years age group followed by a significant decline. A similar pattern was observed for intensity of infection. The prevalence of hepatomegaly in the midsternal line > or = 6 cm peaked at 60% in the fourth decade and remained elevated. A progressive increase in the severity of hepatic periportal fibrosis was observed with age, with advanced fibrosis peaking in the fifth decade. The proportion of individuals with advanced fibrosis was significantly greater in males than in females despite equivalent prevalence and intensity of schistosome infection. In addition, a positive association (P < 0.01) was found between periportal fibrosis and both hepatomegaly > or = 6 cm and splenomegaly. This study suggests that the natural history of schistosomiasis japonica in this hyperendemic community in China is marked by persistence of hepatomegaly and schistosome-induced periportal fibrosis in adults despite a decrease in the prevalence of infection.

Dynamics of collagen accumulation and polymorphism in murine Schistosoma japonicum

The dynamics of hepatic collagen biosynthesis and degradation were studied in mice infected with Schistosoma japonicum. Hepatic fibrosis, the major clinical manifestation of disease, increased during acute infection (0-15 wk). The majority of proline incorporation into hydroxyproline, which was reflective of collagen synthesis, was found within hepatic egg granulomas. As the disease became chronic (20-30 wk) there was a decrease in collagen synthesis and a maintenance of total collagenolytic activity, which resulted in decreased accumulations of both total hepatic and granuloma-associated collagen. In addition to these quantitative decreases in extracellular collagen there was a qualitative change in the type of hepatic collagen synthesized. Early in infection, type I collagen was the predominant biosynthetic product, whereas late in infection type III collagen became the dominant isotype. A similar switch was seen in the substrate specificity of the constitutive collagenolytic activity, with decreasing type I activity and increasing type III activity as the disease progressed from acute (10 wk) to chronic (30 wk). These changes in the quantity and makeup of extracellular collagen may lead to amelioration of disease and potential reversibility of fibrosis.

Malaria in travelers in Rhode Island : a review of 26 cases

PURPOSE We reviewed our experience with malaria in two community hospitals in Rhode Island from 1986 to 1990. RESULTS Twenty-six patients with malaria were identified. Fifteen patients were immigrants who had acquired malaria while visiting their country of origin, particularly West Africa. Fever was present in 67% of cases and gastrointestinal complaints were prominent in 26%. Individuals with a past history of malaria could accurately distinguish current malarial infections from other febrile illnesses. Two patients developed cerebral malaria. Plasmodium falciparum was identified in 77% of the cases. CONCLUSIONS Malaria is an important diagnosis that United States physicians must consider in the medical evaluation of returning travelers. A significant increase in the number of cases of P. falciparum acquired in East Africa has been reported in recent years. P. falciparum infection must be rapidly diagnosed and treated since delays may result in complications of malaria that may lead to death. Mefloquine is currently recommended by the Centers for Disease Control for prevention of malaria in travelers visiting countries endemic for chloroquine-resistant malaria. This change may alter the epidemiology of malaria in the United States in the future.

Kinetics and mechanisms of pulmonary granuloma formation around Schistosoma japonicum eggs injected into mice

Granuloma formation in schistosomiasis japonica differs in several respects from those observed in Schistosoma mansoni infections. We have utilized the lung granuloma model in mice sensitized with subcutaneous injection of Schistosoma japonicum eggs to study the kinetics and mechanisms of this response. Animals injected subcutaneously with a range of 50–50,000 S. japonicum eggs elicited a significant pulmonary granulomatous response around ova subsequently injected intravenously. The pulmonary granulomas were formed of macrophages, lymphocytes, and eosinophils. Both antithymocyte globulin and antieosinophil sera reduced significantly the size of the granulomas and depleted the corresponding cell. Nude athymic mice developed markedly reduced pulmonary granulomas as did mice treated with niridazole or hydrocortisone. Sensitization to the egg antigens was demonstrable as both immediate and arthus-type footpad responses. Our data show that cell-mediated pulmonary granulomas can form around S. japonicum eggs in animals previously sensitized by the subcutaneous route. This model may provide further insights into the pathogenesis of S. japonicum granuloma.

Schistosoma mansoni: characterization of phosphoinositide response.

Signal transduction pathways may have important regulatory roles in cellular events in the human parasite Schistosoma mansoni. The presence of the phosphoinositide response in S. mansoni was examined by radiolabeling intact worms with 20 muCi of [3H]myoinositol for 24 hr and stimulating parasites with 25 mM NaF and 10 microM AlCl3 in the presence of 10 mM LiCl. Total inositol phosphates were increased within 2 min and maximal accumulation was achieved after 30 min. Similar results were seen with the non-hydrolyzable GTP analogues GTP gamma S and GppNHp while only minimal changes were detected with GMP. Neomycin inhibited NaF-induced inositol phosphate production. NaF stimulated a significant 3.6-fold increase of inositol phosphates in females compared to males. These data suggest that stimulation of guanine nucleotide-binding regulatory proteins activates phospholipase C resulting in production of inositol phosphates in S. mansoni.

Function and expression of a human idiotypic network in Schistosomiasis japonica

The cross‐reactive idiotype (Hu‐SJ‐CRIM) is defined by polyclonal human anti‐idiotypic antibodies derived from chronically S. japonicum infected patients. The present study shows that serum levels of Hu‐SJ‐CRIM expressed by antibodies to S. japonicum soluble egg antigen (SEA) are associated with acute infection and hepatosplenic disease. Xenogeneic anti‐idiotypic antisera (anti‐Hu‐SJ‐CRIM) suppressed human lymphocyte blastogenesis to SEA in vitro by 47–82% (P < 005). These anti‐idiotypic antibodies also suppressed in vitro granuloma formation induced by SEA coated beads in a dose dependent manner. This immunosuppression was antigen specific in that mitogen (PHA) or non‐related antigen (PPD) induced blastogenic responses were not suppressed. Surprisingly, anti‐idiotypic antibodies (anti‐SJ‐CRIM), which describe the mouse correlate CRIM were not suppressive in the human blastogenesis or in vitro granuloma formation assays. These data indicate a dichotomy in the function and specificity of the idiotype/anti‐idiotype human and murine immune networks in S. japonicum infection. Thus, only the patient derived molecules and serology form the basis for an immunoregulatory network in Schistosomiasis japonica.