Franz von Lichtenberg

IL‐12 gene‐deficient C57BL / 6 mice are susceptible to Leishmania donovani but have diminished hepatic immunopathology

To determine the in vivo role of IL‐12 in the development of protective immunity in visceral leishmaniasis caused by Leishmania donovani, we examined the course of L. donovani infection in IL‐12‐deficient C57BL / 6 (IL‐12– / –) mice. IL‐12– / – mice displayed significantly higher parasite burdens in their livers and spleens than wild‐type C57BL / 6 mice throughout the course of infection. Despite high parasite burdens, the onset of hepatosplenomegaly was significantly delayed in L. donovani‐infected IL‐12– / –. Moreover, livers and spleens from IL‐12– / – mice displayed significantly less inflammation and poorly formed granulomatous lesions than those from IL‐12+ / + mice throughout the course of infection. Antigen‐stimulated splenocytes from IL‐12– / – mice produced significantly less IFN‐γ but more IL‐4 than IL‐12+ / + mice. These findings indicate that although endogenous IL‐12 is critical for the development of protective immunity to L. donovani, it is also responsible for inducing the significant immunopathology associated with visceral leishmaniasis.

Immunopathology of Schistosoma japonicum and S. mansoni infection in B cell depleted mice

Summary To investigate the role of antibody in the pathogenesis of hepatic granulomas around schistosome eggs, mice were depleted of B cells by treatment from birth with anti‐IgM serum and were subsequently infected with Schistosoma japonicum or S. mansoni. Anti‐IgM treatment did not affect the development or fecundity of the worms or the larvae within the egg shells. Normal circumoval granulomas were present in the livers of B cell depleted mice 7 or 8 weeks after infection clearly indicating that antibody and immune complexes have no necessary role in the formation of granulomas. Hepatic fibrosis was also similar in B cell depleted and untreated mice at these times. Ten weeks after infection the size of S. japonicum egg granulomas in untreated mice had decreased but no change in the size of granulomas had occurred in B cell depleted mice, and hepatic fibrosis was more marked in treated than in untreated mice. Similar changes were noted in S. mansoni infected mice, assayed at 8 and at 12–13·5 weeks after infection. The effects of B cell depletion in the more chronic infections may be related to the absence of antibody but could also be caused by an influence on B cell‐dependent suppressor T cells.

Experimental production of bilharzial pipe-stem fibrosis in the chimpanzee

Abstract Clinical, pathologic, parasitologic, immunologic, and radiologic studies were conducted on five chimpanzees exposed to a single dose of 1000 or 2000 Schistosoma mansoni cercariae and on four chimpanzees exposed monthly for 2 years to 100 or 250 cercariae each. One chimpanzee developed the classical lesions of bilharzial pipestem fibrosis; another animal showed a precursor stage of this lesion and several others had variable lesser degrees of fibrosis predominately of smaller portal fields. The earliest identifiable precursor changes of pipe-stem fibrosis in large portal fields were seen at 7 months and the full-fledged picture developed within 2 years after exposure. Portal fibrosis was correlated with heavy egg deposition in the portal triads and intrahepatic portal radicles, accompanied by granulomatous as well as diffuse inflammation. The clinical evolution of pipe-stem fibrosis in the chimpanzee was similar to that in man. After an initial acute stage there was a prolonged relatively asymptomatic interval which evolved gradually into a compensated stage of pipe-stem fibrosis. As in man, this stage was characterized by extensive liver pathology, splenomegaly and portal collateral formation with relatively minor hepatocellular change. A sizeable submucosal esophageal varix was observed in one chimpanzee. This is believed to be a first finding of this kind in experimental liver disease induced without surgery.

Schistosoma mansoni: kinetics and class specificity of hypergammaglobulinemia induced during murine infection.

Abstract Inbred mice infected with moderate numbers of Schistosoma mansoni cercariae develop a dramatic hyperglobulinemia which occurs in two stages. The first response accompanies the development of the parasite from schistosomulum into adult worm and is characterized by an elevation in serum IgG2a and IgG2b globulins. The second response, initiated several weeks after eggs first appear in the host, consists of a striking 5–13-fold increase in the levels of IgM, IgA, and IgG1 present in the infected mouse sera. The concentration of serum immunoglobulin at the peak of the response is approximately 50 mg/ml with IgG1 globulins accounting for over 80% of this total. A significant portion of the IgG1 immunoglobulins elevated during the infection consists of antibodies specific for schistosome egg antigens. However, much of the elevated IgG1 and essentially all of the elevated IgM immunoglobulins have no demonstrable specificity for parasite antigens.

Extraction of human Langerhans cells: a method for isolation of epidermis-resident dendritic cells

Langerhans cells (LCs) are immature dendritic cells in the epidermis that play a central role in T-lymphocyte mediated skin immunity. Upon activation with antigenic stimuli, they differentiate drastically into mature dendritic cells while migrating from the epidermis to regional lymph nodes. Thus, in order to study biological details of immature LCs, it is crucial to isolate epidermis-resident, immature LCs without dermal dendritic cell contamination. Methods for extracting LCs from human skin as well as in vitro derivation of LC-like cells from hematopoietic progenitor cells have been described previously, but the cell preparations can potentially contain a significant number of dendritic cells that are not identical to epidermal LCs. Here, we describe a technique by which purely epidermis-resident LCs are extracted from human skin. Following digestion of human skin with dispase, the epidermis was separated mechanically without any attached dermal component. The trypsinized epidermal cells were then fractionated by centrifugation with a discontinuous density gradient composed of bovine albumin and sodium metrizoate. The LC-enriched preparation thus obtained contained 80% to >90% CD1a+, E-cadherin+ cells that expressed Birbeck granules and the Lag protein. Consistent with their being at an immature stage, the freshly isolated LCs lacked the expression of CD83, a marker for mature dendritic cells. The purified LCs were able to activate allogeneic T cells, indicating that the cells retained T-cell stimulation ability even after extraction. Thus, the present work offers an opportunity for precise in vitro studies of epidermal LCs.

Immunopathology of Schistosoma japonicum infection in athymic mice

Summary Athymic (nu/nu) mice and heterozgous littermate controls (nu/+) were examined 7 and 10 weeks after infection with 10 cercariae of Schistosoma japonicum. Schistosome infection developed normally in both groups of mice and eggs were produced in normal numbers. Nu/nu mice developed small circumoval granulomas with minimal fibrosis while nu/+ mice developed large fibrotic granulomas. Unlike the mononuclear responses to S. mansoni eggs at 7 weeks, those to S. japonicum often were abscess like with narrow rims of liver cell necrosis or microvesicular fatty change. However, evolving granulomas in nu/+ mice were enriched with eosinophils, epithelioid macrophages, immature granulocytes and plasma cells, all scarce in the corresponding nu/nu lesions as were fibroblasts and collagen fibres, thus accounting for their smaller mean size and better healing. Our aggregate evidence shows that normal granuloma formation and cellularity in S. japonicum infection is controlled by T‐cells as is the case for S. mansoni, and not by antibodies or immune complexes.

Parasite migration and host reaction in mice exposed to irradiated cercariae of Schistosoma mansoni

Abstract Exposure to gamma radiation interferred with the ability of schistosomes to reach maturity in mice. Since the death and disintegration of schistosomula stimulated a considerable degree of inflammation, different dosage levels provided contrasting pathological situations. At 50,000 roentgens equivalent physical (rep) cercarial dermatitis with ulceration and marked vasculitis was the main pathological feature; at 5000 rep numerous granulomatous foci were seen in the lung; and at 2500 rep foci of liver cell necrosis and liver granulomata occurred. Irradiation at 2500 rep appeared to be the best dose since the less heavy concentration of parasites in a single organ produced the least amount of objectionable pathological changes. The host tissue reactions to attenuated cercariae were strikingly similar to those observed following a primary exposure of an abnormal host to nonattenuated cercariae and those observed in the susceptible host which had become resistant to a secondary infection following a primary exposure to schistosome cercariae.

Schistosomiasis as a worldwide problem: Pathology

Low-grade schistosome infection is often well tolerated, except for the danger of ectopic lesions; the risk of life-threatening pathology increases with rising worm burdens. At present, quantitative stool or urine egg counts do not reliably measure individual infection intensity, especially in adult patients, and more precise methods are needed on which to base therapeutic decisions. Timely schistosomicidal treatment will prevent or improve bilharzial lesions, often dramatically, but can not reverse established liver pipe stem fibrosis. Pathological studies in Ibadan and Cairo have shown that in schistosomiasis haematobia the frequency of obstructive uropathy increases in relation to the egg load in urinary tissues. Obstruction, in turn, predisposes to bacterial superinfection and is a significant cause of renal failure and death in highly endemic populations. Urinary bilharzial lesions are most active in the young and tend to become inactive in older patients. Urinary tissue egg burdens first rise, plateau, and ultimately decrease with age, most sharply after the fifth decade. The relationship between tissue egg burden and 24-hr urinary egg output varies according to stage of activity, while the severity of disease depends on egg burden regardless of stage. Therefore, during the inactive stage, severe pathology can coexist with a minimal urinary egg output. Both clinical and autopsy statistics show a correlation between the frequency and the intensity of bilharzial infection. Most of the severe pathology occurs in population groups with an autopsy frequency above a threshold of 30%. The clinical and epidemiological implications of these findings are discussed.

Necrotizing granulomatous gastritis and gastric perforation of unknown etiology: A first case report

A unique case of granulomatous gastritis of unknown etiology is reported. The patient, a 43-year-old Haitian woman, suffered a gastric perforation from a disease process limited to the stomach. The stomach was markedly enlarged and edematous with transmural, serpiginous granulomatous tracks throughout the gastric wall, but most numerous in the fundic region. Accompanying acute and chronic inflammatory infiltrates were scant. No microorganisms, parasites, foreign body particles, or other known granulogenic materials could be identified. Clinical and pathologic features also differed markedly from granulomatous gastritis seen in sarcoidosis, Crohns disease, or isolated granulomatous gastritis as defined by Fahmi et al. Infection by a parasite for which man is not the definitive host seems the most likely etiology.

Schistosoma haematobium: infections in five species of primates.

Abstract Twenty-three primates were exposed to a single dose of 100–1000 cercariae of Schistosoma haematobium . They belonged to five species: Macaca mulatta , (rhesus monkey), Macaca, nemestrina (pigtail monkey), Cercopithecus sabaeus (green monkey), Tupaia sp. (tree shrew), and Aotus trivirgatus (night or owl monkey). All species were susceptible to infection, but the course of infection varied considerably. The tree shrew was least susceptible. No worms were found in four of seven owl monkeys 28 weeks after infection although eggs had been found in their feces during the study. Worm burdens, egg excretion and serologic response varied considerably among individuals of the same species as well as among the different species. Gross and microscopic pathologic changes were minimal in most of these animals. Because of the worm recovery, egg recovery, egg excretion, and pathologic changes exhibited by the green monkey, this animal should be investigated further as a host of S. haematobium .