Severe Lymphoid Depletion Research Articles

Retrospective study of porcine circovirus 2 infection in Japan: seven cases in 1989.

Retrospectively, we demonstrated that seven pigs necropsied in 1989 had characteristic porcine circovirus 2 (PCV-2) lymphoid tissue lesions of severe lymphoid depletion, syncytial giant cell formation, and intracytoplasmic inclusion bodies in macrophages. Immunohistochemically, PCV-2 antigen was detected in these tissues and the distribution of positive staining corresponded to the distribution of inclusion bodies. Electron microscopy demonstrated viral particles compatible with porcine PCV-2. Therefore, the disease occurred in Japan as early as 1989.

Post-weaning multisystemic wasting syndrome (PMWS) in pigs in France: clinical observations from follow-up studies on affected farms

A disease affecting weaned pigs and known as Postweaning Multisystemic Wasting Syndrome (PMWS) is described on French farms. Follow-up studies were designed on cohorts of pigs on a group of 12 severely affected farrow-to-finish operations. Three of them were free of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection. Three thousand and seventy eight pigs were included in the study. Mortality, from weaning to slaughter, was 11% and weeks 11–13 were the most critical. The first clinical sign reported was unthriftiness, then pallor and often fever with associated respiratory or digestive disorders. Wasting could follow rapidly and when clearly established in an individual the prognosis was grave especially when the sick pigs were kept with their penmates. Antibiotics were administered without real efficacy. The lesions affected several viscera including lungs, spleen, kidneys and lymph nodes with a severe lymphoid depletion. The disease did not show a collective impact. From preliminary epidemiological investigations, a strong litter effect on disease susceptibility was suspected. PRRS virus was excluded as a major agent. On the other hand, a porcine circovirus (PCV2) was found associated to the lesions. The environment was suspected as an important determining factor for the effect of PMWS in the herds.

Experimental infection of calves with bovine viral diarrhea virus genotype II (NY-93).

To ascertain the virulence of bovine viral diarrhea virus (BVDV) genotype II, isolate NY-93 was inoculated intranasally into 3 calves, 2 of which were treated with a synthetic glucocorticoid prior to and after virus inoculation. Anorexia, fever (up to 42 C), dyspnea, and hemorrhagic diarrhea developed 6 days after intranasal inoculation with BVDV NY-93. The condition of all calves deteriorated further until the end of the study on day 14 postinoculation. The most significant postmortem macroscopic changes in all calves were limited to the gastrointestinal tract and consisted of moderate to severe congestion of the mucosa with multifocal hemorrhages. Microscopic lesions found in the gastrointestinal tract were similar to those observed in mucosal disease, including degeneration and necrosis of crypt epithelium and necrosis of lymphoid tissue throughout the ileum, colon, and rectum. The basal stratum of the epithelium of tongue, esophagus, and rumen had scattered individual necrotic cells. Spleen and lymph nodes had lymphocytolysis and severe lymphoid depletion. Severe acute fibrinous bronchopneumonia was present in dexamethasone-treated calves. Abundant viral antigen was detected by immunohistochemistry in the squamous epithelium of tongue, esophagus, and forestomachs. BVDV antigen was prominent in cells of the media of small arteries and endothelial cells. The presence of infectious virus in tissues correlated with an absence of circulating neutralizing antibodies. These findings highlight the potential of BVDV genotype II to cause severe disease in normal and stressed cattle.

Effect of concurrent experimentally induced bovine respiratory syncytial virus and bovine viral diarrhea virus infection on respiratory tract and enteric diseases in calves

Abstract Objective To compare experimentally induced concurrent bovine viral diarrhea virus (BVDV) and bovine respiratory syncytial virus (BRSV) infection with single virus infection. Animals 9- to 12-month-old calves. Procedure Calves were allotted to 4 groups: 1, mock-infected control (n = 3); 2, BRSV infected (5); 3, BVDV infected (5); and 4, concurrent BRSV and BVDV infected (5). Total and differential WBC counting was done. Concentration and duration of BVDV in nasal secretions and serum, and duration of BRSV in nasal secretions were determined. Concentration of BVDV in various tissues was determined, and isolation of BRSV from lung tissue was attempted. Histologic examination and immunohistochemical analysis were done to detect lesions and distribution of viral antigens, respectively. Results Calves with concurrent infection developed more severe clinical signs of disease (fever and diarrhea), leukopenia, and more severe lesions. They also shed virus from nasal secretions in greater concentration and for longer duration, and BRSV was isolated from their lungs. Calves with concurrent infection also had more extensive lung lesions. Alimentary epithelial necrosis and severe lymphoid depletion were associated with BVDV infection in calves with or without concurrent BRSV infection. BVDV antigen in lymphatic tissue was detected in stromal cells only. Conclusions Concurrent infection with BRSV and BVDV resulted in more severe respiratory tract and enteric disease than did infection with either virus alone, possibly indicating synergistic effect between the viruses. BVDV’s role in causing respiratory tract disease is attributable, indirectly, to effects on the host’s immune system, not to infection of the lungs. (Am J Vet Res 1998;59:1423–1430)

Detection of a novel strain of porcine circovirus in pigs with postweaning multisystemic wasting syndrome.

Swine infectious agents, especially viruses, are potential public health risks associated with the use of pig organs for xenotransplantation in humans. Therefore, there is a need for better characterization of swine viruses and for the development of diagnostic tests for their detection. We report here isolation of a novel strain of porcine circovirus (PCV) from pigs with postweaning multisystemic wasting syndrome (PMWS). Affected pigs exhibited severe interstitial pneumonia and lymphoid depletion. The complete nucleotide sequence (1,768 nucleotides) of the genome of the PCV isolate was determined and compared with the sequence of the PCV strain isolated from PK-15 cells. Sequence comparison revealed significant differences between the two PCV strains, with an overall DNA homology of 76%. Two major open reading frames (ORFs) were identified. ORF1 was more conserved between the two strains, with 83% nucleotide homology and 86% amino acid homology. ORF2 was more variable, with nucleotide homology of 67% and amino acid homology of 65%. PCR and in situ hybridization demonstrated abundant viral DNA in various organs of pigs with PMWS. In situ hybridization demonstrated that this strain of PCV targets multiple organs and infects macrophages, lymphocytes, endothelial cells, and epithelial cells.

Adenovirus-Induced Inclusion Body Hepatitis in Four-Day-Old Broiler Breeders

Two separate parent broiler flocks originating from the same grandparent flock experienced mortalities of 23% and 40%, respectively, in chicks between 1 and 14 days of age. Chicks affected at 4 days of age had tremors, depression, and hypoglycemia. They had pale yellow, swollen, friable livers. Pancreata were discolored and hemorrhagic. Spleens were swollen and sightly darkened. Microscopic lesions consisted of multifocal areas of acute hepatic and pancreatic necrosis with numerous basophilic intranuclear inclusions with karyomegaly. Splenic sections had severe lymphoid depletion and reticular cell and macrophage hyperplasia. An adenovirus from affected livers was isolated in chicken embryo liver cells. Serologic evidence suggests that the grandparent flock began egg production seronegative to adenovirus antibodies, was exposed during production, and, subsequently, shed adenovirus vertically to its progeny. The clinical syndrome was reproduced by injecting the isolated adenovirus into 1-day-old antibody-negative chicks. Histologic lesions in the experimentally reproduced disease cases were identical to those in the naturally occurring cases.

Histopathologic Findings in the Lymphoid and Reticuloendothelial System in Pediatric Hiv Infection:. A Postmortem Study

The present report describes the histopathological features of lymphoreticular tissues in 29 pediatric autopsies of human immunodeficiency virus (HIV)-infected patients. Mean age for the whole group was 1.77 years; 68.9% and 62% of the cases were 2 years old or less and 1 year old or less at the time of death, respectively. Twenty-one cases were categorized as acquired immunodeficiency syndrome (AIDS) and the rest included seven HIV-positive newborns and infants and two infants belonging to a high-risk group. The thymus (24 cases) showed severe lymphoid depletion (atrophy) in 16 (66.6%) cases, microcystic transformation of Hassall's corpuscles (HCs) in 4, calcified HCs in 3, absence of HCs in 3, and plasmacytic infiltrates and Warthin-Finkeldey-type multinucleated giant cells (also found in lymph nodes and bowel lymphoid aggregates in the same case) in 1. Lymph nodes (25 cases) revealed extensive lymphocyte depletion (68%); selective follicular (2 cases) or paracortical (3 cases) atrophy; hemophagocytosis (44%); some type of hyperplasia (plasmacytosis, enlarged follicles) in 5 cases; some type of lymphadenitis (12 cases), 5 cases of which were due to opportunistic infections (cytomegalovirus, 2; histoplasmosis, cryptococcosis, Mycobacterium avium-intracellulare, 1 each). Main findings in the spleen (28 cases) were extensive lymphocyte depletion (10 cases), limited to the white pulp in 4 and including the red pulp in 7; some type of lymphoid hyperplasia (limited to white pulp in 6 cases and involving the red pulp in 5); hemophagocytosis (7 cases); and foci exhibiting a peculiar arrangement of spindle-shaped cells combined with capillaries, plasma cells, and occasionally siderophages in 11. These we have termed kaposiform areas due to the resemblance to the so-called inflammatory variant of Kaposi's sarcoma. This pattern was also recognized in lymph nodes of two cases. Although atrophy was the main theme, cases with hyperplasia were also noticed. The possible relationship, if it exists at all, between kaposiform areas and Kaposi's sarcoma remains to be established. No tumor was found in this series. No specific histopathologic pattern of lymphoid tissues atributable to HIV emerged form this study aside from kaposiform areas, a microscopic feature not previously reported in this circumstance in pediatrics.

Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication

Previous studies suggested that simian immunodeficiency viruses isolated from African green monkeys (SIVagm) are relatively nonpathogenic. The report describes the isolation and biologic and molecular characterization of a pathogenic SIVagm strain derived from a naturally infected African green monkey. This virus induced an AIDS-like syndrome characterized by early viremia, frequent thrombocytopenia, severe lymphoid depletion, opportunistic infections, meningoencephalitis, and death of five of eight macaques within 1 year after infection. An infectious clone derived from this isolate reproduced the immunodeficiency disease in pig-tailed (PT) macaques, providing definitive proof of the etiology of this syndrome. Although the virus was highly pathogenic in PT macaques, no disease was observed in experimentally infected rhesus macaques and African green monkeys despite reproducible infection of the last two species. Whereas infection of PT macaques was associated with a high viral load in plasma, peripheral blood mononuclear cells, and tissues, low-level viremia and infrequent expression in lymph nodes of rhesus macaques and African green monkeys suggest that differences in pathogenicity are associated with the extent of in vivo replication. The availability of a pathogenic molecular clone will provide a useful model for the study of viral and host factors that influence pathogenicity.

Apoptosis: a mechanism of cell killing by influenza A and B viruses

In previous studies, we observed that the virulent avian influenza A virus A/Turkey/Ontario/7732/66 (Ty/Ont) induced severe lymphoid depletion in vivo and rapidly killed an avian lymphocyte cell line (RP9) in vitro. In examining the mechanism of cell killing by this virus, we found that Ty/Ont induced fragmentation of the RP9 cellular DNA into a 200-bp ladder and caused ultrastructural changes characteristic of apoptotic cell death by 5 h after infection. We next determined that the ability to induce apoptosis was not unique to Ty/Ont. In fact, a variety of influenza A viruses (avian, equine, swine, and human), as well as human influenza B viruses, induced DNA fragmentation in a permissive mammalian cell line, Madin-Darby canine kidney (MDCK), and this correlated with the development of a cytopathic effect during viral infection. Since the proto-oncogene bcl-2 is a known inhibitor of apoptosis, we transfected MDCK cells with the human bcl-2 gene; these stably transfected cells (MDCKbcl-2) did not undergo DNA fragmentation after virus infection. In addition, cytotoxicity assays at 48 to 72 h after virus infection showed a high level of cell viability for MDCKbcl-2 compared with a markedly lower level of viability for MDCK cells. These studies indicate that influenza A and B viruses induce apoptosis in cell cultures; thus, apoptosis may represent a general mechanism of cell death in hosts infected with influenza viruses.

Silicate pneumoconiosis in pigs: Optical and scanning electron microscopical investigations with X-ray microanalysis

Four cases of silicate pneumoconiosis are described in pigs raised near several chalk quarries and two cement works. The pulmonary changes were characterized by thickened alveolar septa, resulting in distorted airspaces, and small foci of initial fibrosis. In the bronchiolar and alveolar sites, as in the interstitium, free and intracytoplasmic dust was detected. An energy dispersive X-ray microanalysis coupled with a scanning electron microscope revealed that this dust was composed mainly of silicon, calcium, potassium, sulphur, aluminium and iron. In lung-associated lymph nodes, severe lymphoid cell depletion and dilatation of peritrabecular and subcapsular sinuses were constant findings. The inorganic material found in the lymph nodes contained the elements listed above. Air samples from the same geographical area revealed particulate pollutants, the qualitative features of which were similar to those found in lung and lymph nodal tissue. It is concluded that domestic animals raised in polluted environmental conditions represent an important biological source from which helpful data may be obtained for assessing risks to human health.

Subclinical infectious bursal disease in an integrated broiler production operation.

A field study was designed to determine the prevalence of subclinical infectious bursal disease (IBD) in broiler chickens from a commercial poultry company. Bursae of Fabricius (BF) from two vaccinated and three nonvaccinated broiler flocks were evaluated histologically, and antibody profiles of these broiler and matched parent breeder flocks were established. Lesions of IBD, including lymphoid necrosis, stromal edema, and infiltrates of heterophils and macrophages, were first detected in BF at 24 days of age in both vaccinated and nonvaccinated chickens. At 41 days, all BF had lesions characteristic of IBD, including severe lymphoid depletion, proliferation of epithelial cells, and mild fibroplasia. Although mean maternal antibody levels (measured by enzyme-linked immunosorbent assay) in broilers were apparently protective through day 12, IBD antibodies decreased to nonprotective levels (below 1,000) by day 16 or 20. Titers began to increase by day 28 or 32 because of field exposure. Sentinel birds, placed with broiler flocks, also developed IBD antibody titers. Broiler breeders had low and nonuniform antibody titers. Prevalence of field IBD exposure was high, and existing vaccination programs were not effective.

Transplacental Antiretroviral Therapy with 9-(2-Phosphonylmethoxyethyl)adenine Is Embryotoxic in Transgenic Mice

Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3'-azido-3'-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.

Spectrum of disease in macaque monkeys chronically infected with SIV/SMM

Twelve rhesus and one pig-tailed macaque have been monitored for 28–41 months following experimental infection with 10 4 TCID of SIV/SMM. Twelve of the 13 animals became virus positive and seroconverted within 3 to 6 weeks of exposure; the remaining animal seroconverted at 6 months, but has remained virus negative. Six of the 13 animals (46%) died between 14 and 28 months post-infection, following prolonged clinical disease characterized by chronic diarrhea and weight loss, peripheral lymphadenopathy and hemogram abnormalities. Histologic findings ranged from prominent follicular hyperplasia to severe lymphoid depletion, with lymphoid tissues often showing an infiltrate of syncytial giant cells. One animal had intestinal cryptosporidiosis and two had brain lesions comparable to those seen in AIDS encephalopathy in humans. Three of the remaining seven animals have an ARC-like disease and are showing gradual deterioration of their clinical condition. These animals, as well as animals that died, had progressive decreases in CD4 + cells and CD4 +/CD8 + cell ratios. These observations further document the marked clinical, pathologic and immunologic similarities between human AIDS and the SIV-infected macaque model.

Acquired immune deficiency syndrome: report of an autopsy case

Authors report the first autopsy case of acquired immune deficiency syndrome in Korea. The patient was a 26 years old Korean male who died of respiratory failure due to mixed pulmonary infections. He had history of homosexual contacts with partners of both domestic and foreign nationalities. Initial presentation was unexplained fever for two months. Serological test and western blot test for anti-HIV were positive and T-cell subset analysis revealed T3/T4/T8 to be 73/8/67%. Pulmonary tuberculosis with mediastinal lymphadenopathy and esophagonadal fistula and oral candidiasis were presented. Respiratory infection progressed gradually and he died seven months after the initial symptom. Autopsy findings were generalized severe lymphoid cell depletion, especially of T-cell population and mixed pulmonary infections with Pneumocystis carinii and cytomegalovirus (CMV). The CMV infection involved lungs and adrenals. Oral candidiasis was also demonstrated.

Effect of CI-949 and CI-959 on immune function and lymphoid organs in rats

The immunotoxic properties of two experimental antiallergic drugs, CI-949 and CI-959, were investigated. Wistar rats were gavaged once (CI-949) or twice (CI-959) daily for 21 days with the drugs. Immunotoxicity was assessed using the enzyme-linked immunoabsorbant assay (ELISA) for humoral immunity, a delayed-type hypersensitivity (DTH) procedure for cell-mediated immunity, and natural killer cell (NKC) activity to evaluate spontaneous cytotoxicity. Ratios of body weight to spleen, thymus, liver and kidney weights were determined. Routine histopathology was performed on lymphoid tissue and other body organs. Although 100 mg/kg/day of CI-949 had some stimulating effect on antibody production and NKC cytotoxicity, no consistent immunomodulation was apparent. Except for a significant increase in liver weight at the 100 mg/kg dose of CI-949, no other toxic effects were observed. In contrast to CI-949, CI-959 significantly ( P<0.05) suppressed antibody production at the 100 mg/kg dose and impaired the DTH reaction, although not significantly. Natural killer cell cytotoxicity was unaffected by 100 mg/kg CI-959. Decreased body weight and histopathological lesions were observed in the thymus and spleen of rats administered 100 mg/kg CI-959. These lesions ranged from mild to severe lymphoid depletion which was also reflected in significantly ( P<0.05) reduced spleen and thymus organ weight to body weight ratios. Since 100 mg/kg of CI-959 produced toxicological and pathological alterations in the exposed rats, these data suggest that CI-959 is not highly or specifically immunotoxic at dosages lower than those that alter conventional toxicological parameters used in new drug testing programs. The no-effect dose for both drugs in these experiments was 30 mg/kg, since all changes noted occurred at the 100 mg/kg level. However, additional studies are necessary to establish a maximal no-observable-effect dose level.

Depression of vaccinal immunity to marek's disease by infection with chicken Anaemia agent

Chicken anaemia agent (CAA) depressed protective vaccinal immunity against Marek's disease (MD) when vaccinated chicks were inoculated with CAA at 1 to 14 days of age. In chicks inoculated with CAA alone, a typical CAA infection as manifested by early mortality, decrease in haematocrit value, severe lymphoid depletion in the lymphoid organs, and aplasia of the bone marrow occurred only when one-day-old chicks were inoculated. When both turkey herpesvirus (HVT) and CAA were inoculated, a typical CAA infection occurred even if chicks were inoculated with CAA at 8 days of age. The response of splenic lymphocytes to mitogen stimulation was more severely depressed in chicks dually inoculated with HVT and CAA than in chicks inoculated with CAA alone. These results suggest that the depressive effect of CAA infection on HVT vaccinal immunity may be due to a severe impairment to T cell-mediated immunity resulting from enhanced pathogenicity of CAA in vaccinated chicks.

Leukemia prevention and long-term survival of AKR mice transplanted with MHC-matched or MHC-mismatched bone marrow.

The current studies were designed to evaluate the effectiveness of marrow transplantation within and outside the major histocompatibility complex (MHC) on the long-term survival and occurrence of spontaneous leukemia in AKR mice. AKR mice, which were lethally irradiated and received MHC-matched marrow from CBA/J mice (CBA----AKR), never developed leukemia and were alive and remained healthy for up to 280 days post-transplant. These long-term surviving chimeras possessed substantial immune vigor when both cell-mediated and humoral responses were tested. Lethally irradiated AKR mice, which had received MHC-mismatched marrow (anti-Thy-1.2 treated or nontreated) from C57BL/6J mice (B6----AKR), never developed leukemia and survived up to 170 days post-transplant. However, both groups of these chimeras began dying 180 to 270 days post-transplant due to a disease process which could not be readily identified. Histological analysis of B6----AKR chimeras revealed severe lymphoid cell depletion in thymus and spleen; however, none of these chimeras exhibited classical features of acute graft versus host disease. Concanavalin A mitogenesis, primary antibody responses to sheep red blood cells and the production of interleukin 2 (IL-2) were suppressed in B6----AKR chimeras. IL-2 treatment of B6----AKR chimeras was shown to partially correct these deficiencies without stimulating mixed lymphocyte responsiveness to donor or host lymphocytes. These studies indicate that the use of MHC-mismatched marrow for the prevention of spontaneous AKR leukemia may rely on augmentative IL-2 therapy for complete immune reconstitution of leukemia-free chimeras.

Effect of cyclophosphamide pretreatment on autoimmune encephalomyelitis in rats

We studied the effect of a low dose cyclophosphamide (CY) treatment on the clinical course of experimental autoimmune encephalomyelitis (EAE) in rats from three resistant or low-susceptible strains: Fischer, Brown-Norway, PVG, and the F1 hybrid between the two former strains. Treatment with 40 mg/kg two days before immunization resulted in a marked potentiation of EAE development in Fischer and PVG rats, but not in BN rats or F1(BN X F) hybrids. The effect of the CY treatment was a short period of severe lymphoid cell depletion with an increase in the quotient between T cells reacting with w3/25 monoclonal antiserum and such reacting with ox-8 antiserum, indicating a relative reduction in suppressor/cytotoxic cell counts. Treatment of Fischer or PVG rats, after CY treatment, for five days with thymic hormone factor (THF) normalized T cell ratios and restored the rats to a state of low susceptibility. It is concluded that Fischer and PVG rats have an EAE suppressive mechanism dependent on CY-sensitive suppressor lymphocytes, while there may be other mechanisms of resistance to EAE in BN rats.

New perspectives in the diagnosis and treatment of adenosine deaminase (ADA) deficiency.

Severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency (ADA) exhibits autosomal recessive inheritance, and may account for up to 20% of cases (1). Accumulation of intracellular toxic deoxynucleotides and/or S-adenosyl homocysteine particularly in T cells, is considered responsible for the severe lymphoid depletion and dysfunction observed in affected children (2). Unlike other forms of SCID, this variety is amenable to enzyme replacement therapy using regular fresh irradiated red blood cell transfusions as the source of enzyme. Another form of therapy suggested from in vitro studies, is the use of deoxycytidine which theoretically would act as a competitive substrate for deoxycytidine kinase, the enzyme considered responsible for the intracellular accumulation of deoxy-ATP (dATP). This study reports our experience of various treatments in three ADA deficient children.

Some Observations on an Adenovirus Isolated from Specific Pathogen Free Chickens

An avian adenovirus associated with high mortality and lesions of hepatitis, pancreatitis, and anemia was isolated from chemically bursectomized progeny of a breeder flock maintained under specific pathogen free conditions and monitored for adenovirus infection by the agar gel precipitin test. The chemical immunosuppression appeared to trigger the clinical disease in the progeny and lead to the recognition of virus infection in parent flock. Infection was eradicated in subsequent generations of breeders by use of a standard technique for disinfection of premises and a special surveillance program for adenovirus infection.The isolant induced a severe lymphoid depletion in the bursa and spleen of experimentally infected chicks. Serotyping, using specific antiserum to this isolant, indicated that the isolant shares antigenic determinants with 2 of the 10 serotypes of the avian adenovirus group. The suggested designation for this isolant is Regional Poultry Laboratory type.