Interstitial Mononuclear Infiltration Research Articles

Sequential study of the histopathology and cellular and humoral immune response during the development of an autoimmune orchitis in Wistar rats.

Wistar rats immunized with an homologous testicular homogenate (TH) and complete Freund's adjuvant, followed by i.v. injection of Bordetella pertussis, developed an autoimmune orchitis (EAO). Animals were studied at 7, 16, 30, 50, and 80 days (d) after the first immunization. An important lesion of the testis only appeared at 50 d, increasing in severity and incidence (77%) at 80 d. Lesions were characterized by a prevalent aspermatogenesis with tubular atrophy and mild interstitial mononuclear infiltrates. Delayed-type hypersensitivity response (DTH) against TH was detected early at 7 d and, except for 16 d, it increased with time, reaching a maximum at 80 d. A good temporal relationship between DTH and histopathology was found. Circulating antibodies to TH, detected by ELISA, were only present in 64% of the animals with testis lesion, while no deposits of IgG or C3 in the seminiferous tubules were seen. We describe a sequence of immunological events, concomitant with pathological changes of the testis, during the development of a severe EAO in Wistar rats.

Mechanism of lung injury in cotton rats immunized with formalin-inactivated respiratory syncytial virus.

Respiratory syncytial virus (RSV) seronegative cotton rats were immunized intramuscularly at four and eight weeks of age with either formalin-inactivated, alum-precipitated RSV grown in HEp-2 cell tissue cultures or virus-free HEp-2 cell tissue cultures similarly prepared. Sham-immunized animals served as controls. At 12 weeks of age, all animals were challenged with 6 x 10(5) plaque forming units of live RSV via the intranasal route. Animals were killed at predetermined days and evaluated for RSV antibody, virus replication and pulmonary histopathology. Of animals immunized with inactivated-RSV, 88% developed neutralizing antibody to RSV. Virus replication in the lungs of such animals was significantly reduced compared with tissue-culture-immunized animals. Surprisingly, however, both groups exhibited pulmonary histopathology, characterized by polymorphonuclear and mononuclear interstitial infiltrates. The virus-immunized animals manifested a more severe inflammatory reaction that reached a peak earlier than the virus-free, tissue-culture-immunized control group. In contrast, sham-immunized animals, when infected with live RSV for the first time, developed little or no pulmonary histopathology. The data suggest that the pathogenesis of pulmonary injury during natural RSV infection in the immunized host is due primarily to prior sensitization to the virus. In the animal model, sensitization to non-viral tissue culture components also contributes to lung injury.

Inclusion body myositis in post-poliomyelitis muscular atrophy

A 38-year-old male developed a new muscle weakness in his left thigh 35 years after having acute paralytic poliomyelitis with residual right distal leg weakness and atrophy. EMG studies showed widespread denervation in proximal and distal muscles regardless the clinical involvement. Muscle biopsy from an affected muscle showed the findings of inclusion-body myositis consisting of perivascular and interstitial mononuclear infiltration, sarcoplasmic granular inclusions with membranous whorls and typical filamentous inclusions in several myonuclei. This raises the possibility of inclusion body myositis in other cases of progressive post-poliomyelitis muscular atrophy, especially those with perivascular infiltration of mononuclear cells in the muscle biopsy.

Pulmonary cadmium oxide toxicity in the rat.

Although occupational exposures to cadmium have usually involved inhalation of insoluble cadmium oxide (CdO) particles, experimental studies of pulmonary cadmium toxicity have relied on aerosol exposures to soluble cadmium chloride particles. The present study describes a model of acute lung injury based on single 3-h exposures of rats to 0.5 and 5.3 mg/m3 CdO. Biochemical changes were correlated with pathological observations for 15 d postexposure to CdO. Four days following CdO exposure, histopathological observations included focal areas of epithelial hyperplasia, a mononuclear interstitial infiltrate, and increased numbers of alveolar macrophages. In the high-dose group, these changes were correlated with increases in tissue protein and DNA contents of 217% and 195% of controls, respectively. While lungs from the low-dose exposures had returned to a normal appearance by 15 d postexposure, high-dose-exposed lungs exhibited an increase in noncellular thickening of the interstitium and a continued general hypercellularity at this time. In the high-dose exposure group, activities of the enzymes glutathione peroxidase, glutathione reductase, and the dehydrogenase of glucose 6-phosphate and 6-phosphogluconate were significantly elevated two- to fivefold at 2-4 d postexposure. When a correction was made for changes in lung cell number, significant increases were observed only in activities of the pentose-cycle dehydrogenases at 180-238% of controls. These increases suggested an enhanced ability of CdO-exposed lungs to generate the pentose-cycle products NADPH and ribose 5-phosphate, which would be needed for lipid and nucleic acid biosynthesis expected during the proliferative stages of epithelial repair. This study has demonstrated that the response to CdO exposure includes the induction of enzymatic activities that are related to antioxidant defense and lung repair.

Cyclosporine-associated renal arteriopathy resulting in loss of allograft function

Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

Chlamydial pneumonitis induced in newborn guinea pigs.

One- to three-day-old guinea pigs were inoculated intranasally with the chlamydial agent of guinea pig inclusion conjunctivitis. Physical signs of infection included a marked increase in respiration rate on days 5 to 10 of infection and radiographic evidence of pneumonia on day 6. When animals were killed at various times after infection and lung tissue was examined by histopathology, evidence of pneumonia was found beginning on day 4 and lasting as long as day 12, with maximal pathological changes on days 6 to 8. The pneumonia was generally unilateral and consisted of an acute inflammatory component in the bronchioles with granulocytes in both the lumen and the wall of the bronchioles and an interstitial and intra-alveolar mononuclear infiltrate in the parenchyma of the lung. Chlamydial antigen was detected in the bronchial epithelial cells by immunoperoxidase staining, and the guinea pig inclusion conjunctivitis organism was isolated from lung tissue on days 6 to 9. No other significant bacteria were isolated from lung tissue or seen on gram stains of lung sections. Both immunoglobulin M and immunoglobulin G serum antibodies to the guinea pig inclusion conjunctivitis agent were detected as early as day 8 and reached peak levels on day 12. The infection was apparently self-limiting. This model presents the opportunity to investigate pathophysiological and immunological aspects of chlamydial respiratory infections in a neonatal animal.

A survey of the pathology of marmosets (Callithrix jacchus) under experiment.

A survey of the pathology of 567 laboratory-bred cotton-eared marmosets (Callithrix jacchus) is presented. There were few significant pathological changes in animals used in studies up to 6 months in duration, suggesting that the marmoset can be a useful non-human primate species for routine toxicology. The most common pathological changes encountered were chronic colitis, chronic thyroiditis and interstitial mononuclear infiltration in the kidney. No internal parasites were encountered, nor were any viral or bacterial diseases identified. Fungal disease was confined to a few cases of oesophageal mycoses. In a long term study a variety of pathological changes have been observed, including a 'wasting' syndrome, not related to skeletal muscle myopathy, with atrophy of the gastrointestinal tract, salivary glands and gonads, haemosiderosis and fatty change in the liver and osteoporosis. It is suggested that these changes may be related to protein deficiency and that the nutritional requirements of the marmoset require further investigation.

The effects of metrizamide on the lung.

The pathologic effects of metrizamide on the lung were studied at 24 h and 48 h after its instillation in varying concentrations selectively into the right lungs of a series of immature dogs. Iso-osmolar and slightly hyperosmolar concentrations of metrizamide were found to cause mononuclear interstitial infiltration, focal areas of pneumonia and in some cases alveolar hemorrhage. Control bacterial studies showed that the reaction was aseptic.

Neuropathology of S. Paulo south coast epidemic encephalitis ( Rocio flavivirus)

The neuropathology of 8 cases of S. Paulo south coast epidemic encephalitis (Rocio flavivirus), a new arbo B virus encephalitis, is described. The topographic pattern of the lesions appears to be almost specific. The gray matter is predominantly affected. Interstitial mononuclear infiltration, microglial proliferation and perivascular lymphocytic cuffing were seen. Neuronophagia was seldom seen except during the acute phases of the disease. Throughout the neuraxis, the gray matter was affected to a greater degree than white matter. The more damaged structures, in descending order, were as follows: thalamus, dentate nucleus, substantia inominata, brain stem, spinal cord and basal nuclei. Most of the cases exhibited thalamic inflammatory necrosis. Electron microscopy disclosed in one case virus-like particles, resembling those described in other arbo B viruses in the cytoplasm of thalamic neurons. In this case, virus was isolated from the brain and an immunofluorescence test also showed antigenic material in the thalamic neurons.

Proliferative glomerulonephritis, hypocomplementemia, and nucleic acid antibodies in rats infected with Trypanosoma rhodesiense.

Host immunologic responses were studied in Sprague-Dawley rats infected with a human isolate of Trypanosoma rhodesiense. Retro-orbital sinus bleedings were obtained on days 0 and 14 and at 21 or 28 days. Infected and control rats were sacrificed on day 21 or 28 of the infection. Mild glomerulitis, as assessed by increased cellcularity and/or widening of the mesangial region, was apparent in 6 of 7 infected animals. Finely granular deposits of IgM and IgGl were found in most glomeruli with less prominent deposits of IgGa and IgA. Focal cortical mononuclear interstitial infiltrates were present in 2 of 7 rats. Subepithelial or mesangial electron dense deposits were present in the glomeruli of infected rats. Hypocomplementemia was present by day 21 and involved both the classical and alternative pathways of complement activation. Antibodies to native DNA and single-stranded RNA were present by day 21. These studies indicate the feasibility of studying trypanosomal glomerulonephritis in rats and will provide a convenient model for detailed immunologic and morphologic investigation of host immune responses in African trypanosomiasis.

Allergic Alveolitis Caused by Home Humidifiers

Allergic alveolitis (hypersensitivity pneumonitis) developed in two patients who were exposed to home humidifiers contaminated by thermophilic actinomycetes. Diagnosis was difficult because severe dyspnea was chronic and not easily associated with specific environmental exposure. Furthermore, chest roentgenograms were normal for long periods despite severe physiologic abnormalities. After several years of disabling symptoms, open lung biopsy findings suggested allergic alveolitis rather than sarcoidosis because a mononuclear interstitial infiltrate overshadowed the granulomas. Also, plasma cells were prominent and there was an intense bronchiolitis. Cultures of the humidifier water grew thermophilic organisms to which the patient's sera formed precipitins. Both patients experienced notable subjective and objective improvement following removal of the contaminated appliances. The ultrastructure of alveolar macrophages and basement membranes was similar to that described in animal models, suggesting cell-mediated hypersensitivity in the patients.

Nephropathy in patients with drug addiction. Evolution of pathological and clinical features.

The course of the nephropathy in patients with drug addiction has been studied in six subjects. The nephrotic syndrome with the presenting feature in all, with two progressing to terminal renal failure in less than a year. Serial percutaneous renal biopsies revealed the basic lesion to be a mild non-specific increase in PAS-positive material in the mesangial areas. This was more marked in the two patients with renal failure who, in addition, had segmental PAS-positive material in the glomerular capillary loops, focal tubular dilatation and atrophy, interstitial edema and mononuclear cell infiltration. Immunofluorescent staining revealed lumpy granular staining. IgG, present at the onset of the nephrotic syndrome, subsided as the first two patients developed renal failure, while beta1C and IgM, negative at the onset, became positive. Electron microscopy revealed focal basement membrane thickening and deposition of homogenous, finely granular electron-dense material predominantly in the mesangial areas. Our findings indicate that renal damage secondary to immune-complex deposits develops in the addict. The presence of interstitial swelling, mononuclear infiltration and tubular dilatation signals rapid deterioration of renal function and a grave prognosis, while their absence indicates a more prolonged indolent course.

Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis.

Abstract Antitubular basement-membrane antibodies were detected by indirect immunofluorescence in the serum of a patient in whom severe renal failure developed while he was receiving methicillin. A renal biopsy showed a severe mononuclear interstitial infiltrate with focal areas of tubular degeneration. IgG, C3 and a methicillin antigen assumed to be dimethoxyphenylpenicilloyl were present in a linear pattern along the tubular basement membrane but not along the glomerular basement membrane. The dimethoxyphenylpenicilloyl-tubular-basement-membrane hapten protein conjugate apparently led to an immune response with antitubular basement-membrane antibodies being involved in the immunopathogenesis of the patient's interstitial nephritis. (N Engl J Med 291:381–384, 1974)

Broncopneumopatias a vírus: análise crítica de alterações histológicas encontradas no estudo de afecções respiratórias não bacterianas na infância

Os autores apresentam 69 casos de afecções respiratórias em crianças que atribuem a agentes não bacterianos, provavelmente virais. Usam para isto um critério clínico, outro morfológico, em uma revisão de 372 pneumopatias infecciosas em casos de autópsias. Caracterizaram morfologicamente a resposta à agressão viral pela presença de: infiltrado mononuclear intersticial, predominantemente peribronquilar; alterações degenerativas ou mesmo necrose e hiperplasia do epitélio respiratório; membrana hialina; descamação epitelial; células gigantes sinciciais alveolares e bronquiolares; inclusões nucleares e citoplasmáticas; edema proteináceo alveolar e septal, proliferação intersticial conjuntiva incipiente. Criticam o erro por excesso de diagnósticos de "pneumonia mononuclear intesticial" e o erro por falta quando o acometimento bacteriano dificulta o diagnóstico de lesão atribuível a vírus. Além disso realçam a importância de achado de bonquiolite aguda como fundamental para o diagnóstico. Estas lesões - ao lado de achados clínicos-radiológicos e epidemiológicos - cosntituem o que a experiência adquirida julga como reação do pulmão a vários vírus conhecidos (Adenovírus, Influenza, Parainfluenza, Vírus Sincicial Respiratório e Sarampo).

The induction of vascular renal allograft rejection by leukocyte sensitizatin.

Abstract Human renal allograft rejection occurring within the first 2 months after surgery is frequently a vascular phenomenon, characterized by fibrinoid necrosis and endothelial cell proliferation of small vessels and plugging of glomerular capillaries with platelets and fibrin. This contrasts with interstitial edema and mononuclear cell infiltration, and only minimal vascular involvement, usually seen in renal allograft rejection in animals but also seen in man. To investigate this difference, 18 dogs were administered intravenous donor buffy coat prior to transplantation. These were compared to 7 dogs similarly treated except that buffy coat was not administered. Three autografts served as controls. All dogs received azathioprine daily (3 mg. per kilogram) beginning on the day of the operation. Daily assays of renal function, dog survival time, platelet counts, platelet survival times, and repeated biopsy specimens were compared. A marked difference between the immunized and nonimmunized groups was apparent morphologically. In the immunized group, vascular wall necrosis, platelet and fibrin plugging of glomerular capillaries, and endothelial cell proliferation were striking features of the rejection process. The over-all appearance was similar to that often seen in severe early (but not hyperacute) rejection in man. No significant difference in dog survival times or platelet studies was demonstrable between the groups. It is suggested that in man, the morphologic changes seen in early vascular rejection are a result of prior sensitization to transplantation antigen. Drug trials in animal transplantation aimed at studying reversal of the vascular aspects of rejection should be performed on animals exposed preoperatively to donor antigen.

Homologous disease in the adult rat, a model for autoimmune disease. II. Findings in the joints, heart, and other tissues.

Polyarthritis and cardiac lesions have been observed in the adult rat with homologous disease. Changes in the lymphoid tissue and kidney have also been noted. A migratory polyarthritis occurred in over half of the affected animals, and cardiac involvement of varying intensity was present in all. Histologically, the arthritis was characterized by a mononuclear synovial inflammatory reaction. In the heart, the valves and myocardium demonstrated a similar type of response. Cultures of involved joints and hearts for pyogens and pleuropneumonia-like organisms were negative. The lymphoid tissues showed progressive changes in three stages: (a) disappearance of follicles; (b) increase in plasma-like cells and histiocytes; and (c) fibrosis. The second stage tended to coincide with the development of the polyarthritis. The kidney showed mild interstitial mononuclear infiltration. The pathologic changes described appear to be a consequence of reaction between foreign immunologically competent cells and host antigens, but the possibility that these lesions represent a response to antigens derived from unknown infectious agents is, however, not ruled out.

AN EXPERIMENTAL STUDY OF PAROTITIS (MUMPS)

Cats injected into the parotid gland and testicle with a bacterial sterile filtrate of the salivary secretion of children in the active stage of parotitis or mumps can be made to develop a pathological condition having several points of resemblance to the condition present in mumps in human beings. After an incubation stage of from five to eight days definite changes have been noted in the temperature, blood leukocytes, and inoculated organs. The temperature rise begins within twenty-four hours of the inoculations and reaches a maximum in from seven to fourteen days. The febrile rise fluctuates between 1 degrees and 2.5 degrees C. The white blood cells begin to increase on the second day following the inoculation. The first change is a polymorphonuclear leukocytosis which precedes the glandular swellings. This initial rise is followed by a decline, after which the lymphocytes increase. The increase is confined to the small lymphocytes, which increase to from 7 to 10 per cent of their initial number. The inoculated glands become swollen and tender. The swelling and tenderness become apparent from the fifth to the ninth days and persist for a variable period. The parotid changes are less constant or less obvious than are the testicular. The latter are constant and endure from eight to twelve days. The rise of temperature and the leukocytosis precede the glandular swelling, but all the changes reach the maximum at about the same time, after which they decline gradually. What may be regarded as normal conditions are reestablished in four weeks or less. The intraparotid and intratesticular injections of extracts of normal parotid gland and testicles may cause a mild rise of temperature and leukocytosis of brief duration, but swelling and tenderness are absent. The white cells increased are the polymorphonuclears and not the lymphocytes. The intraparotid and intratesticular injections of filtrates of normal saliva may cause a mild rise of temperature of very brief duration, but leukocytosis, swelling, and tenderness do not appear. The histological changes in the parotid gland when present consist chiefly of edema of the interlobular connective tissue with mononuclear interstitial infiltration about the ducts and elsewhere. In cases of long duration the ducts may be dilated. But in some instances the swollen gland while showing congestion and edema in gross showed inconspicuous changes under the microscope. The histological changes in the testicle are of two kinds: inconstant changes of cellular invasion between the tubules and swelling or even multiplication of the interstitial cells, constant ones consisting of degeneration of the epithelium and interference with spermatogenesis, a condition to which we have applied the term "spermatorrhexis." The pathological conditions set up by the filtrate derived from the salivary secretion of cases of acute parotitis are intensified by successive transfers through a small series of cats of the extract and emulsion of the parotid gland and testicle previously inoculated. The pathological changes are also prevented or reduced when the extract or emulsion is previously incubated with a quantity of blood serum obtained from a cat which has survived inoculation. Normal serum, on the other hand, has no such inhibiting effect. The deduction from these experiments is to the effect that the salivary secretion in parotitis or mumps contains a filterable substance capable of setting up a series of definite pathological conditions when inoculated into the testicle and parotid glands of cats. Whether this active material is a microorganism and if so whether it is the specific microbic cause of parotitis or mumps remains to be ascertained.