Focal Lymphocytic Infiltration Research Articles

Laboratory evaluation of patients with Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration of the lacrymal and salivary glands, leading to severe dryness of eyes (keratoconjunctivitis sicca) and mouth (xerostomia). SS may exist as a primary disorder (1 degree-SS) or in association with other autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus or progressive systemic sclerosis (scleroderma). Diagnosis of 1 degree-SS is confirmed by minor salivary gland biopsy and the presence of circulating autoantibodies. Minor salivary gland biopsies exhibit focal lymphocytic infiltrates that are present in the majority of lobules. Incorrect methods of biopsy and failure to determine the average focus score are common causes for false-positive and false-negative biopsies. SS patients frequently have a positive antinuclear antibody test due to presence of SS-A (Ro) and SS-B (La) autoantibodies. Molecular analysis has revealed multiple "SS-A" proteins (60 kd, 54 kd, 52 kd) that react with sera from SS patients, as well as a 48 kd SS-B protein. Rheumatoid factor (anti-IgG Fc antibody) in 1 degree-SS patients exhibits restriction in its light chain-associated idiotype, in contrast to RA patients where no restriction of idiotype was detected. Other autoantibodies found in a subpopulation of SS patients include anti-ADP ribose polymerase, anti-cardiolipin, anti-mitochondrial, anti-mitotic spindle apparatus, anti-parietal cell, and anti-thyroid associated antibodies. Due to the high frequency of dryness syndromes in patients due to other causes (ranging from drug side effects to normal aging processes), the use of strict criteria for diagnosis of SS will lead to improved cost-efficient medical care avoiding needless anxiety in the patient.

Primed and naive helper T cells in labial glands from patients with Sjogren's syndrome

This study has investigated the presence and distribution of B cells, T cells and T-cell subsets within labial glands of patients with primary Sjogren's syndrome (n = 9) and secondary Sjogren's syndrome associated with rheumatoid arthritis (n = 8) using a sequential double immunoperoxidase technique and true colour image analysis. The composition of the inflammatory infiltrates was similar in glands from both patient groups. B cells were normally present within large foci with few detected in diffuse infiltrates such that the ratio of T:B cells in foci (2.4:1) was significantly lower than in diffuse infiltrates (7.3:1; P less than 0.001). In all infiltrates helper T cells (CD8-, CD3+) predominated over suppressor/cytotoxic cells (CD8+, CD3+; 2.7:1). Analysis of primed (CD45RA-, CD45RO+) and naive (CD45RA+, CD45RO-) CD8- T cells showed that the ratio of the primed to naive subset was significantly higher in focal (4.2:1) compared to diffuse (1.5:1; P less than 0.001) areas of lymphoid infiltration. These results indicate that the focal lymphocytic infiltrates characteristic of Sjogren's syndrome contain B cells associated with a T-cell population consisting predominantly of primed CD8- helper T cells. This latter population may be responsible for upregulating glandular B-cell activity in Sjogren's syndrome.

Hashimoto's Thyroiditis as a Risk Factor of Thyroid Lymphoma

Hashimoto's thyroiditis (struma lymphomatosa), first described by Hashimoto in 1912, is an autoimmune inflammation of the thyroid commonly affecting middle-aged women. Histologic features of Hashimoto's thyroiditis (HT) include diffuse infiltration of lymphoid cells usually with formation of lymphoid follicles, varying degrees of fibrosis, oxyphilic change or squamous metaplasia in the epithelial cells. When the presence of focal lymphocytic infiltration is assumed to be an adequate criterion for diagnosis of autoimmune thyroiditis, the incidence appears to be as high as 16-23% in elderly females. An etiologically important role of HT in the development of thyroid lymphoma had been postulated, and recently, this was confirmed by epidemiological studies. In this article, a brief review of HT is given, together with results of our studies on thyroid lymphoma, and a discussion in the light of the pertinent literature. Immunologic and immunohistologic studies revealed that all of the thyroid lymphomas were of the B-cell type. Malignant lymphomas developing in patients with other autoimmune diseases such as Sjögren syndrome and rheumatoid arthritis have also been reported to be B-cell derived. Therefore it is suggested that immune deficiency is a causal factor for B-cell lymphoma.

Noninvasive detection of cardiac allograft rejection by analysis of the unipolar peak-to-peak amplitude of intramyocardial electrograms

The use of standard electrocardiographic monitoring to detect cardiac allograft rejection has become unreliable since the advent of cyclosporine immunosuppression. Unipolar peak-to-peak amplitude analysis has been shown to be a quantitative measure of ischemic myocardial injury. This study was performed to determine if unipolar peak-to-peak amplitude analysis could accurately detect cardiac allograft rejection as determined by blinded endomyocardial biopsies. Ten adult mongrel dogs underwent heterotopic (n = 7) or orthotopic (n = 3) cardiac transplantation with placement of sutureless screw-in electrodes (Medtronic, Inc, Minneapolis, MN) on the anterior and posterior aspect of each ventricle. Postoperatively, animals were immunosuppressed for seven to ten days with cyclosporine and prednisone and then allowed to reject the transplant. Digitally processed intramyocardial electrograms were obtained daily. Endomyocardial biopsy was performed 1 week postoperatively and then at three to five day intervals for histological correlation. A unipolar peak-to-peak amplitude decline of 15% or greater occurred one to three days before the biopsy detection in 10 of 10 episodes of rejection. There were no false negatives and one false positive (although a small focal lymphocytic infiltrate was present). Thus, noninvasive unipolar peak-to-peak amplitude analysis was 100% sensitive and 90% specific in predicting and detecting cardiac allograft rejection.

Lymphocytic infiltrates and epithelial HLA-DR expression in lip salivary glands in connective tissue disease patients lacking sicca: a prospective study.

Focal lymphocytic infiltrations indistinguishable from what has been described in Sjögren's syndrome (SS) were found in lip salivary gland (LSG) biopsies in 15 of 80 patients with various connective tissue diseases (CTDs) lacking sicca. During a 4-year follow-up period, none of the patients developed symptoms or signs of decreased lacrimal or salivary gland function. Focal lymphocytic infiltrates of LSGs seemingly unrelated to glandular function are to be found in patients' various CTDs and therefore the diagnostic value of a positive LSG biopsy in this context has to be questioned.

Acute toxicity of methyl isocyanate, administered subcutaneously in rabbits: Changes in physiological, clinico-chemical and histological parameters

Subcutaneous administration of methyl isocyanate (MIC) in 0.5 LD50 and 1 LD50 doses in female rabbits resulted in significant changes in physiological, clinico-chemical and histological parameters. There was a fall in arterial blood pressure and cardioacceleration in both the 0.5 LD50 and 1 LD50 groups, while the respiration showed a differential response in these groups with the former showing hyperpnoea and the latter showing respiratory inhibition. A significant increase in the arterial blood lactic acid, lactate/ pyruvate ratio and 2,3-diphosphoglycerate levels, and the significant changes in acid-base status of both arterial and venous blood indicated tissue hypoxia of a stagnant type. Histopathological observations revealed a mild to moderate degree of congestion, focal lymphocytic infiltrations and necrosis in all visceral organs examined. These findings suggest that acute toxicity of MIC in vivo may be mediated by its effects on vascular beds.

Metastatic spermatocytic seminoma. A case report with light microscopic, ultrastructural, and immunohistochemical findings

A case of metastatic spermatocytic seminoma with metastases to homolateral retroperitoneal paraaortic lymph nodes in a 50-year-old man is described. The metastases were detected 18 months after orchiectomy. A retroperitoneal biopsy with cytoreductive lymphadenectomy was performed followed by radiotherapy and consecutively by combination chemotherapy. The patient died 25 months after orchiectomy of complications arising after a second course of chemotherapy. No signs of further tumor spread were observed. Autopsy was not performed. The tissue of the metastases fulfilled the light microscopic criteria for spermatocytic seminoma and ultrastructurally showed intercellular communications with typical intercellular bridges. The absence of placental alkaline phosphatase in tumor cells is also consistent with this diagnosis. The metastases differed from the primary tumor in the presence of focal lymphocytic infiltration and granulomatous reaction. This patient represents the first fully documented case of a metastasizing spermatocytic seminoma.

AN AUTOPSY CASE OF IDIOPATHIC ENLARGEMENT OF THE RIGHT ATRIUM, AND A REVIEW OF THE LITERATURE

A 69-year-old man in whom idiopathic enlargement of the right atrium was revealed at autopsy is described. The patient had had cardiomegaly of at least 19 years' duration prior to his death, even though cardiac symptoms were absent. Cause of death was pancreatic carcinoma. Postmortem examination revealed marked and diffuse dilatation of the right atrium and moderate dilatation of the left atrium. Measurement of the cardiac chambers showed that the right and left atria were 7.6 and 4.7 times as large as those of normal hearts, respectively. The volume of either ventricle was about twice the normal value. Histologically, widespread cardiac muscular degeneration and necrosis, diffuse fibrosis, and focal lymphocytic infiltration were found in the right atrium and also, to a lesser degree, in the left atrium. Such pathologic changes were not found in either of the ventricles. The etiology of these muscular changes, which might have been related to atrial enlargement, was unclear. The present case was thought to be consistent with idiopathic enlargement of the right atrium, and a brief review of the literature is given.

Focal adenitis in lacrimal and salivary glands. A post-mortem study.

In the present study the submandibular, labial, and lacrimal glands of 102 postmortem subjects were studied as to the presence of inflammatory foci, fibrosis, atrophy and fatty change. Focal lymphocytic infiltration of these glands with focus scores exceeding 1, one of the findings on which the diagnosis of Sjögren's syndrome is based, was found in 19 cases (18.6%). Fibrosis, atrophy, and fatty change occurred most often in the labial salivary glands of patients over 50 years of age with or without high focus scores. Fibrosis, atrophy and fat infiltration hardly ever occurred in the lacrimal glands although this was the type of gland in which high focus scores occurred most often. The findings suggest that a wider than hitherto recognized spectrum of systemic inflammatory diseases may contribute to lymphocytic adenitis and degeneration of the exocrine glands. The diagnosis of Sjögren's syndrome should be confirmed by additional diagnostic tests.

Early myocardial lesions in mice with EMC virus myocarditis. Electrocardiographic and morphological findings

Seventy male outbred NMRI mice (6 weeks old) were inoculated with a virus suspension containing 10 p.f.u. of the myocardiotropic variant of EMC virus. Ten mice were killed every other day, electrocardiography and histology were analyzed in a standardized form. ECG recordings at day 0 were used as own controls. We found that the chronological occurrence of ECG abnormalities correlates well with histopathological findings in the acute stage of EMC virus myocarditis. The typical time course in our mouse population was as follows. On day 4 early patchy necrosis was visible, without histological evidence of lymphocytic infiltration. ST displacement was already visible in most cases. Beginning of focal lymphocytic infiltration was seen on day 6 and widespread patchy necroses were observed. Intraventricular conduction defects became more common in addition to AV an SA block on day 8; the first extrasystoles were observed and the QRS voltage started to decrease. Heavy lymphocytic infiltrates occurred on day 10; at this time virtually all animals showed ST displacement. On day 14 infiltrates started to diminish and fibrosis began to appear prominent.

Subacute Study of Rats Fed Ground Beef Treated with Aqueous Chlorine — Anatomic Pathology

This research evaluated the anatomic pathology of rats fed diets containing ground beef which had been treated with aqueous chlorine. The anatomic pathology of 240 rats fed 92 d with diets containing ground beef treated with 0, 50, 200 or 600 ppm chlorine was carried out according to National Institutes of Health bioassay pathology procedures. The major rat tissues were evaluated and the incidence of histopathological conditions was recorded. The inclusion of chlorine-treated meat in the diet was not associated with any increase in incidence of neoplastic lesions, inflammatory lesions or degenerative changes. However, all male rats fed the meat diet both with or without chlorine exhibited mild to moderate hepatic fatty metamorphosis. In all likelihood, the fatty livers were due to the high fat content of the diet (about 35%). The adrenal glands of the control and treated males exhibited fatty metamorphosis. This effect is not explained by diet because even the male rats on the commercial rat feed had fatty adrenal glands. Other histopathologic conditions such as focal hepatitis, triaditis, focal myocarditis, focal lymphocytic infiltration, chronic murine pneumonia, chronic tracheitis, focal acute gastritis, dacryoadenitis, cataract, hyperplastic hepatic nodule or ultimobranchial cysts, when found were not associated with any treatment or sex group. The treatment of ground beef with aqueous chlorine before incorporation into a diet fed rats for 92 d exhibited no apparent effect on the anatomic pathology of rats.

Lung and heart pathology in fatal drug addiction. A consecutive autopsy study

Lung and heart sections from 33 drug addicts submitted for medico-legal autopsy at the Institute of Forensic Medicine in Copenhagen were studied together with tissue sections from 20 ‘normal’ persons. In the drug addict cases focal bleedings in lung tissue were found in 94%, signs of earlier bleedings, haemosiderin containing histiocytes, were seen in 91%, and focal fibrosis in 46%. The bleeding episodes may be due to hypoxia in connection with heroin intake. In 94% of the drug addicts birefringent material in lung tissue was demonstrated, in 58% in granulomas and giant cells, in 27% in giant cells only and in 9% in isolated histiocytes. The material was localized in the wall of pulmonal arteries and/or in the interstitial tissue, undoubtedly depending on the duration of the abuse. In 18% angiothrombosis was seen, in all cases granulomas/giant cells were observed in the wall of the vessel concerned. The results indicate periodical intravenous injection of dissolved tablets in addition to heroin. Histological signs of pulmonary hypertension were not seen, possibly due to the fact that abuse of central stimulants is very rare in Denmark. Regarding heart alterations no significant differences were demonstrated between drug addicts and controls. The only note-worthy finding was focal infiltration of lymphocytes in the atrio-ventricular bundle in two drug addicts, the meaning of which is uncertain.

Histopathology of herpes simplex virus keratouveitis.

Twenty-four eyes removed for complications of HSV keratitis were studied histopathologically. There were 20 men and 4 women with an average age of 61 years. Severe keratitis was seen in 14, moderate in 7, and mild in 3 eyes. Common features associated with severe keratitis were: acute perforation, granulomatous keratitis with giant cells in the stroma and Descemet's region, stromal inflammatory cells, angle-closure, severe iridocyclitis with diffuse or focal infiltration of lymphocytes and plasma cells, low-grade vitritis, choroiditis, and/or retinal periphlebitis. Specimens with moderate to mild keratitis had a similar distribution of inflammation but a lower incidence of granulomatous keratitis.

Age-related increase of focal lymphocytic infiltration in the human submandibular glands.

Histopathological studies were made on the submandibular glands, obtained from 207 autopsy cases of patients, ranging in age from 40-98 years who had not had collagen diseases. Focal lymphocytic infiltration of the submandibular glands was more frequently seen in the cases of patients over 70 years (80.3%) than in those of under 70 years (53.8%). Generally, the incidence of focal lymphocytic infiltration showed a trend to gradual increase with age. Immunohistochemically, a predominance of T cells (60-80%) was found in submandibular lesions with the majority (60-70%) belonging to the Leu 3a+ subset (Helper/Inducer) and with less than 20% belonging to the Leu 2a+ subset (Cytotoxic/Suppressor). The percentage of Leu 2a+ subset was found to increase in the lesion of the periacinar area, and the acinar parenchyma appeared gradually to be damaged by the infiltrating lymphocytes. The findings in the present study suggest that focal lymphocytic infiltration in submandibular glands is a focal sign of immunological disorder, based on the autoimmunity associated with aging.

Focal lymphocytic infiltration in the human labial salivary glands: a postmortem study

Focal lymphocytic infiltration in the human labial salivary glands was examined in a series of 190 postmortem subjects after suitable exclusion had been made. Focal lymphocytic infiltration, with or without a slight degree of parenchymal atrophic change, was found in 22.4% of the males and in 35.7% of the females. Of these, 9.0% (12 subjects) of the males and 10.7% (6 subjects) of the females with focal lymphocytic infiltration did not show any atrophic changes of the parenchyma. In the series reported here, the prevalence of focal lymphocytic infiltration apparently differs from the results of earlier investigators who had reported that none of the postmortem subjects without autoimmune diseases or connective tissue diseases showed focal lymphocytic infiltration in minor salivary glands. Although the pathological significance of focal lymphocytic infiltration in the minor salivary glands remains obscure, its diagnostic value for Sjögren's syndrome is discussed.

Biological activity of region 65–102 of the myelin basic protein

Region 65-102 of the myelin basic protein (MBP) houses a number of antigenic determinants known to induce delayed-type hypersensitivity, experimental allergic encephalomyelitis (EAE), suppressor cell function, and antibodies. In this report we describe the biological activity of synthetic peptides S53, S55, and S49 with sequence homology to region 69-84 of the rat, guinea pig, and bovine MBP. Peptide S53-A, defined by residues 75-84 of the guinea pig (SQRSQDEN) and of the rat (SQRTQDEN) MBP induced clinical signs of disease in Lewis rats. These included weight loss, flaccid tail, "muscle wasting," and hind-leg weakness. Histological examination of brain, spinal cord, and sciatic nerve sections of diseased rats revealed the complete absence of focal and perivascular lymphocytic infiltrates characteristics of demyelinating EAE lesions. Elongation of peptide S53 by three or six residues to residue sequences naturally found at its N-terminal end gave rise to peptides S55S (PQKSQRSQDEN) and S49S (GSLPQKSQRSDQDEN), respectively. Lewis rats challenged with either S55S or S49S developed classical clinical and histological signs of EAE. Severe hind-leg paralysis was accompanied by incontinence and sometimes death. Injected in the form of carrier-free peptide, S53 was a meager B cell immunogen. S53 conjugated with methylated-bovine serum albumin was also a potent immunogen and produced clinical signs of disease without CNS pathology. By comparison, carrier-free S55S and S49S were potent immunogens giving rise to antibodies that cross reacted completely and competitively with S55S but considerably less so with S53. The results show that the sequence of S53 defines an epitope responsible for the formation of anti-S53 antibodies. Elongation of the S53 sequence at its N-terminal end generated an additional epitope which induced cell-mediated immunity responsible for the concomitant development of pathological signs of EAE. It may be concluded that the induction of classical signs of EAE requires specific and defined sequences capable of expressing both B cell and T cell functions.

Focal lymphocytic infiltration in thyroids of elderly people. Histopathological and immunohistochemical studies.

Histopathological studies were made on the thyroid glands obtained from 169 autopsy cases of patients, ranging in age from 63 to 97 years, who had not had collagen diseases. Focal lymphocytic infiltration was found in 29 (17.2%) of 169 thyroid glands. Although the relationship between the incidence and age was unclear among elderly people, there was a tendency of a prevalence in females with respect to severity of focal lymphocytic infiltration. Immunohistochemically, a predominance of T cells (80-90%) was found in the thyroid lesions. The infiltrating T cells were composed of chiefly OKT 4+ or Leu 3a+ subset (60-80%) and lesser number of OKT 8+ or Leu 2a+ subset (20-40%). An increase in the percentage of OKT 8+ or Leu 2a+ cells, however, was observed in the tiny lesions infiltrating the interfollicular connective tissues. In aged patients over 63 years old, the average weight of thyroid glands without lymphocytic infiltration, obtained from female patients, was approximately 11 g, and the average weight of those with focal lymphocytic infiltration was approximately 17 g, whereas there was no significant difference in the weight of thyroid glands obtained from male patients with and without focal lymphocytic infiltration (14 g). The findings in the present study suggest that focal lymphocytic infiltration in thyroid glands is a focal sign of an immunological disorder which is based on autoimmunity associated with aging.

Histopathology of the duodenum and rumen of goats during experimental infections with Paramphistomum cervi

On microscopic examination after experimental infection with Paramphistomum cervi, tissue reactions in the duodenum were more pronounced during early stages of the infection (20th day post-infection (DPI)). Immature parasites were seen migrating to the muscularis layer, and focal infiltration of macrophages and lymphocytes was observed in the lamina propria and in the interstitial tissue of Brunner's gland. At places, there was cystic dilatation of Brunner's gland. At 40 DPI, the parasite was not present in the duodenal sections, and cellular infiltration was more diffuse and consistent. With the passage of time, the tissue reactions and cellular infiltration in the duodenum became less pronounced, but at 80 days parasites were attached to the villi of the rumen. Infiltration of mononuclear cells in the supporting connective tissue of the rumen was also observed. Thus, it is concluded that the immature forms of Paramphistomum cervi caused more severe damage in the duodenal tissue, whereas the adult form inflicted mild tissue damage in the rumen of the experimental kids.

Respiratory tract lesions from infectious laryngotracheitis virus of low virulence.

The pathogenicity of the A4557-5 strain of infectious laryngotracheitis virus for eight-week-old chickens was investigated by aerosol route of infection; chickens were necropsied five days after infection. The virus caused mild catarrhal tracheitis, peribronchial lymphoid infiltration, and focal lymphocytic infiltration in the lung and focal lymphocytic infiltration in the air sacs of some chickens. Chickens infected with this virus developed low levels of humoral antibody and were resistant to intratracheal challenge with the virulent V154 strain. By comparison, aerosol infection with a similar dose of virulent V154 strain caused severe necrotizing laryngotracheitis with marked suppurative bronchopneumonia and airsacculitis.

Evidence for cellular mediated immunity in an animal model of autoimmune pituitary disease.

The anterior pituitary gland can be involved in an inflammatory reaction mediated by lymphocytes that leads to various degrees of dysfunction. In seven rabbits immunized with homologous pituitary tissue in complete Freund's adjuvant, a focal lymphocytic infiltrate, and increased fibrosis was observed in five. These changes were patchy in distribution and limited to the anterior pituitary. No inflammation was observed in five control animals. When incubated with pituitary extract, partially purified lymphocytes from four of the five animals with altered pituitary histology demonstrated a significant (p less than 0.05) stimulation of 3H-thymidine incorporation. Measures of antipituitary antibodies using indirect immunofluorescence were negative in experimental as well as control animals. The present studies characterize the histologic changes and suggest that cellular immunity plays a role in the pathogenesis of experimentally induced autoimmune pituitary disease.