Areas Of Granulomatous Inflammation Research Articles

Disseminated Histoplasmosis Presenting as Granulomatous Hepatitis in a Patient with Psoriatic Arthritis

Histoplasma capsulatum(HC) is known to cause systemic infections in immunodeficient hosts. It most commonly originates in the lungs, and then may spread to involve the gastrointestinal tract, liver and bones. However, presentation as acute granulomatous hepatitis without preceding pulmonary symptoms is very rare. A 54-year-old woman with psoriatic arthritis, previously treated with methotrexate and adalimumab, was admitted for worsening jaundice, abdominal pain and 20-pound weight loss. Physical exam revealed tenderness in the upper quadrants of the abdomen, with no appreciable hepatosplenomegaly. Cell counts were normal. Total and direct bilirubin were 11 and 8.4 mg/dl respectively. Alkaline Phosphatase was high at 1064 mg/dl, with mildly elevated AST/ALT. Hepatitis panel was negative. Liver ultrasound showed a cirrhotic appearance, mild hepatomegaly and a few simple appearing cysts. There was no evidence of ascites, ductal dilatation or cholecystitis. She underwent a liver biopsy, which revealed well-formed portal and lobular caseating granulomas with small yeasts. In addition, bile duct proliferation, biliary infarcts and moderate macro vesicular steatosis involved 40% of the hepatic parenchyma. The Gomori's methenamine silver stained slide also revealed small yeasts in the areas of granulomatous inflammation. The morphology was consistent with HC. Urine HC antigen, and serum antibodies were also positive. Mycobacterium infection was ruled out by tissue polymerase chain reaction. Patient was started on 2 weeks of amphotericin B 4mg/kg with 12 months course of Itraconazole to follow. She was seen in clinic for follow-up and reported resolution of her symptoms. The pathogenesis behind early liver involvement and pulmonary sparing, remains unknown till date. Patients with immune suppression and extremes of age are known to have ten times higher the risk of HC, when compared to general population. Therefore, granulomatous hepatitis, as an initial manifestation of systemic histoplasmosis is only reported in patients with AIDS or renal transplants. A high index of suspicion is required for appropriate work up leading to this diagnosis. We report the first case of such a presentation in a patient with psoriatic arthritis. Interestingly, our patient had well-controlled disease and was not on immune-suppressive therapy for past year. She responded well to the anti-fungal treatment with normalization of her liver enzymes and marked improvement in her symptoms.

Interstitial Granulomatous Dermatitis Associated with Rheumatoid Arthritis.

Dear Editor: Interstitial granulomatous dermatitis (IGD) is a rare and peculiar disorder with cutaneous and joint manifestations1. IGD may be associated with rheumatologic and hematologic disorders of underlying malignancies2,3. Herein, we report a case of IGD associated with rheumatoid arthritis (RA). A 59-year-old Korean woman presented with multiple erythematous plaques on both extremities for 10 days (Fig. 1A). Upon physical examination, the plaques were linear shaped, non-tender, and palpable. She had been diagnosed with RA 17 years earlier. She had taken prednisolone, nonsteroidal anti-inflammatory drugs, and methotrexate to treat RA for 7 years. One month earlier, her arthritis symptoms had stabilized and the rheumatologist withdrew methotrexate. Laboratory test findings were non-specific except for an elevated C-reactive protein (CRP) level (7.12 mg/dl; normal range, 0.01~0.47 mg/dl) and erythrocyte sedimentation rate (ESR) (81 mm/h; normal range, 0~15 mm/h). Histopathologic findings indicated perivascular and interstitial lymphohistiocytic infiltration through the dermis and chronic granulomatous inflammation with collagen degeneration in the upper dermis. Immunohistochemically, most of the infiltrating inflammatory cells were CD 68-positive. Alcian blue staining revealed no mucin deposition in the areas of granulomatous inflammation (Fig. 2). Based on clinical and histological findings, she was diagnosed with IGD. A 7.5-mg methotrexate dose was given weekly and the daily prednisolone dose was increased from 5 mg to 15 mg. A topical 0.1% tacrolimus ointment and methylprednisolone cream were also applied daily for 2 months. The lesions were nearly cleared and ESR and CRP were found to be within normal limits after 2-month follow-up (Fig. 1B). Fig. 1 (A) Multiple, erythematous, palpable, and linear shaped plaques on both extremities. (B) Nearly clearing of lesions after a 2-month follow-up. Fig. 2 (A) A perivascular and interstitial lymphohistiocyte infiltration in the entire dermis (HE B: ×100, C: ×400). ... The most common clinical findings of IGD are asymptomatic multiple papules and plaques (70%~90% of cases)2. The rope sign was named for the linear prominent cutaneous cord-like lesions, considered pathognomic for IGD1. However, these lesions are not an essential feature, and are reported in only 9% of cases3. The histopathologic findings show interstitial CD 68-positive histiocyte infiltration around focally degenerated collagen2,4. Epidermal changes, mucin deposition, neutrophil and/or eosinophil infiltration, and vasculitis are usually absent 2. Differential diagnoses include interstitial granuloma annulare (IGA), interstitial granulomatous drug reaction (IGDR), and palisaded neutrophilic and granulomatous dermatitis (PNGD)1,2,4. In IGA, prominent mucin deposition and only focal interstitial infiltration could be found. Recent change of medication is present in IGDR, and IGDR presents with basal cell vacuolization and lichenoid changes with eosinophils2. Leukocytoclastic vasculitis and pandermal infiltration of neutrophil frequently present in early lesion of PNGD, and palisading granulomatous inflammation is the typical feature of fully developed one1. The pathogenesis of IGD may be associated with immune complex deposition caused by immune reactants of systemic inflammatory diseases5. Interestingly, IGD lesions in our case began to occur in association with the flare-up of RA after methotrexate withdrawal, although the causal relationship remains unknown. From our case we suggest that IGD should be considered among the differential diagnoses for patients with rheumatologic disease and cord-like skin lesions.

Tularemia of European Brown Hare (Lepus europaeus)

The European brown hare (Lepus europaeus) plays an important role in the ecology of tularemia, and it may serve as a significant source of human infection. The aim of the present study was to examine the lesions induced by Francisella tularensis in 50 cases of naturally infected seropositive European brown hares. Gross pathological examination revealed scant to numerous grayish-white foci with diameters of 0.1 to 1.0 cm in single organs (24 cases) or multiple organs (20 cases) in 44 of 50 cases (88%). These lesions proved to be areas of granulomatous inflammation, frequently encompassing necrosis. F tularensis antigen was detected with immunohistochemistry in 46 of 50 cases (92%), whereas F tularensis ssp holarctica was isolated by culture and identified by polymerase chain reaction from 35 of 50 cases (70%). Infection by the respiratory route is suggested by the presence of the tissue lesions in thoracic organs of 44 of 50 cases (88%). These results emphasize the importance of the European brown hare as a reservoir of tularemia.

Osteopontin immunoreactivity in the ileum and ileocecal lymph node of dairy cows naturally infected with Mycobacterium avium subsp. paratuberculosis

Osteopontin (Opn), a highly acidic glycoprotein, promotes cellular adhesion and recruitment and has been shown to be upregulated in the granulomas of mycobacterial infections. Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is associated with granulomatous enteritis. The objective of this experiment was to identify Opn in the ileum and ileocecal lymph node (ICN) of dairy cows naturally infected with MAP and to compare the frequency and intensity of staining between noninfected healthy controls, subclinical and clinical cows. Sections from these three groups of animals were selected from a tissue archive. Immunohistochemical analysis was used to determine the location and expression of Opn. The frequency and intensity of staining was also reported. Confirmation of acid-fast bacilli in the tissue sections was achieved by the Ziehl-Neelsen method. Within the ileal tissue, macrophages, lymphocytes, and plasma cells stained positive for Opn. Clinical cows expressed Opn at a greater frequency in the lamina propria. Control and subclinical cows did not have areas of granulomatous inflammation but cells staining for Opn were equally intense for the three groups. The frequency of staining for Opn in the ICN was not affected by MAP infection. Results of this study confirm for the first time, the expression of Opn in the ileum and ICN of MAP-infected cattle.

Granulomatous enteritis and lymphadenitis in Iberian pigs naturally infected with Lawsonia intracellularis.

Intestinal samples and/or lymph nodes of two Iberian pigs from two different farms were submitted for histopathologic examination. Both pigs had proliferation of ileal and/or cecal crypts with almost complete absence of goblet cells. Infection by Lawsonia intracellularis was demonstrated by immunohistochemistry and polymerase chain reaction assay. The mesenteric lymph node of one pig had moderate lymphocyte depletion with granulomatous inflammation of the lymph node parenchyma. Histiocytes and multinucleated giant cells from the lymph node of one pig contained L. intracellularis antigen within the cytoplasm. This pig had also porcine circovirus type 2 (PCV-2) infection, but nucleic acid and antigen of this virus were not demonstrated in the lymph node. The second pig had lymphocyte depletion and marked granulomatous inflammation in Peyer's patches. Histiocytes and multinucleated giant cells in areas of granulomatous inflammation contained L. intracellularis antigen; no PCV-2 nucleic acid or antigen was detected in the tissues of this pig. This is the first description of granulomatous ileitis and lymphadenitis associated with L. intracellularis infection.

Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis

The peribiliary vascular plexus plays an important role in physiology of bile flow. Disturbance of the microcirculation may contribute to ductal injury, but little is known about alterations in the vascular supply of small bile ducts in liver disease. Immunoperoxidase stains for vascular endothelium ( Ulex europaeus, factor VIII-related antigen, CD34) were used to study the peribiliary vascular plexus in 20 cases of primary sclerosing cholangitis (PSC) and 27 cases of primary biliary cirrhosis (PBC), two diseases characterized by bile duct destruction. Normal liver from 10 autopsy cases of sudden cardiac death was used as a control. Interlobular bile ducts (20- to 80-μm diameter) were identified on AE1/AE3 immunostain; vessels adjacent to the basement membrane of these ducts were counted. Normal interlobular bile ducts had an average of 2.15 vessels per duct (range, 1.68 to 2.71). Few PBC or PSC cases had a normal number of peribiliary vessels. There was a trend toward vasopenia at higher stage, although vascular loss was noted in early stages as well. The pattern of vascular loss was different for the two diseases; in PSC, the periductal capillaries were often preserved but were pushed away from the basement membrane by concentric deposits of collagen. Small residual vessels could be identified within fibrous scars of obliterated bile ducts in PSC. In 4 stage 3 or 4 PSC cases with little bile duct injury, vessel/ duct ratio approached normal levels. In PBC, vessels were obliterated in areas of granulomatous inflammation and heavy lymphocytic infiltrate around bile ducts. In conclusion, loss of peribiliary vessels is common in PSC and PBC. Vessel loss is seen in early stages and may contribute an element of ischemia to continued small bile duct loss but is probably secondary to the inflammatory process.

The histological response to auto-augmentation gastrocystoplasty (AAGC) in a sheep model

A number of surgical techniques have been used (with variable success) to increase bladder size in patients with reduced bladder volumes. Sewing vascularized flaps of intestinal muscularis propria into opened bladders has had limited success due to subsequent fibrosis, and full thickness gastric flaps in the absense of autoaugmentation have resulted in ulcerative cystitis. The following study in 16 sheep over an 8 month period describes the local histologic response to a new technique in which exposed bladder subepithelial connective tissue and mucosa was covered with a demucosalised gastric muscularis propria flap (AAGC). In the initial postoperative stages the dome of the bladder was formed by an inner pouch of viable subepithelial connective tissue and mucosa with a covering of fibrin, opposed to fibrin coated submucosa of the gastric flap. At the end of the first week the 2 layers had fused, and there was a marked chronic inflammatory Infiltrate with granulation tissue formation at the anastomosis site of the bladder and gastric muscle coats. Multinucleated foreign body type giant cells surrounded suture material. By 4 wks the inflammation was beginning to subside and dystrophic calcification was found only in the areas of granulomatous inflammation at the anastomosis site. From 8 wks through to 8 mths there remained only a very mild granulomatous inflammation around suture material, with no significant inflammation in any of the layers of the autoaugmentation or gastrocystopiasty . At every stage, all layers of the bladder and stomach patch remained viable, the kidneys were unremarkable and the residual stomach showed no treatment-related changes. Contrast and urodynamic studies demonstrated normal function and improved bladder volume. Thus, in demonstrating continued viability with minimal fibrous scarring in the augmented sheep bladder, this study lends support to the further application of autoaugmentation gastrocytoplasty in the treatment of bladder volume disorders.

Endocytotic activity in epitheloid and Langhans’ giant cells

In the experimental tubulo-interstitial (anti-basement membrane) nephritis in the rat, electron microscopic studies after the in vivo microinjection of native ferritin in areas of granulomatous inflammation near the surface of the kidney indicate that epitheloid and multinucleate Langhans' giant cells are capable of endocytosis and particularly of micropinocytosis. This suggests the possibility that endocytotic activities as well as secretion phenomena are important in the immune defense mechanisms linked with these "specifically" developed cells.

Lung Repair and Granuloma Formation: Tubercle Bacilli Stimulated Neutrophils Release Chemotactic Factors for Monocytes

The common underlying host response in tuberculosis and other granulomatous repair processes is formation of granulomata. These granulomata include mononuclear phagocytes which originate from peripheral blood monocytes (MN).1 Since neutrophils precede monocytes at areas of granulomatous inflammation,2 we hypothesized that neutrophils initiate these inflammatory responses by releasing chemotaxins which attract monocytes. Our results supported this premise (Fig 1). First, neutrophils stimulated by tubercle bacilli released chemotactic factors for monocytes, both in vivo and in vitro.

Heterotopic calcification in swine.

Pigs on nutritional studies developed heterotopic calcifications in the left atrial endocardium, submucosa of the gastric fundus and to a lesser extent in other sites. Light and electron microscopy of mineralized tissue showed early edema and connective tissue change, deposition of calcium, granulomatous reaction and repair. There was no alkaline phosphatase activity at the sites of calcification and the distribution of this enzyme activity was normal in other tissues. Increased acid phosphatase activity was demonstrated only in the lysosomes of macrophages in areas of granulomatous inflammation. Calcium and magnesium were within normal range in serum and femoral bone. The character and distribution of the lesions suggested the possibility of protracted low grade hypervitaminosis D3.

Mitosis of type B alveolar cells in the early hyperplastic response to Freund’s adjuvant

Numerous areas of granulomatous inflammation develop in the lungs of rabbits following the intravenous injection of Freund's complete adjuvant (FCA). Within a few days after FCA injection, hyperplasia of type B (type I) alveolar cells is present on the surface of the septa in which an inflammatory reaction is developing. Mitosis of type B cells is detected 12 h after FCA injection and is common over the next 120 h. In addition, there are morphologic changes that are consistent with migration of these cells. The type B cells in mitosis extend across alveolar septa as well as along the alveolar surface. The extension of type B cells through alveolar septa is not limited to cells in mitosis, but is also observed in non-mitotic type B cells. Stimulation of mitosis and hyperplasia of type B cells is discussed in relation to the focal tissue injury and inflammatory response.