Murine chronic tubulointerstitial nephritis: induction by human uveitis mycoplasma-like organisms.

Mycoplasma-like organisms (MLO) are non-cultivated intracellular cell wall deficient pathogenic bacteria with a distinctive ultrastructural appearance. Diagnosis of MLO disease rests on finding the organisms in parasitized cells using a transmission electron microscope. MLO are a well studied cause of transmissible chronic plant vascular disease responsive to antibiotics. MLO have recently been found to cause human chronic progressive ophthalmic disease including uveitis. In human uveitis MLO are readily found within parasitized intraocular fluid leucocytes. Inoculation of human uveitis MLO into mouse eyelids produced a high incidence of chronic progressive ophthalmic disease including uveitis. MLO also disseminated to produce randomly distributed lethal systemic inflammatory disease. MLO parasitized leucocytes and microvascular alterations were found in the disease sites by electron microscopy. This report describes the chronic progressive tubulointerstitial nephritis in 12 of 100 human uveitis MLO eyelid inoculated mice versus 0 in 200 control mice (p < 0.0001). MLO parasitized leucocytes accompanied by tubular and microvascular alterations were found by electron microscopy in all 12 inflamed kidneys versus 0 of 4 control kidneys. Pathobiology of the MLO-induced murine nephritis, resemblance of this nephritis to human idiopathic chronic tubulointerstitial nephritis, bacterial molecular biology, and antibiotic therapy of MLO disease are discussed.

Experimental murine chronic hepatitis: results following intrahepatic inoculation of human uveitis mycoplasma-like organisms.

Mycoplasma-like organisms (MLO) are non-cultivated intracellular cell-wall deficient pathogenic bacteria with a distinctive ultrastructural appearance. Diagnosis of MLO disease depends on finding the organisms in parasitized cells using a transmission electron microscope. MLO are a well studied cause of transmissible chronic plant disease responsive to antibiotics. MLO have recently been found to cause human chronic uveitis, orbital, and retinal disease with autoimmune features. Ophthalmic leucocytes in these patients display MLO parasitization. Inoculation of human uveitis MLO into mouse eyelids produced chronic uveitis. MLO also disseminated to produce randomly distributed lethal systemic disease including chronic hepatitis. MLO parasitized leucocytes were present in all disease sites. Direct intrahepatic inoculation of human hepatic pathogens is a simple and efficient technique to produce murine hepatitis. This report describes the delayed onset widespread inflammatory liver disease produced by direct intrahepatic inoculation of human chronic uveitis MLO in 12 of 20 mice versus 0 in 40 controls (P < 0.05). The liver disease was accompanied by elevated serum SGOT levels, splenomegaly, and accelerated mortality. All 12 inflamed livers displayed MLO parasitized leucocytes versus 0 of 10 control livers. The resemblance of human chronic active hepatitis, massive hepatic necrosis, and post-necrotic cirrhosis to the MLO induced murine liver disease, the role of molecular biologic techniques in the detection and classification of those bacteria, and in therapy of MLO disease are discussed.

Mycoplasma-like organism induced murine cardiac microvasculopathy. A transmission electron microscopic study.

Mycoplasma-Like Organisms [MLO] are intracellular cell wall deficient bacteria that cause ocular chronic vasculitis in man and chronic vascular disease in plants. Since MLO do not grow in culture, diagnosis of MLO-induced disease requires identification of the organisms by electron microscopy. Ultrastructurally, MLO appear as pleomorphic tubulo-spherical and filamentous organisms. In human ocular disease MLO have been detected in parasitised leucocytes and retinal pigment epithelial cells. We have previously reported the results of injecting MLO infected human vitreous into mouse eyelids. Two thirds of the mice developed chronic disease at the inoculation site, but, more importantly, the mice also developed lethal systemic MLO disease. Carditis with histologic features similar to those of various types of human carditis occurred in 18% of the mice. This report describes the ultrastructural features of the cardiac microvascular MLO disease in those 18 mice that died of carditis after inoculation with human MLO-infected vitreous. MLO were identified in leucocytes and endothelial cells of the murine vascular lesions. The vascular lesions were characterized by destruction of vessel walls as well as proliferation of endothelial cells. Electron dense deposits were seen in basement membranes and pericytial tissues. Similar features have been described in other bacterial vascular infections and in human idiopathic carditis. We suggest that MLO could be a cause of human cardiovascular disease and should be looked for in such cases.

Postinflammatory cataracts in the mouse: induction by human mycoplasma-like organisms.

Cataracts often occur in humans secondary to uveitis. Uveitis may be caused by various infectious agents, but rarely is the agent detected in the cataract. Mycoplasma-like organisms (MLO) were recently reported to cause human uveitis and retinitis. Cataracts were often present in those inflamed eyes. MLO are intracellular cell wall deficient pathogenic bacteria. They are pleomorphic tubulospherical and filamentous organisms with a characteristic ultrastructural appearance. No MLO culture system has been found despite 20 years of effort. The diagnosis of MLO disease rests on detection of the organisms in parasitised cells by a transmission electron microscope and response to antibiotics. In human intraocular inflammatory disease MLO are detectable in parasitised leucocytes and retinal pigment epithelial cells at the disease sites. Inoculation of MLO from a human source into mouse eyelids produced intraocular, chronic, progressive, inflammatory disease, with intraocular leucocytes parasitised by MLO in 15 of 100 mice versus 0 in 200 controls (p less than 0.05). This report describes the cataracts with MLO-parasitised intralenticular leucocytes in the inflamed eyes of 14 of those 15 mice versus 0 in 200 control mice (p less than 0.05). The results indicate that MLO penetrated the lens capsules to produce the cataracts, and they suggest that MLO could cause human cataracts. Alternative methods for detection of MLO and rifampin treatment of MLO intraocular disease are discussed.

Primary biliary cirrhosis in the mouse: induction by human mycoplasma-like organisms.

Human intraocular and orbital chronic inflammatory disease with autoimmune features has been reported to be caused by mycoplasma-like organisms (MLO). MLO are intracellular cell-wall deficient pathogenic bacteria, closely related to rickettsia, with a characteristic ultrastrural pleomorphic tubulo-spherical and filamentous appearance. No culture system has been developed for MLO and diagnosis of MLO disease is made by detecting these bacteria within infected cells using a transmission electron microscope. In human MLO ocular and orbital disease the organisms are found in parasitized leucocytes at the disease site. Inoculation of human MLO into mouse eyelids produces a high incidence of orbital and introcular disease. MLO disseminate to produce randomly distributed lethal systemic disease with infected leucocytes found in all disease sites and with similar histologic features in all disease sites. Microvasculitis is the initial lesion. Disease progression results in lysis of vascular and parenchymal structures, stromal lymphocytic infiltrates, granulomas, and fibrosis. This report describes the hepatic portal chronic progressive inflammatory disease in 11 of 100 of those mice versus 0 in 200 controls. MLO parasitized portal leucocytes are present in all 11 inflamed livers versus 0 in 5 control livers (P less than 0.05). The resemblance of the animal liver disease induced by MLO to human primary biliary cirrhosis and rifampin treatment of MLO disease are discussed.

Ulcerative colitis associated chronic uveitis. Parasitization of intraocular leucocytes by mollicute-like organisms.

Uveitis is inflammation of the ocular vascular coats. Most uveitis is chronic, idiopathic, and considered to have an endogenous, possibly autoimmune pathogenesis. Chronic idiopathic uveitis occurs in isolation or with various systemic diseases including inflammatory bowel diseases. Using a transmission electron microscope vitreous leucocyte parasitizing and destroying mollicute-like organisms (MLO) are often found to cause chronic uveitis. Mollicutes are cell wall deficient bacteria. Mollicutes have a characteristic ultrastructural appearance. Extracellular mollicutes are fastidious, lipid-rich, and contain various potent cytotoxins. They cause human and animal diseases with autoimmune features. Morphologically similar organisms are intracellular non-cultivable pathogens that bear the eponym MLO. MLO are cytopathogenic, and cause host cell proliferation, destruction, and dysfunction. Uveitis producing MLO are detectable within parasitised vitreous lymphocytes, monocytes, and polymorphonuclear leucocytes. They appear as intracytoskeletal 0.005-0.01 micron diameter filaments and undulating pleomorphic trilaminar membrane bound 0.01-1.0 micron tubulo-spherical bodies. Cell wall deposition to form distinctive 'spore-like' cocci may also be seen. Inoculation of human uveitis MLO into mouse eyelids produces chronic uveitis. MLO also disseminate to produce chronic inflammatory disease in all organs including the gut. MLO are detectable in all the diseased organs. This report describes MLO parasitised vitreous and aqueous leucocytes in five ulcerative colitis patients with chronic uveitis. No microorganisms were cultivated using a wide variety of cultural techniques. The results indicate that MLO caused the uveitis of these patients. The possible role of this pathogen in human gut disease and Rifampin treatment of MLO disease are discussed.

Juvenile rheumatoid arthritis inflammatory eye disease. Parasitization of ocular leukocytes by mollicute-like organisms.

Patients with juvenile rheumatoid arthritis (JRA) commonly develop serious eye disease, particularly chronic uveitis. Most chronic uveitis is idiopathic. Mollicute-like organisms (MLO) were recently reported to be a common cause of chronic uveitis. MLO are pathogenic intracellular cell wall deficient bacteria. No culture system exists for MLO. Disease diagnosis is based on detection using a transmission electron microscope. Uveitis producing MLO are detectable within parasitized intraocular leukocytes. They appear as intracytoskeletal 0.005-0.01 micron diameter filaments and undulating pleomorphic 0.01-1.0 micron tubulospherical bodies. This report describes MLO parasitized lesional leukocytes in the inflammatory eye disease of 5 patients with JRA. Our results indicate that MLO caused the uveitis of these patients. The significance of these findings and rifampin treatment of MLO disease are discussed.

Chronic orbital inflammatory disease: parasitisation of orbital leucocytes by mollicute-like organisms.

Chronic orbital inflammatory disease (COID) is usually considered non-infectious and idiopathic. Treatment is empirical, palliative, and may not prevent disease progression. COID occurs in isolation or in association with various systemic diseases. Exophthalmos may be an important presenting sign. Vasculitis, lymphoid infiltrates, and granulomas are common. Mollicute-like organisms (MLO) parasitising and destroying vitreous leucocytes are often found to cause human chronic uveitis when an appropriate search is made. Inoculation of these MLO into mouse eyelids produced chronic uveitis and exophthalmic orbital inflammatory disease. Mollicutes are cell wall deficient bacteria. Extracellular mollicutes cause human and animal diseases characterised by lymphoid infiltrates, immunosuppression, and autoantibody production. Intracellular morphologically similar bacteria are non-cultivable pathogens termed MLO. Identification is based on direct detection in diseased cells by transmission electron microscopy. MLO are cytopathogenic and detection is aided by the alterations they produce. MLO replace the cytoplasm, destroy the organelles, and alter the nucleus. This results in cell proliferation, destruction, and dysfunction. MLO parasitise lymphocytes, monocytes, and polymorphonuclear leucocytes. This report describes orbital leucocytes parasitised by MLO in three patients with isolated COID. Rifampicin treatment of MLO disease is discussed.

Sarcoidosis associated uveitis. Parasitization of vitreous leucocytes by mollicute-like organisms.

Mollicute-Like Organisms (MLO) have been reported to be a cause of uveal tract and orbital chronic inflammatory disease. MLO are intracellular cytopathogenic cell wall deficient bacteria. No culture system exists for MLO, MLO disease diagnosis is based chiefly on direct detection of the organisms within diseased cells using a transmission electron microscope. Uveitis producing MLO are detectable within vitreous leucocytes as 0.005-0.01 micron filaments and undulating pleomorphic 0.01-1.0 micron tubulo-spherical bodies. Human uveitis producing MLO can be passed to laboratory animals. Inoculation into mouse eyelids produced intraocular, orbital, and lethal systemic chronic progressive inflammatory disease. MLO parasitised lesional leucocytes were found in all the disease sites. The MLO induced mouse chronic interstitial pneumonitis displayed 'sarcoid-like' granulomas. This report describes MLO parasitised vitreous leucocytes in the chronic uveitis of four sarcoidosis patients. The results indicate that MLO caused the uveitis. The implications of the results and Rifampin treatment of MLO disease are discussed.

Crohn's disease uveitis. Parasitization of vitreous leukocytes by mollicute-like organisms.

Crohn's disease (CD) is an idiopathic chronic inflammatory gut disease with frequent extragut inflammatory manifestations in the eyes, orbit, lungs, joints, and skin. A bacterial cause of CD is suspected, but cultivation of a specific pathogen has not been forthcoming. Mollicute-like organisms (MLOs) were recently reported to cause human chronic ocular inflammatory disease. Inoculation of this MLO into mouse eyelids produced chronic progressive granulomatous ocular and orbital inflammatory disease. In addition, MLOs disseminated to produce similar disease in the gut, heart, and lungs. MLOs are noncultivable cell wall-deficient bacterial pathogens. Because they also pass bacteria-retaining 0.450-micron filters, they can be overlooked or confused with viruses. Because MLOs have a characteristic ultrastructural appearance, they can be identified in diseased cells with the use of a transmission electron microscope. MLOs parasitize and destroy leukocytes. They alter the nucleus, replace the cytoplasm, and destroy organelles. MLO-caused disease is treatable by certain antibiotics. This report describes MLO-parasitized vitreous lymphocytes, monocytes, and polymorphonuclear leukocytes from three patients with CD who had chronic uveitis. The results indicate that MLOs probably caused the uveitis of these patients with CD. The gut as the possible source of the MLO is suggested. Rifampin therapy of Crohn's and MLO-caused disease is discussed.

Mouse interstitial lung disease and pleuritis induction by human Mollicute-like organisms.

Mollicute-Like Organisms (MLO) are cell-wall deficient intracellular bacterial pathogens. As MLO are non-cultivable, detection is based on finding typical Mollicute bodies within the host cell using a transmission electron microscope. Extracellular Mollicutes cause disease by a variety of mechanisms. MLO cause disease by similar mechanisms, and in addition directly alter the host cell nucleus, replace the cytoplasm, and destroy the organelles. MLO parasitization of plant cells causes a well studied chronic vascular disease reversible by tetracycline antibiotics. Recently similar MLO were reported to cause human chronic ocular vasculitis. As it parasitizes, lyses, and destroys leucocytes, it has been termed Leucocytoclastic MLO. Inoculation of this MLO into mouse eyelids produced delayed onset chronic ocular and lethal cardiac vasculitis. All lesions demonstrated tissue lysis with leucocytic infiltrates and MLO parasitized leucocytes. MLO-caused human and mouse disease responds to Rifampin. This report describes the 40 interstitial lung disease lesions in 21 of 100 of those MLO inoculated mice vs 0 in 200 controls (P less than 0.05) and 27 pleuritis lesions in 17 mice vs 0 control mice (P less than 0.05). The lung and pleural disease were associated in 13 lesions and unassociated in 41 lesions. MLO parasitized leucocytes were found in both the lung and pleural lesions from six of six MLO inoculated mice versus none of six controls. As most human interstitial lung and pleural diseases are idiopathic and closely resemble this mouse disease, they may be induced by MLO and treatable by Rifampin.

Mouse lethal cardiovascular disease: induction by human leucocyte intracellular Mollicutes.

Plant pathologists have known for several years that intracellular Mollicutes (M), i.e. cell wall deficient bacteria, are plant vascular pathogens, but because those M are non-cultivatable, they can only be studied by Transmission Electron Microscopy (TEM). Only recently have similar M been shown to be human and animal pathogens. Those human ocular Vasculitis (V) and mouse chronic ocular and lethal systemic V producing M parasitize vitreous polymorphonuclear leucocytes, lymphocytes, and monocytes as 'viral-like' 0.005-0.010 micron elemental particles which grow within the leucocyte into 0.01-0.03 micron diameter tubules, 0.3-1.5 micron spherules, and distinctive 0.5-0.7 micron cocci with spore-like cell walls. This report describes the 48 arteriolar and capillary sized V, Aschoff nodules, valvulitis, and myocytolytic lesions in the heart and great vessels in 18 of 100 human vitreous VM containing eyelid inoculated mice versus 0 of 200 controls (P less than 0.05) plus VM within parasitized leucocytes in 15 of 15 of those lesions by TEM. The results indicate dissemination of VM from the eyelid to produce a significant incidence of distinctive multifocal VM directly induced cardiovascular micro-V lesions that probably contributed to their excessive mortality. Because several human idiopathic diseases develop similar cardiovascular lesions a TEM search for VM parasitized leucocytes in those human diseases seems justified.

Chronic intracellular leucocytoclastic bacterial vitritis. A transmission electron microscopic study of the monocytes.

Vitritis, the presence of leucocytes in the acellular ocular vitreous, often accompanies ocular vasculitis (V). Non-cultivatable intracellular mollicutes (M), i.e. cell wall deficient bacteria, readily identified by transmission electron microscopy (TEM), are well known plant vascular pathogens. Recently similar intracellular polymorphonuclear leucocytes (PMNL) and lymphocytes (L) parasitising/destroying and mouse ocular and lethal systemic V producing M-like bacteria were reported to be a common cause of human ocular V. In this TEM restudy of 8 human and 3 mouse VM induced chronic ocular V materials severe nuclear and cytoplasmic alterations associated with generalized cytoskeletal nuclear-anchoring 0.005-0.010 micron particles, 0.01-0.05 micron diameter branching filaments and tubules, and trilaminar membrane bound complex internal structure containing 0.1-1.9 micron spherules, all indistinguishable from VM, were observed within 1-3% of the monocytes in all 11 specimens. The results indicate that VM also parasitise and destroy both human and mouse monocytes. VM induced alterations in monocytes, PMNL, and L are compared, and the monocyte nuclear damage/Rifampin beneficial effect relationship in VM induced ocular V is discussed.

Mouse exophthalmic chronic orbital inflammatory disease. Induction by human leucocyte intracellular Mollicutes.

Mollicutes are cell wall deficient bacteria which may be overlooked or confused with viruses because of indistinct light microscopic morphology, poor staining, difficulty in cultivation, and the ability to pass 0.450 micron filters. As they have a distinctive ultrastructural appearance they can be identified using transmission electron microscopy [TEM]. Using TEM vitreous leucocytes from chronic endogenous uveitis patients may demonstrate non-cultivable intracellular 0.005-1.0 micron mollicute-like organisms [MLO], some of which develop into distinctive cell walled cocci, 0.5-0.7 micron in diameter. Inoculation of those MLO containing human vitreous into mouse eyelids produces chronic cardiac and uveal vasculitis with orbital inflammation. Similar MLO are found within the mouse lesional leucocytes. This report describes the chronic orbital inflammation with vasculitis in 67 of 100 of those MLO inoculated mice versus 0 of 200 controls (P less than 0.05). Exophthalmos with inflammation also occurred in 12 of those 67 mice (P less than 0.05). MLO were found within orbital lesional leucocytes of 10 of 10 of those mice using a TEM versus 0 of 10 controls. The results indicate that vasculitis and exophthalmos were important features of this MLO induced mouse orbital inflammation. The implication of these results for human idiopathic chronic orbital inflammatory disease is discussed.

Chronic leucocytoclastic bacterial vitritis. A lymphocyte transmission electron microscopic study.

Ultrastructurally unique and distinctive non-cultivable human and mouse uveitis and vitritis producing bacteria (B) that parasitise, differentiate into both cell walled and cell wall deficient variants within, and destroy polymorphonuclear leucocytes (PMNL) were recently reported to be commonly present in the vitreous of chronic idiopathic vitritis patients. In this transmission electron microscopic restudy of the lymphocytes in 8 human and 3 mouse chronically inflamed ocular specimens, all of which had demonstrated those B within PMNL, in each specimen about 3-15% were larger atypical variants and 0.5-1.0% also harbored those B. The earliest detectable B, the 0.005-0.010 micron spherical elemental particles, had a paranuclear cytoskeletal location, where they produced cytoskeletal lysis and nuclear envelope and chromatin lesions. From that site the elemental particles proliferated, elongated, branched, and enlarged into tightly coiled 0.03-0.05 micron in diameter cell wall deficient tubules and elaborated ultrastructurally distinctive 0.5-0.7 micron cell walled B, eventually replacing the cytoskeleton and destroying the lymphocyte.