key: cord-007362-pjpkz6wv
authors: Bielefeldt-Ohmann, Helle
title: The Pathologies of Bovine Viral Diarrhea Virus Infection: A Window on the Pathogenesis
date: 2016-01-06
journal: Vet Clin North Am Food Anim Pract
DOI: 10.1016/s0749-0720(15)30461-8
sha: 
doc_id: 7362
cord_uid: pjpkz6wv

Pathologic lesions caused by bovine viral diarrhea virus (BVDV) infections comprise a wide spectrum of type, degree, and, by implication, pathogenesis, including congenital defects, necrotic-erosive lesions in mucosal epithelia and skin, and reactive as well as degenerative changes in lymphoid tissues. At least some of the pathology may not be solely due to BVDV replication per se, but rather caused by a host response to the virus, particularly the production of pro-inflammatory cytokines.

The pathologic lesions caused by bovine viral diarrhea virus (BVDV) infections comprise a wide spectrum of both types and degrees, and are, like the clinical manifestations,6, 102, 114 a result of the interactions of factors such as strain and biotype of the virus (see the article by Donis, this issue), 35, 36, 51-53, 60,77,113,116,121 ,122 the host genotype, age, and immune status of the animal at the time of infection, the immune response induced, and intercurrent infections or other stress factor(s). 2, 29, 44, 45, 96 Some of the lesions are not specific for BVDV, reflecting the limitations in tissue reactions to noxae or parallels in pathogenic mechanisms. In other cases, only microscopic or submicroscopic changes are present, and, thus, not apparent in a routine postmortem examination. Other lesions, or rather simultaneous occurrence of a set of lesions, however, may be near pathognomonic for BVDV, and when combined with clinical manifestations and epidemiologic data, they can have conclusive diagnostic value. The latter may be the case for "typical" mucosal disease (MD) and for the occurrence of congenital defects of epidemic proportions. With the improvements in and wider application of virus diagnosis in clinical practice, however, it has become apparent that BVDV may be the cause of a much wider spectrum of clinical and pathologic phenomena, some of which in the past probably went undetermined. 96 Traditionally, the pathologic (as well as clinical) manifestations of BVDV infection are presented under the categories (1) fetal infections, (2) acute virus diarrhea, (3) MD. This categorization will largely be maintained, although it should be emphasized that these groupings are only truly useful for didactic purposes, and that extensive overlap can be expected in the occurrence and severity of any particular type of lesion, between animals or outbreaks,I4, 18, 36, 113, 114 and that pathologic lesions can only be suggestive of a BVDV infection. A final diagnosis must rest on isolation of the virus and/or detection of specific viral antigen in appropriate samples.

In this section, special emphasis will be given to the histopathologic features and immunocytochemical analysis in persistently infected (PI) animals, whether clinically normal or suffering from MD, as a basis for a final discussion of pathogenic mechanisms, which, in addition to the virus replication per se (see articles by Donis and Bolin, this issue), may contribute to the varied picture of lesions in BVDV infections.

Transplacental spread of BVDV during a clinically inapparent or apparent viremia of the dam may be the most crucial event in the entire BVDV complex (see articles by Moennig and Bolin, this issue). Considering the difficulties often encountered in field cases in retrospectively establishing the exact time for the fetal infection, much emphasis has been given to the experimental evidence of the gestational agedependency of particular types of pathology. Although this temporal categorization will not be disputed and is used here, it should be remembered that the possibility that some BVDV strains may have relatively low pathogenicity; therefore, their effect may be more insidious or slow, resulting in morphologic and/or clinical manifest changes only after a prolonged effect on the germinal tissues. 14 , 17, 111, 146 Additionally, lesions that have been examined and seem to be similar in the perinatal period of a full-term calf may be the end stage of basically different processes, e.g., interference with normal stem cell differentiation and tissue development versus repair processes after an inflammatory process. 12 , 14, 41, 72 Conclusive differentiation between these possibilities based on morphologic criteria may not be possible. 14 Fetal infections in the first trimester of gestation may result in embryo/fetal death followed by absorption, mummification, or abortion, with expulsion occurring at any time up to several months later. Pathologic and virologic examinations, therefore, are rarely informative if performed on isolated cases at the time of expulsion. lo , 105 As previously suggested, some of the congenital defects observed in full-term calves that often are ascribed to infections in the second trimester actually may have been caused by infections at the time of organ blastems differentiation in the first trimester, whereas an infection in the second trimester is more likely to provoke an inflammatory response and result in reparatory rather than regenerative processes and, thus, organ defects. 14 , 40, 41 The teratogenic lesions recognized as possible consequences of a intrauterine infection with BVDV are listed in Table l .

The ocular and central nervous system (CNS) lesions have attracted special attention, both in studies of field cases 14 , 34,58 and in experimental work. 40 , 41, 72, 127 The chorioretinopathy often consists of variable depigmentation and loss of neurons as well as cone-and rod-cells (Fig. 1) . The lens may be affected by capsular cataract and degenerative changes in the lens fibers,40 and there may be signs of inflammation of the cornea and gliosis in the optic nerve. 14 The cerebellar hypoplasia may be constituted by subtle changes such as reduction of the molecular layer and granule cell numbers, as well as reduction and displacement of Purkinje cells,14, 144 frank loss of overall structure, and total loss of Purkinje cells. 41 ,58 In the latter cases, the remains of an inflammatory process such as leukocyte infil tra tion may still be evident. 41 In other cases, demyelination seems to be the most prominent histopathologic finding. 34 ,58 So far studies of virus distribution in CNS lesions have been inconclusive with respect to pathogenic mechanisms. 14 , 72, 144 It also remains unresolved whether these variations are the result of differences in virus strains (pathogenicity and tissue tropism), gestational stage at initial infection, host genotype, a combination of these, or some other factor(s), including the purely technical. 144 The fact that only one or a few of the possible teratogenic lesions previously listed are seen in anyone field case/outbreak could be explained by several of these factors.

The thymus hypoplasia/atrophy has attracted much attention and speculation in the context of the purported immunosuppressive effect of BVDV (see the article by Potgieter, this issue).5 Alternative results can be found elsewhere. 76, 87 Although BVDV antigen may be present in the thymus at the time of birth (Fig. 2) , it does not always result in hypoplasia, as discussed in later sections. Although thymocytes seem to be responsive (or susceptible) to signals for apoptosis such as antigen at inappropriately high levels or presented in the absence of appropriate costimulatory signals, corticosteroids, or certain cytokines,47, 90, 92,97,141 it may be questioned whether the BVDV infection is the cause of the atrophy or whether other events (parturition stress, neonatal infection, insufficient nutrition) around the time of delivery are the (additional?) cause(s) of an acute involution, which could have been reversible and inconsequential given time and appropriate care. l1 , 68 The generalized intra-uterine growth retardation, most often noted in PI calves (see section on persistent infection without overt clinical disease) may have significant clinical implications in relation to the "weak-calf syndrome," although the extent of the problem is not known because of the defect's subtle character (see the article by Baker, this issue). 114 Intra-uterine infection in the last trimester is not usually thought to cause serious consequences for the fetus. At this stage, the fetus has attained immunocompetence/o, 126 although still with some deficits,67,125 and will respond to the infection with BVDV-specific antibody production. 9 , 10, 126 Whether the virus is eliminated in all cases,lO, 14,30 and whether an infection at this stage could potentially contribute to the problem of growth-retardation and/or weak calves does not seem to have been subjected to thorough investigation.

Despite being the first described clinical picture of BVDV infection,l1O acute virus diarrhea remains one of the two least well-characterized BVDV-associated syndromes (the other being respiratory disease, see later) mainly because of its perceived negligible long-term effect and mortality. Primarily described as a disease of cattle aged 6 to 24 months,6 it remains unclear exactly what role BVDV plays in neonatal disease. 83, 84, 107 In either case the pathologic lesions usually are subtle and rather nonspecific, whether the infecting virus is of the noncytopathic (NCP) or cytopathic (CP) biotype,107, 143 comprising flaccid, edematous intestines, occasionally with ecchymotic hemorrhages, and mild reaction in the mesenteric lymph nodes. Oral and esophageal lesions characterized by small erosions or shallow ulcerations have also been described. 61 Occasionally, lesions resembling those seen in MD (see section on mucosal disease and Figs. 3 and 4A) and consisting of linear erosions and hemorrhages, Peyer's patch-atrophy and hemorrhage, and erosion of the proximal colon occur. 36 ,43 Virus antigen may be detected in the intestinal epithelium, as well as in tonsils, lymph nodes, and lungs. 

The importance of BVDV in bovine respiratory disease (BRD) remains another contentious subject. 3 , 6, 113, 116 Clinical signs of respiratory distress are common in animals with both acute virus diarrhea 43 , 59 and in MD. In many cases, however, these do not seem to be accompanied by gross pathologic changes, and are thought to be a consequence of high fever and/or abdominal pain. 1l4 In other cases, particularly in young animals, either PI or infected postnatally, BVDV is seen as a predisposing factor for bacterial infection, similarly to that of bovine herpesvirus-I (BHV-I), parainfluenza-3, and others. 3, 22, 29 In PI calves, BVDV can be isolated from lung tissue, and virus antigen is widespread in bronchiolar and alveolar epithelial cells, however, without accompanying histopathologic changes (see section on persistent infection without overt clinical disease and Fig. 5 ).17 Conversely, a proportion (the size varying with study) of cattle succumbing to BRD are positive for BVDV, by virus isolation from or antigen detection in lung tissue, but the ensuing pathologic changes cannot be distinguished from those of other viral pathogens in the BRD complex (perhaps with the exception of BHV-P5), and usually are dominated by the pathology caused by the secondary bacterial agent. 3 , 29, 96 It is quite conceivable, although it remains to be shown experimentally, that the pathogenic mechanisms involved in the respiratory tract pathology of BHV -I plus bacteria also occur in BVDV -associated respiratory disease. 19 , 22,94,115,116 Whether strain differences exist with respect to pneumopathogenicity as it does for other aspects of the BVDV complex remains unresolved. 43 , 113, 115, 116 Although of considerable interest in its own right and as a model-system for host-virus interactions,2° an elucidation of this aspect may require an extensive experimentation.

Despite the generally accepted notion that infection of immunocompetent animals with either NCP or CP BVDV results in no apparent or Figure 5 . Demonstration of BVDV antigen in tissues of persistently viraemic, clinically normal calves. A, lung. Bronchiolar epithelial cells appear to label intensely for viral antigen (original magnification, x 100). B, Esophageal epithelium. Despite intense virus antigen labeling of cells in the basal layer, no inflammatory reaction is seen, and the epithelium seems to be morphologically intact (original magnification, x 100). a relatively innocuous disease (see section on acute virus diarrhea), more severe outbreaks of diarrhea preceded by severe thrombocytopenia and widespread hemorrhages have been described. 52 , 53, 96,120 This syndrome, so far only described in the United States and Canada, is mainly, but not exclusively, seen in young calves. 96 , 114,120 At this stage it remains unclarified whether cases of hemorrhagic diathesis seen in cattle in England 56 and continental Europe,137 as well as North American outbreaks of severe peracute-acute BVD with pneumonia, diarrhea, and abortions 43 , 59 represent the same syndrome.

Peracute death with an overall lack of gross lesions or with hemorrhages of the Peyer's patches as the only grossly apparent lesion may be a frequent event in this syndrome? Other gross pathologic findings may consist of petecchial and ecchymotic hemorrhages throughout the body, including on the sclera of the eyes, the margins and inner surfaces of the eyelids, the mucosal surfaces of the cheeks and gingiva, the tip of and ventrally on the tongue and soft palate, in the esophageal and ruminal epithelium and the mucosal surface of the abomasum and intestines, on the epicardium and subperiosteally on the calvaria. Additionally, some calves may have secondary bacterial pneumonia. 52 , 53, 96,120 Although only likely to be diagnosed under clinic and experimental conditions, the cardinal sign seems to be megakaryocytosis, detected in bone marrow aspirates and core biopsies. 52 Although the syndrome has some superficial resemblance to dengue hemorrhagic syndrome in humans 68 and hog cholera lesions,47 similarities in the pathogenic mechanisms have been ruled out,53 leaving the possibility that it is a virus-strain specific phenomenon 36 , 113 to be further explored.

PI calves born as a result of an intra-uterine infection most likely in the first trimester of gestation, may be indistinguishable from noninfected animals,17, 100 or may seem to be growth retarded, at or soon postpartum. 6 ,58 A large serologic survey of healthy adult cattle showed that up to 1 0 /0 of such animals may be PI virus carriers.loo It is not known how many of these animals would have had microscopic evidence of the infection. However, in other, more limited studies of PI animals (natural or experimental infections), histopathologic lesions were detected in some, but not all, 17, 18 clinically healthy animals, and comprised local interstitial infiltrations of mononuclear cells (MNC) in kidneys and local thickening of the glomerular basement membrane,15, 54, 70 mild accumulation of MNC in liver triads, increased frequency of peribronchiolar lymphonoduli, and microfocal necrosis in the epithelium of the tongue and esophagus accompanied by moderate subepithelial MNC accumulation. 15 Conspicuously, in these same studies the lymphoid tissues of PI animals were indistinguishable from those of normal animals of comparable age and environmental exposure. 1 8 ,54 In animals with obvious growth retardation, both macroscopic and microscopic evidence of skin lesions may be present. Macroscopically, the changes may resemble those seen in chronic MD (see section on the gross pathology of acute and chronic MD) and consist of varying degrees of scurfiness and shallow erosive lesions around orifices and in the interdigital cleft. Microscopically, the changes may vary from slight attenuation of the rete pegs and mild subepithelial MNC infiltration (mainly macrophages) to more pronounced changes of parakeratotic and hyperkeratotic character, as seen in MD (see section on mucosal disease). Similar changes may be found in the keratinized epithelia of esophagus, rumen, reticulum, and omasum. Frank epithelial necrosis, however, is not common. 15 Mild retina lesions, of a type described in the section on congenital infections and not diagnosed clinically, may also occasionally become evident on histologic examination.

Despite the absence or very limited extent of histopathologic changes, virus occurrence seems to be widespread, with little variation between animals, regardless of the clinico-pathologic manifestations l7 , 18,91 ( Table 2 , and see Figs. 2 and 3). This distribution is similar to what is found in cases of MD, but differs with respect to extent, i.e., number of cells infected and/or virus antigen-labeling intensity, potentially reflecting virus-replication level and/or the biotype present. 66 This phenomenon is most notable in the gut in which in the fundi of the crypts of PI healthy cattle only few, often scattered, cells were found to be infected in comparison to more uniform infection in MD calves (Figs. 2 and 6).13,17,91 Moreover, epithelial infection was not detected beyond the ileocaecal orifice. Below this anatomical site the alimentary infection was confined to intraepitheliallymphocytes and MNC in the propria. 17 Before euthanasia, virus was not or was only intermittently isolated from fecal samples, whereas NCP BVDV was readily isolated from blood and nasal swabs. IS The clinically healthy PI animals also may differ from MD cases with respect to virus distribution in the CNS, although some discrepancies have been noted between published reports. In several studies, widespread occurrence of viral antigen in neurons, especially in the deep lamina of the cerebral cortex, was described,54, 64, 71, 144 whereas other studies have found that only microglia (macrophage-like cells) may be infected in PI clinically normal cattle, and large neurons only became virus-antigen positive in animals with MD.15 Likewise, discrepancies exist regarding the presence of virus antigen in endothelial cells of small vessels, although the latter may be explained by the use, in some studies, of antibodies with nonspecific affinity for endothelia and/or adventitial cells. 27 As an extension of PI cells of the lymphoid tissues, a proportion of peripheral blood MNC seems to contain BVDV antigen and replicating virus 16 , 17, 24, 31, 37, 95, 132 with no or only minor apparent consequence for total leukocyte numbers, relative frequencies, or the fine structure of the cells, perhaps with the exception of slight "activation" of the blood monocytes. 24 Whereas there is agreement between reports as to the virus-carrier state of blood monocytes and T lymphocytes, there seems to be some discrepancy with regard to the B lymphocytes. 16, 31, 37, 95, 132 Whether this is ascribable to differences in methodology (including sensitivity and specificity of reagents), host genotype or virus strains involved remains unclarified, as does the importance of the infection of the leukocyte types to the pathogenic processes (see the section on Multifactorial Nature of MD Pathology).13, 102

Although MD is a relatively uncommon form of the BVD spectrum of diseases, it has attracted much attention and continues to challenge the veterinary research community and virologists because of its elusive nature. The clinical manifestations and gross pathologic lesions of MD can be extremely varied, although this is mostly in degree rather than in type. 6 , 9,114 This has led a number of authors to distinguish an acute and a chronic form of MD.6, 119 Whether this is entirely justified in terms of clinical entities must await clarification of the roles played by the previously mentioned factors such as the virus strains involved, host genotype, and the degree of "tolerance" and, therefore, host-reaction to the infecting virus(es) in the pathogenic processes (also see the section on Multifactorial Nature of MD Pathology).17, 18, 42, 102

Classically, the gross pathologic lesions comprise necrotizing and erosive/ulcerative lesions on the muzzle and lips (see Fig. 3 ), the buccal mucosa, gingiva and the tongue, in the latter case particularly on the latero-posterior surfaces. Minor erosions may also occur on the external nares and in the nasal cavity. Elongated (.5-2 mm in width, 1-2 cm in length) necrotic-erosive lesions are common in the esophagus (see Fig.  3A ), as are erosions on the rumenal pillars (see Fig. 3C ), in the reticulum and omasum. It should be emphasized, however, that especially in the chronic (protracted) cases of MD gross lesions in the upper alimentary tract may be completely absent or subtle, although histologic examination usually will show micro-lesions similar in type to those described in the section on PI without overt clinical disease (see Fig. 7 A) .

Erosive edematous and hemorrhagic lesions are seen in the abomasum. The enteritis can vary from catarrhal to hemorrhagic, fibrinonecrotic, and erosive/ulcerative. The Peyer's patches as well as the lymphoid tissue in the proximal colon may seem hemorrhagic and necrotic (see Fig. 4 ). The thymus is usually atrophic, and in many cases, only leaves a stringy fibro-epithelial, partly fat-infiltrated tissue. Peripheral lymph nodes may be enlarged, edematous, or hypoplastic, depending on degree of inflammation in the drainage bed, length of clinical disease course, and/ or virus-host cell interactions in the organ.

Most animals will have apparent skin lesions, although with considerable individual variations in degree and extent of distribution. Lesions are most common and most pronounced in the neck, shoulder, and perineal region. The changes present as an eczema resulting from crustlike dermatosis and hyperkeratosis and parakeratosis accompanied by hypotrichosis or alopecia. Underneath the dry scales, the corium seem hyperemic and occasionally thickened. Where the crustous formations are well-delineated, a hyperemic zone can be observed in the edge as well as local alopecia. In some cases, the dermatitis is of a generalized seborrhagic nature with hyperkeratinization and alopecia. Erosive lesions may be found in the perineal area, around the preputial opening or vulva. Erosive lesions with or without lichenification and exudation are also common in the interdigital cleft and around the skin-hoof junctions. Suppuration may occur due to secondary bacterial infection, although this is less common than might be expected. Generally, the skin lesions may be more pronounced in the protracted (chronic) cases, but there seems to be considerable variation between published descriptions-perhaps due to differences in the clinical categorization of acute versus chronic.

Conjunctivitis is an almost consistent finding. Bronchopneumonia and fibrinous pleuritis may occur, but can then usually be ascribed to secondary bacterial infection (often Actinomyces bovis or Pasteurella species).

Despite the variation in the gross-pathologic appearance, the histologic picture in anyone particular organ or organ-system is one of uniformity of type with variations ascribable to intensity and progression of the lesions, and perhaps modified by mechanically or, more rarely, bacterially induced secondary changes.

The initial changes in keratinized epithelia (skin, the muzzle, and upper alimentary tract including rumen, reticulum, and omasum) is a focal infiltration of MNC in the papillar and reticular strata in propria/ dermis, often with a tendency to periarteriolar and pericapillary localization, but never developing into distinct "cuffing," thus, probably reflecting migration in progress, rather than a reaction to vascular changes (see Fig. 7 A) . A thickening of propria occurs by widening and lengthening of the dermal papillae, often at the expense of the epithelial basal folds, which may appear lamella-like. The tissue may be hyperemic with diapedesis hemorrhage. In the epithelium degeneration and eosinophilic necrosis of scattered cells in stratum spinosum seems to constitute the initial changes, which progress to widespread cellular necrosis with disruption of the intercellular junctions. At the same time, MNC infiltration of the epithelium occur, often without apparent relation to the necrotic epithelial cells, but perhaps directed toward cells inapparently modified by virus infection. IS As this process progresses, well-delineated foci with a reticulated appearance arise in the stratum spinosum. They may remain covered by an intact stratum corneum. However, eventually this layer also loses integrity and erodes (Fig. 7B) . The basal layer usually remains intact while the previously mentioned processes are in progression, but eventually necrobiotic and metaplastic changes may also occur. The basal cells may become squamous, but unless ulceration and/or secondary bacterial infection occur, the layer will remain uninterrupted.

In other areas, especially in the skin in the neck and shoulder regions, the epithelial changes may be dominated by hyperkeratotic and parakeratotic processes, with formation of thick keratinoid masses, often 50 to 100 (cell) layers thick, interspersed with varying amounts of necrotic cell debris, keratin, and infiltrating MNC. The hair follicles and sweat glands seem to become involved only relatively late in the processes of the skin, with initial periglandular and perifollicular MNC-infiltration and later degenerative and necrotizing changes of the follicles similar to those previously described. It is presumably at this stage that hypotrichosis and alopecia develops.

In the intestines and abomasum pathologic changes are selectively localized in the fundi of the crypts. The initial changes occur in scattered single or small groups of neighboring cells, and consist of cytoplasmic condensation followed by vacuolation, rounding off, and desquamation. Electron microscopic examinations, supported by immunocytochemistry for virus antigen (see below), have shown that this cellular reaction occurs in cells with extensive viral replication, presumably CP virus. 9 ,23, 66, 91 Cell debris and mucus accumulate in the crypt lumina that may become occluded and dilated with flattening of the epithelium and disappearance of microvilli. 23 Especially over the Peyer's patches these changes progress to a state of complete atrophy of crypts and villi, leaving a flat epithelium covering a lamina propria of fibrotic, almost acellular tissue (see Fig. 4 ). Although such areas seem especially prone to ulceration, it is worth noting that the unecrosis" described macroscopically in many, if not most, cases corresponds to areas with complete epithelial atrophy/metaplasia as seen in Figure 4 .

In some cases, or some areas/parts of the intestine mucus cell metaplasia may dominate the crypt changes, and is accompanied by excessive mucus production and accumulation. The lamina propria reaction is usually dominated by massive infiltration of MNC, especially macrophages. Other changes may include edema in the subepithelial layers, hyperemia, and diapedesis.

Although there may be general agreement in the literature that clinical MD is accompanied by changes in the lymphoid tissues, there seems to be a conspicuous lack of attempts at staging the changes and correlating, if possible, these with functional characteristics of the "immune tolerance" and "suppression," presumed to be central to the pathogenesis of MD.42,102 As previously mentioned, no or very subtle morphologic changes occur in lymphoid tissues (thymus, spleen, lymph nodes, Peyer's patches) of PI clinically healthy animals despite widespread virus infection of all or most of the cellular elements. 17 Changes may occur (thymus atrophy, lymph node reactivity) in growth-retarded, weak calves, but may be caused by intercurrent infections and stress rather than as an antecedent to secondary infections. 67 , 125 Unfortunately, no thorough description of changes in lymphoid tissues of experimentally reproduced MD cases has yet appeared. The descriptions of changes in the thymus and Peyer's patches to follow, therefore, are based on natural cases of MD in which a staging was attempted based on clinical appearance and duration of the disease. 9 In acute cases of brief duration (1-4 days) the overall structure of the thymus is retained, but a clear reduction occurs primarily affecting the cortex, which may be dominated by apoptotic and disintegrating thymocytes (Fig. SA) , prominent epithelial cells and large, actively phagocytosing macrophages. By electron microscopy degenerative changes are apparent in the epithelial cells, in particular in the cortical zone. Variable thymocyte depletion characterizes the medullary changes, but signs of frank cell death are rarely seen.

In subacute to distinctly chronic cases of MD, the thymus is characterized by progressive loss of zonal organization (Fig. SB) . The cortex may remain as a thin layer of "collapsed" epithelium, surrounding a fibro-reticular tissue with prominent Hassall's corpuscles and myoid cells. Few lymphocytes may persist in scattered islets, and fat infiltration may become prominent, especially in older animals.

The Peyer's patches already seem to be severely depleted of lymphoid cells during the peracute to acute clinical phases, which especially affects the follicles as well as the interfollicular and subepithelial zones. The follicular changes comprise apparent hypertrophy followed by degeneration of the follicular dendritic cells (FDC) and replacement with a homogenous fibroid material (Fig. 9 ). The structure of the Peyer's patches may be distorted further by extension of crypts into the submucosa and crypt-dilation followed by degeneration.

In more protracted (chronic) cases of MD, the Peyer's patches are characterized by atrophy. Often only a condensed/retracted (hyalinized) fibrotic tissue with small lymphoid islets remain (Fig. 9B) , which are surrounded by concentric layers of fibrous tissue. The interfollicular zones comprise a narrow zone under the muscular layer with few lymphocytes, monocytes, and macrophages between fibroblasts and col-lagen. The high-endothelial postcapillary venules (HEV) are no longer distinguishable.

In contrast to the thymus and Peyer's patches, a staging based on clinical criteria has not been possible for the parietal and mesenteric lymph nodes,9 which not only vary in appearance between animals, but also vary within an animal. The most conspicuous changes comprise lymphocyte-depletion of the peripheral subsinusoid zone and regressive changes in primary and secondary follicles, the numbers of which seem to be comparable to that which occurs in conventionally raised noninfected or PI healthy calves. In secondary follicles, the germinal center may be replaced by a lightly stained eosinophilic, homogenous (structureless) cytoplasmic stroma, consisting of large dendritic cells, identified by electron microscopy as FDC. Distinct fibrosis, sometimes with a pericapillary origin, may be present. Scattered macrophages with large phagolysosomes may surround this area, partly embedded in an irregular and ill-defined lymphocyte corona. The central fibrosis may progress to a state in which the FDC have disappeared and the germinal center is completely replaced by an acellular, condensed hyalin fibroid mass that is surrounded by few scattered lymphocyte islets.

The paracortex may be depleted of lymphocytes to varying degrees; directly related to this event is a flattening of the endothelial cells of the HEV and decreased transendothelial migration of lymphocytes. The number of interdigitating cells may either remain within the normal range or decrease.

The medulla may be relatively or actually expanded. This is partly the result of a prominent sinus reaction characterized by accumulation of lymphocytes and typical monocytes, as well as large II activated" macrophages ( Fig. 10) . This is especially true for the more protracted cases and in the parietal lymph nodes, in which these cells may attain epithelioid cell characteristics, inclusive electron microscopically detectable Birbeck granules and micropinocytosis vermiformis (Fig. 11) .

Changes in the bronchial and retropharyngeal lymph nodes may often be compounded by reactions to secondary respiratory bacterial infections and are not examined in this article. Changes in the tonsillar lymphoid tissue resemble those described for the Peyer's patches and lymph nodes, with a progression similar to that described for Peyer's patches. In the spleen, lymphocyte depletion of the periarteriolar lymphoid sheath and follicle changes that are similar to, albeit less pronounced, than those in the lymph nodes are characteristic findings.

Generally, BVDV antigen distribution in cattle with MD corresponds to that described for PI clinically healthy calves (see section on PI without overt clinical disease, Table 2 ; Figs. 6 and 12). A number of notable variations, however, should be examined. As the thymus involution progresses, the amount of detectable virus antigen also decreases and eventually is limited to MNC in the adventitia of blood vessels and scattered macrophages. The same occurs to the secondary follicles in peripheral lymphoid organ. As the germinal centers become depleted of FDC and are replaced by acellular matrix, the virus antigen disappears. In contrast, the occurrence of virus antigen in lymph node medullary cord and sinus cells increases with protraction of the clinical course. Most of these cells seem to be macrophages, as determined by doublelabeling for virus antigen and phenotypic (CD)-markers. The degeneration of HEV is notably not accompanied by virus antigen presence in the endothelial cells.

In the skin, virus antigen-positive cells occur as fairly evenly scattered cells in the basal lamina, inclusive of hair follicles. They may be more concentrated and the labeling more intense in areas of early and progressed subepithelial inflammatory reactions. Additionally, some of the infiltrating macrophages and T cells are virus antigen positive (see Fig. 6 ). 18 In the oral cavity, esophagus, and keratinized fore stomachs, the antigen distribution tends to be more focal, even in areas without visible inflammatory reactions or frank erosion, although considerable variation between different anatomical sites of the same animal is usual. 13 In the intestines of cattle with MD, more widespread occurrence of virus antigen-positive cells occur in the crypts compared with PI healthy calves, and the cells tend to label more intensely (compare Figs. 2 and 6). 13, 17, 18, 66, 91 This is the case in the epithelium associated with submucosal lymphoid tissues (Peyer's patches in ileum and in the proximal colon). Additionally, many macrophages in the lamina propria are virus antigen positive (see Fig. 6 ), although it remains unknown whether this is due to productive infection in all cases, or if it reflects extensive uptake of cellular debris from surrounding infected and lysed cells in some cells.

In animals succumbing to MD, the previously described hyperkeratotic and parakeratotic changes, as well as necrotizing lesions, are accompanied by massive infiltration of MHC class II antigen-positive macrophages and cells with dendritic morphology. T lymphocytes (predominantly CD8 + cells) also occur, whereas B lymphocytes are rare. Using macrophage differentiation markers as immunocytochemical target antigens, it was determined that the majority of macrophages in the infiltrates may be relatively undifferentiated but highly activated,18, 28, 33 and this may reflect a highly dynamic process with continuous influx from the blood circulation and either premigratory or postmigratory activation. 33 Macrophages of all maturation stages as well as T lymphocytes occur in the lamina propria of the digestive tract (inclusive in Peyer's patches) with occasional focal concentration of CD8+ cells perivenularly.

From the findings in natural cases of MD and with the use of only a limited set of lymphocyte surface markers, detection of consistent selective losses of anyone particular subset of lymphocytes from lymphoid tissues, or significant changes over time in the composition of cell infiltrates in other tissues has not been possible.I 8 With the availability of a larger panel of CD-specific reagents and the possibility of reproducing MD experimentally, however, it would now be feasible to conduct such studies in a controlled and sequential manner.

The role of cytokines in the pathogenesis and pathology of BVDV infections in general and in MD in particular, so far has only attracted limited attention/I, 25, 33 but deserves thorough investigation. Lesions comparable to those seen in the intestines, lymphoid tissues, and cutaneous epithelia can be provoked by either overexpression, overproduction, or gene-disruption of several cytokines, including TNFa/ 6 ,73 GM-CSF, 85 TGFfj,129 and IL-6.32, 74 The lesions characteristic of BVD-MD are likely to have a multifactorial cause: by a combination of virus-cpe and specific and nonspecific immune responses, with the latter comprising local cytokine production by nonlymphoid cells as well as macrophages and perhaps CDS + T cells and "null" cells in response to cell injury or other cytokines. In the unveiling of such mechanisms, however, it will be crucial to take into account the temporal relationships.22, 57,112 Liebler et al have begun such studies, but much remains to be done. 91 Another aspect of the pathogenesis of MD that needs clarification is the tissue/cell location for the events leading to a biotype change.I, 98, 99, 136 A number of studies have documented that flavivirus genome mutations and selection of variants only occur in certain cell types. 50, 93 It is notable that the CP virus seems to have a somewhat restricted distribution,66,91 and it is even more notable that this includes FDC, tissue macrophages, and other dendritic cells. A similar, although not identical, distribution was described in lymphocytic choriomeningitis virus (LCMV) infections in which specific types of mutations in the viral genome caused the virus to become either macrophage-tropic, lymphocytotropic, or both, i.e., amphotropic. 1 ,80 Likewise, in visna virus infection tissue tropism is determined by a specific genome segment. 131 Although the noted distribution for CP-BVDV cannot be taken to imply that these are the types of cells in which the change(s) occurs, the preferential replication of CP-BVDV in professional antigen presenting cells (APC) makes it possible that the cleavage products of the 125kDa protein, after genomic changes, are processed and presented differently to the immune system than NCP-virus products. 106 The tolerant state may be "broken" with the subsequent development of immunopathologic, perhaps even autoimmune-like, disease.109, 123 That a measurable antibody (AB) response does not always occur,11, 15,62 which might other-wise be expected,65, 147 does not contradict this hypothesis, because such a response would not only depend on a time-factor, i.e., survival time, but also on the type of T-cell response induced. 4 , 103, 104, 112, 142 If this is preferentially a CD8+ T-cell response, which might be inferred from the predominance of CD8 + to CD4 + cells in inflammatory foci, submucosae, and lymphoid tissues,18 and is followed by destruction of antigen-positive cells, including the FDC (see Figs. 9B and 12),108 the B-cell response would be abrogated?9, 117 Such mechanisms have been demonstrated to occur in LCMV infection,108 and are thought to take place in HIV infections. 63 If at the same time as the APC are presenting "new" virus-protein epitopes to the immune system one or more of their accessory functions, such as expression of co stimulatory surface molecules or production of cytokines, have been altered directly or indirectly due to the virus infection, 1 apoptosis may be the outcome rather than stimulation of a proliferative T-cell response. 89 , 141 Such a scenario could be invoked to explain the apparent "acuteness" of thymocyte depletion (see Fig. 8A ), as well as lymphocyte depletion of peripheral lymphoid tissues. 117 In addition, factors such as corticosteroids and sudden excessive release of certain cytokines may contribute to the depletion by directly inducing apoptosis in lymphocytes. 48 ,90 The resulting disruption of lymph node, Peyer's patches, and tonsil architecture would result in an abnormal (even if in some cases subtle) distribution of lymphocytes within these tissues. This reaction combined with the productive virus infection of both lymphocytes, macrophages, and dendritic cells (see Figs. 2 and 12) may profoundly impair normal cell-cell interactions. 16 , 17, 31, 66 Such mechanisms may help to explain why neither T nor B lymphocytes are particularly prominent in the inflammatory processes in epithelial lesions. 18 Furthermore, the absence of de novo expression of MHC class II antigens on endothelia and epithelia suggest that either IFN-y is not produced locally to any significant extent/ 2 ,25 or the IFN-y effect is antagonized by other cytokines. Because inflammatory macrophages in the lesions express high levels of MHC class II antigen, however, this would suggest that cytokines such as IL-10 and TGF~ may not play major roles in the inflammatory reactions,55, 139, 140 despite at least the latter's known involvement in skin pathology.38, 129 Instead, to explain the inflammatory process in the cutaneous epithelia the role of IL-1u and IL-1~ may be invoked. Keratinocytes are known to express large amounts of intracellular pro-IL-1u and pro-IL-~.82, 101 Cell injury, due to virus-CPE or a cell-mediated cytotoxic response, would result in release of the cytokines. Because pro-IL-1u is biologically active, its release could initiate the inflammatory reaction by induction of adhesion molecules on endothelia and the production, by keratinocytes and macrophages, of chemokines and other proinflammatory cytokines such as CSFs, IL-6, TNFu, and fibroblast and keratinocyte growth factors. 81 The process may start with the damage of only a few keratinocytes, and thereby create the impression of MNC-infiltration preceding the epithelial lesions (see section on histopathology of MD and see Fig. 7 A). Furthermore, it is possible that such a process could become self-perpetuating. 81 An alternative, although not a mutually exclusive possibility, is that the cutaneous lesions in MD are initiated by CP-BVDV replication in Langerhans cells. These cells are potent APC and cytokine producers,86 and the latter function could be envisioned to be upregulated on infection, in particular of such pro-inflammatory mediators as IL-l, IL-6, TNFa, and chemokines, which subsequently could stimulate the keratinocytes as well as attract macrophages. Another possibility is virusinduced depletion of Langerhans cells, directly or indirectly,l28 with subsequent loss of an important immunoregulatory component of the skin. 4, 8, 124, 133 Thus the question of distribution and density variation of epidermal and mucosal Langerhans cells as a determining factor in the distribution and/or severity of the lesions in cutaneous epithelia, such as has been described in other dermatologic reactions,39, 130, 138, 145 becomes pertinent. So far the cutaneous lesions characteristic for MD have received comparatively little attention; further study in this area is needed.

Despite the impressive progress in the unveiling of the molecular phenomena involved in the biotype-change, from NCP to CP, of BVDV98, 99,118,135,136 (see the article by Donis and Bolin, this issue), the biological significance of the pBO protein at the level of host cell-virus interaction(s) remains unresolved.134 It is by no means clear that the pBO protein is the cytopathogenic factor, and the possibility remains that this protein represents only an epiphenomenon or convenient marker for other more crucial events in the host-pathogen relationship.

Thus, before jumping to (easy) conclusions about virus-CPE as the main, if not sole, cause of tissue pathology and ultimate death of the animal,42,98, 136 it might be prudent to remember a number of characteristic features of the MD pathology and to place these in context of what is currently known about inflammatory processes and induction of pathomorphologic changes in lymphoid tissues, as well as the possible role of target cell distribution. It also should be remembered that many of the lesion types characteristic of MD can also be found in acute outbreaks of BVD in which the causative strain is NCP.43, 56, 96, 114 A broader and more integrated approach may be needed to succeed in unraveling the enigmas of the pathogenesis of MD and of BVDV infections in general.

Molecular basis of organ-specific selection of viral variants during chronic infection

Bovine coronavirus as the causative agent of winter dysentey: Serological evidence

Serological titers to bovine herpesvirus 1, bovine viral diarrhea virus, parainfluenza 3 virus, bovine respiratory syncytial virus and Pasteurella haemolytica in feedlot calves with respiratory disease

Promethean viruses?

Suppression of in vitro immunoglobulin biosynthesis in bovine spleen cells by bovine viral diarrhea virus

Bovine viral diarrhea virus: A review

Reduced Langerhans' cell Ia antigen and ATPase activity in patients with the acquired immunodeficiency syndrome

Bovine Viral Diarrhoea Virus-Infections. Studies in Spontaneous and Experimentally Infected Animals

Bielefeldt Ohmann H: Immunoglobulin levels in non-aborted and aborted fetuses from Danish herds of cattle

H: unpublished data

Experimental fetal infection with bovine viral diarrhea virus. II. Morphological reactions and distribution of viral antigen

Bielefeldt Ohmann H: Pathogenesis of bovine viral diarrhoea-mucosal disease: distribution and significance of BVDV antigen in diseased calves

Bielefeldt Ohmann H: An oculo-cerebellar syndrome caused by congenital bovine viral diarrhoea virus-infection

H: unpublished data

Bielefeldt Ohmann H: Double immuno-Iabeling systems for phenotyping of immune cells harboring bovine viral diarrhoea virus

Bielefeldt Ohmann H: BVD virus antigens in tissues of persistently viraemic, clinically normal cattle: Implications for the pathogenesis of clinically fatal disease

Bielefeldt Ohmann H: In situ characterization of mononuclear leukocytes in skin and digestive tract of persistently BVD virus-infected, clinically healthy calves and calves with Mucosal Disease

The role of cytokines in the pathogenesis and treatment of respiratory disease

Viral infections in domestic animals as models for studies of viral immunology and pathogenesis

Influence of interferons-all and -"I and of tumour necrosis factor-a on persistent infection with bovine viral diarrhoea virus in vitro

Cytokine synergy with viral cytopathic effects and bacterial products during the pathogenesis of respiratory tract infection

Electron microscopic studies of bovine viral diarrhoea virus in tissues of diseased calves and in cell cultures

BVD virus infection in peripheral blood mononuclear cells from persistently viraemic calves studied by correlative immuno-electron microscopy

Induction of MHC class II antigens on bovine cells of non-lymphoid origin by recombinant interferon-'Y and tumor necrosis factor-a

In vivo effect of continuous treatment of cattle with cachectin/tumor necrosis factor-a

Indirect immunofluorescence using F(ab')z-immunoreagents for the demonstration of bovine viral diarrhoea virus (BVDV) antigen in lymphoid tissue

Surface antigen expression on bovine alveolar macrophages: Functional correlations and influence of interferons in vivo and in vitro

Unpublished data

Experimental fetal infection with bovine viral diarrhea virus. I. Virological and serological studies

Demonstration of bovine viral diarrhoea virus in peripheral blood mononuclear cells of persistently infected, clinically normal cattle

Interleukin-6 involvement in mesothelioma pathobiology: Inhibition by interferon-a immunotherapy

A monoclonal antibody detects a macrophage maturation antigen which appears independently of class II antigen expression: reactivity of monoclonal EBM11 with bovine macrophages

Neurological disorders, virus persistence and hypomyelination in calves due to intrauterine infections with bovine virus diarrhoea virus

Serological detection and practical consequences of antigenic diversity among bovine viral diarrhea viruses in a vaccinated herd

Differences in virulence between two noncytopathic bovine viral diarrhea viruses in calves

Frequency of association of noncytopathic bovine viral diarrhea virus with mononuclear leukocytes from persistently infected cattle

Transforming growth factor-I) in disease: The dark side of tissue repair

Different in situ distribution patterns of dendritic cells having Langerhans (T6 +) and interdigitating (RFD1 +) cell immunophenotype in psoriasis, atopic dermatitis, and other inflammatory dermatoses

Pathogenetic studies of infection of the bovine fetus with bovine viral diarrhea virus. II. Ocular lesions

Virus induced congenital anomalies of the bovine fetus. II. Histopathology of cerebellar degeneration (hypoplasia) induced by the virus of bovine viral diarrhea-mucosal disease

The pathways for bovine virus diarrhoea virus biotypes in the pathogenesis of disease

Severe acute bovine virus diarrhea (BVD) in Ontario in 1993

A study of some pathogenic aspects of bovine viral diarrhea virus infection

An experimental contribution to the study of the pathogenesis of bovine viral diarrhea virus infection

Langerhans cells in human warts

The pathogenesis of chronic hog cholera (swine fever)

Histologic, immunofluorescent, and electron microscopic studies

Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death

Femoral and tibial fractures in a newborn calf after transplacental infection with bovine viral diarrhoea virus

Virulence and pathogenesis of yellow fever virus serially passaged in cell culture

Monoclonal antibody analysis of cytopathic and noncytopathic viruses from fatal bovine viral diarrhea virus infections

Thrombocytopenia and hemorrhages in veal calves infected with bovine viral diarrhea virus

Severe thrombocytopenia in young calves experimentally infected with noncytopathic bovine viral diarrhea virus

Lesions in clinically healthy cattle persistently infected with the virus of bovine viral diarrhea-Glomerulonephritis and encephalitis

Transforming growth factor-~l modulates the expression of class II histocompatibility antigens on human cells

Severe disease in adult dairy cattle in three UK dairy herds associated with BVDV infection

Tumor necrosis factor inhibits the development of viral meningitis or induces rapid death depending on the severity of inflammation at time of administration

Bovine virus diarrhoea-mucosal disease virus: Pathogenicity for the fetal calf following maternal infection

An outbreak of peracute BVD in Pennsylvania cattle

Genetic diversity and BVD virus

Bovine virus diarrhoea-mucosal disease infection in cattle

Clinical and virological observations of a mucosal disease outbreak with persistently-infected seropositive survivors

Multifactorial nature of human immunodeficiency virus disease: Implications for therapy

Viral antigen distribution in the central nervous system of cattle persistently infected with bovine viral diarrhea virus

Breakdown of self-tolerance in anergic B lymphocytes

Distribution of cytopathogenic and noncytopathogenic bovine virus diarrhea virus in tissues from a calf with experimentally induced mucosal disease using antigenic and genetic markers

Ontogeny of the immune response: effect of protein energy malnutrition in neonatal calves

Light and electron microscopic study of the normal and pathological thymus of the rat. II. The acute thymic involution

Pathogenesis of Dengue. Challenges to molecular biology

Kidney lesions in cattle persistently infected with bovine viral diarrhoea virus

Immunohistological detection of bovine viral diarrhoea virus antigen in the central nervous system of persistently infected cattle using monoclonal antibodies

Porencephaly, hydranencephaly and leukoencephalopathy in bovine fetuses following transplacental infection with bovine virus diarrhoea virus: Distribution of viral antigen and characterization of cellular response

Expression of a tumor necrosis factor a transgene in murine pancreatic ~ cells results in severe and permanent insulinitis without evolution towards diabetes

Interleukin-6 and its relation to inflammation and disease

RNA virus populations as quasispecies

Immune response to other agents of calves persistently infected with bovine virus diarrhea virus (BVDV)

Comparative pathogenicity of selected bovine viral diarrhea virus isolates in gnotobiotic lambs

Congenital cerebellar hypoplasia and ocular defects following bovine viral diarrhea-mucosal disease infection in pregnant cattle

Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice

In vivo selection of lymphocyte-tropic and macrophage-tropic variants of lymphocytic choriomeningitis virus during persistent infection

The activated keratinocyte: A model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses

Human keratinocytes contain mRNA indistinguishable from monocyte interleukin 1 alpha and beta mRNA

Bovine viral diarrhea virus and Escherichia coli in neonatal calf enteritis

Bovine viral diarrhea in the neonatal calf

Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage

Activated Langerhans cells release tumor necrosis factor

Bovine virus diarrhoea virus induces in vitro a proliferative response of peripheral blood mononuclear cells from cattle immunized by infection

Congenital curly haircoat as a symptom of persistent infection with bovine virus diarrhoea virus in calves

Polyclonal activation of T cells, apoptosis, and memory in viral infection

Interleukin-2 programs mouse a~ T lymphocytes for apoptosis

Distribution of antigen of noncytopathogenic and cytopathogenic bovine virus diarrhea virus biotypes in the intestinal tract of calves following experimental production of mucosal disease

Interferon ' Y plays a critical role in induced cell death of effector T cell: A possible third mechanism of self-tolerance

Host cell selection of Murray Valley Encephalitis virus variants altered at an RGD sequence in the envelope protein and in mouse virulence

Cellular inflammatory response in the lungs of calves exposed to bovine viral diarrhea virus, Mycoplasma bovies, and Pasteurella haemolytica

Presence of bovine viral dial"rhoea virus in lymphoid cell populations of persistently infected cattle

Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigens

Viral cytopathogenicity correlated with integration of ubiquitin-coding sequences

Rearrangement of viral sequences in cytopathogenic pestiviruses

Epidemiology of bovine virus diarrhoea virus

Different strategies of IL-1 production and processing in keratinocytes and monocytes

The pestiviruses

Mechanisms of recovery from acute virus infection: Treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response

Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells

Lesions in aborted bovine fetuses and placenta associated with bovine viral diarrhoea virus infection

Interference with the binding of a naturally processes peptide to class II alters the immunodominance of T cell epitopes in vivo

Experimental infection of calves with two strains of bovine virus diarrhoea virus: Virus recovery and clinical reactions

Virus-triggered acquired immunodeficiency by cytotoxic T -cell-dependent destruction of antigen-presenting cells and lymph follicle structure

Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice

An apparently new transmissible disease of cattle

Virus-induced alterations in homeostasis: Alterations in differentiated functions of infected cells in vivo

Effects of IL-12 on the response and susceptibility to experimental viral infections

Identification of a new group of bovine viral diarrhea virus strains associated with severe outbreaks and high mortalities

Bovine virus diarrhea-Clinical syndromes in dairy herds

Experimental production of bovine respiratory tract disease with bovine viral diarrhea virus

Comparison of the pneumopathogenicity of two strains of bovine viral diarrhea virus

A form of immunological tolerance through impairment of germinal center development

Analysis of the bovine diarrhea virus genome for possible cellular insertions

New concepts in the pathogenesis, diagnosis and control of diseases caused by the bovine viral diarrhea virus

Thrombocytopenia associated with acute bovine virus diarrhea infection in cattle

Hybridization analysis of genomic variability among isolates of bovine viral diarrhoea virus using cDNA probes

Antigenic and genomic comparison between non-cytopathic and cytopathic bovine viral diarrhoea viruses isolated from cattle that had spontaneous mucosal disease

Infection breaks T-cell tolerance

Langerhans cell production of interleukin-1

Bovine herpesvirus-I-induced pharyngeal tonsil lesions in neonatal and weanling calves

Developmental aspects of the fetal bovine immune response: A review

Virus induced congenital anomalies of the bovine fetus. I. Cerebellar degeneration (hypoplasia), ocular lesions and fetal mummification following experimental infection with bovine viral diarrhea-mucosal disease virus

Dendritic cells that have interacted with antigen are targets for natural killer cells

Targeted disruption of the mouse transforming growth factor-131 gene results in multifocal inflammatory disease

Regional variations in antigenic properties of skin. A possible cause for disease-specific distribution of skin lesions

The visna virus long terminal repeat directs expression of a reporter gene in activated macrophages, lymphocytes, and the central nervous system of transgenic mice

Detection of bovine viral diarrhoea virus p80 protein in subpopulations of bovine leukocytes

Skin-associated lymphoid tissues (SALT): Origins and functions

RNA-stimulated NTPase activity associated with the p80 protein of the pestivirus bovine viral diarrhea virus

Processing of poly-ubiquitin in the polyprotein of an RNA virus

Pathogenesis of mucosal disease: A cytopathogenic pestivirus generated by an internal deletion

Kasuistischer Beitrag zu hemorrhagischen Diathesen bei Kalbern mit BVD-Virusinfektion

Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB

Interleukin-lO treatment can suppress stromal keratitis induced by Herpes Simplex virus type 1

Interleukin 10 (IL-I0) and viral IL-I0 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression

Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4 + T cells is regulated by the antigen-presenting cell

Intracerebral cytokine mRNA expression during fatal and nonfatal alpha virus encephalitis suggests a predominant type 2 T cell response

Experimental primary postnatal bovine viral infections in six-month-old calves

Distribution of bovine virus diarrhoea viral antigens in the central nervous system of cattle with various congenital manifestations

Role of epidermal Langerhans cells in resistance to Herpes Simplex virus infection

Altered growth, differentiation, and responsiveness to epidermal growth factor by persistent rubella virus infection

Virus-induced autoantibody response to a transgenic viral antigen