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This article was published in 1978
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Mucosal Disease and Its Familial Incidence
Ian R. Littlejohns, B.V.Sc., M.A.C.V.Sc., Assistant Principal Veterinary Research Officer, Veterinary Research Station, Glenfield
This report is concerned with two findings that have implications in regard to our understanding of both the epidemiology and the pathogenesis of mucosal disease (MD). These are that:
1. In herds in which MD is enzootic, a low proportion of carrier animals, perhaps of the order of 1 or 2%, may be demonstrated.
2. Both disease and the carrier state are sometimes found to occur in family clusters.
It is fundamental to these considerations that a clear distinction should be drawn between MD virus infection and MD as a disease. Also, it should be recognised that all pathological manifestations consequent upon MD virus infection are not necessarily part of a single disease syndrome. For the purposes of this discussion MD is defined as a progressive erosive disease of the alimentary tract which is associated with coronitis and lymphadenopathy, is debilitating and almost invariably fatal. It does not include infertility, abortion, congenital disease, immune complex disease or any of the relatively benign intestinal or respiratory conditions that have, rightly or wrongly, been attributed to the infection.
The conventional view of MD virus * and the consequences of infection are represented in Fig. 1. Apart from sub-clinical infections the same virus produces either BVD or MD depending on whether or not the animal is immunologically competent. Immunological incompetence is often regarded as the factor which allows fatal disease to develop instead of the infection running a sub-clinical or mild course. This view will be challenged.
* The virus is properly, according to the International Committee for Virus Nomenclature, identified as bovine virus diarrhoea (BVD) virus, determined by the rules of precedence. From the viewpoint of veterinary pathology such rules, which determine viral taxonomy and nomenclature without reference to virulence, pathogenicity or recently acknowledged disease manifestatians, may favour names which cause confusion.
In speculating on the reason for some animals being immunologically incompetent, two possible mechanisms are usually considered; immune tolerance or virus induced immunosuppression.
Immune tolerance may be induced when a foetus experiences a foreign antigen while its immune system is undeveloped. The foreign antigen is then recognised as self and, when the immune system is developed, antibody is not produced against the antigen in question. That this general rule in immunology applies when MD virus is the antigen is indicated by experimental infections in both sheep and cattle. However, because MD can be induced in a small proportion of animals having post-natal experimental infection or vaccination as their first experience of MD virus, it seems that immune tolerance cannot be the only mechanism providing a basis for persistent viraemia and progressive disease.
Virus induced immunosuppression has been demonstrated to occur in many circumstances in experimental pathology. As lesions in lymphoid tissue are commonly a prominent feature of MD it is tempting to think that the virus may be immunosuppressive. However, although there appears to be a deficiency of B cells among circulating lymphocytes, there is no convincing evidence of immunological deficiency of a broad specificity. On the contrary, animals suffering from MD have been comparable to their normal herd-mates in ability to produce antibody against IBR virus or egg albumen.
Therefore these two mechanisms do not provide an adequate basis from which to explain all cases of MD.
Against this background the significance of the finding of carrier animals and familial incidence can be considered. It should be noted that the hypothesis of immune tolerance as a mechanism for incompetence requires that normal infected animals do occur over the period between birth and the time when clinical disease develops. However, the circumstances in which normal viraemic carrier animals have been demonstrated go much further than this and include animals, which live for years and produce calves each year, without ever showing signs of disease identifiable as MD. These animals are equally as incompetent for antibody production as are diseased animals. Hence the important conclusion can be drawn that immunological incompetence, and the persistent viraemia that goes with it, are not essential events in the pathogenesis of MD but, more probably, simply define a population of animals within which clinical cases of MD may develop. Note that this reasoning refers to MD as defined above and does not refer to other consequences of MD virus infection. These may represent quite different syndromes.
The familial incidence of MD was suspected on a number of occasions when unusually high incidences were encountered in routine diagnostic work. It was confirmed on two occasions when material was provided by Veterinary Inspectors Clem Gee of Goulburn and Chris Bourke of Coonamble. In both cases viraemic cows produced viraemic calves over two or more generations. Some members of viraemic families developed MD.
Families of incompetent viraemic animals could, presumably be maintained through the mechanism of immune tolerance. But, as mentioned above, such a mechanism does not adequately account for all circumstances in which MD occurs. In any case, there would have to be a foundation member for each family, and, as MD-viraemic families tend to die out due to an incidence of MD or other inter-current disease in which MD may not be la recognisable part, there is need for some mechanism for a new input of families or foundation members.
A revised scheme to accomodate the observed incidence of carrier animals and the familial incidence of persistent infection and disease is presented as Fig. 2.
The extra-familial origin of a foundation member may be due to either the occasional primary infection of a pregnant female carrying a foetus at a susceptible pre-immunocompetent state, or to a genetically determined incompetence. Against the first alternative is that some foeti exposed in this way will develop incapacitating congenital disease. Although it is possible that some may survive without major debility to provide foundation members for viraemic families, this mechanism cannot account for MD cases observed to develop after post-natal infection. The possibility that foundation members are determined genetically is suggested. It could provide for new sporadic cases and generate new families from affected females. There is at present no direct evidence for it but it is suggested by default or alternative mechanisms that can be proposed. Analogous situations occur in experimental pathology, where it is well established that capacity to produce antibody to a specific antigen may be genetically determined.
Whatever controls the production of a population of cattle within which MD may occur, it seems likely that some trigger is required to induce disease in an animal which is unable to produce MD antibody and is persistently viraemic. Stress, nutritional, toxic or infectious factors could be considered. From diagnostic work at Glenfield there is some evidence that another infectious factor may be involved. On several occasions it has been found that virus isolated from the bowel of a clinical case has been cytopathogenic, while virus recovered from the blood of the same animal has been non cytopathogenic. Investigations into the difference between the two isolates suggest that another agent is involved and may be a trigger to precipitate disease. Such a situation could fit the natural circumstances in which MD occurs as a sporadic condition of low incidence.
From a practical point of view the finding of carrier animals and families offers some opportunity for control and eradication. At least in closed herds with annual calving, it seems that removal of carrier animals may remove the reservoir of infection and eliminate disease from the group. Actually it is likely that it is the susceptible animals that are being removed and elimination of the virus occurs coincidentally.
If there is a genetic basis to the origin of new susceptible animals or families then there is opportunity for recognition of gene carriers to eliminate them from studs. Current activities include a search for circumstances where inherent MD susceptibility might be recognised and studied. It seems most likely that this might be achieved if a substantial incidence of disease and viraemic state can be recognised in stud herds.
Technology for demonstration of MD virus and antibody is now sufficiently developed that blood samples can be examined in quite large numbers. Whole herd tests are feasible and should be considered if MD is a substantial or continuing problem. This could follow, or be concurrent with examination for a familial incidence by the testing of relatives, through female connections of clinical cases.
| Clinical | Course | Immunity | Viraemia |
|---|---|---|---|
| MD | Malignant | Incompetent | Persistent |
| BVD | Benign | Competent | Transient |
| Sub-clinical |
Fig. 1. Conventional view of MD virus infection and its consequences.
| Clinical | Course | Immunity | Viraemia | Familial |
|---|---|---|---|---|
| MD | Malignant | Incompetent | Persistent | Some |
| Carrier * | Potentially Malignant | Yes + | ||
| BVD | Benign | Competent | Transient | 'Normal' Population |
| Sub-clinical |
* Carriers may become clinically affected.
+ Females may be primary foundation members of families or secondary dependent members. Males occur within established families. Their primary occurrence has not been observed but might be anticipated.