Felipedia

©A. Kipar, J. Kremendahl, M. L. Jackson and M. Reinacher Comparative Examination of Cats with Feline Leukemia Virus-associated Enteritis and Other Relevant Forms of Feline Enteritis Vet Pathol 38:359-371 (2001). http://www.vetpathology.org/cgi/content/full/38/4/359

Feline leukemia virus (FeLV)–associated enteritis (FAE)is one of the non-neoplastic conditions that may be seen in catspersistently infected with FeLV.^26,43–45 The small intestinein cats with FAE bears histopathologic features similar to thoseof cats with feline panleukopenia, but bone marrow depletionis missing. At the same time, parvovirus (PV) cannot be demonstratedand FeLV infection is present.^26,28,29,43 A study on the differentialexpression of FeLV proteins in the small intestine showed strongexpression of FeLV envelope proteins gp70 and p15E in cats withFAE, suggesting a pathogenic role for these proteins or theirprecursors in the development of the disease.²⁶ This featurehas also been proposed for FeLV-related feline acquired immunodeficiencysyndrome (FeLV-FAIDS).^13,26,40,41

In the morphologically normal jejunum regardless of the ageof the cat and in cats with PV enteritis, mild to moderate T-cell–dominatedinfiltration of the mucosa was seen. Thus, in the jejunum asin the duodenum, a moderate T-cell infiltration is normal.⁵⁵However, there are differences between experimental and natural PV enteritis. In the former, many neutrophils are found aroundand within crypts in the early phase of disease.⁸ Therefore,cats naturally infected with PV either might not die in theearly phase of the disease or might suffer from a lack of recruitableleukocytes due to granulocytopenia in the course of bone marrowhypoplasia and lymphoid depletion.^2,29 In cats with FAE, infiltrationof the intestinal mucosa was generally more intense but alsowas T cell dominated. Together with the fact that the majorityof T cells were CD8 positive at least in the normal feline colon,findings may indicate an FeLV-specific local cytotoxic T-cellresponse in FAE.⁵³ In FeLV-positive cats without enterocytealterations, however, B cells were relatively numerous amonginfiltrating cells, suggesting a specific humoral response toFeLV antigens. In most cats with Parvovirus enteritis (EUE), numerous myeloid/histiocyte antigen-positive macrophages were found among infiltrating cells. Additionally, a portion of infiltrating mononuclear cells failedto stain with T-cell, B-cell, and monocyte/histiocyte markersin the jejunal mucosa. In humans, resident macrophages are negativefor the myeloid/histiocyte antigen (calprotectin), the synthesisof which cannot be induced in mature macrophages.^4,50 About25% of infiltrating cells in the normal feline duodenum arecells with a histiocytic morphology.⁵⁵ Therefore, the numberof macrophages among infiltrating cells in EUE might actuallybe even higher, and recruitment of peripheral blood monocytesin the course of mucosal inflammation is suspected.^50,55

Lymphoid tissue activity and bone marrow activity were generallynormal in FeLV-negative cats without enterocyte alterationsregardless of the other lesions these cats showed. FeLV-positivecats without enterocyte alterations showed variable lymphoidtissue activity and a tendency towards increased bone marrowactivity, confirming that both lymphoid tissue hypoplasia and hyperplasia and bone marrow hyperplasia can develop as a resultof FeLV infection.¹⁷ In cats with FAE, however, bone marrowactivity was normal and lymphoid tissue was either normal orhyperplastic. This phenomenon has also been observed in theinitial phase of experimental infection with FeLV–felineAIDS(FAIDS) variants, which are (as natural variants) consideredas a potential aetiology of FAE.^19,26 Although viral replicationcan be anticipated in lymphoid tissues of cats with FeLV-FAIDSand FAE, there is no evidence of a cytopathic effect of FeLVon lymphoid and hematopoietic cells in either syndrome.¹⁹ Incats with PV enteritis/feline panleukopenia, however, lymphoidtissue depletion is observed.^8,29 Many cats in the present studyshowed decreased bone marrow activity with depletion of myelomonocyticmyeloid/histiocyte antigen-positive cells, a feature which isalso seen in the early phase of experimental PV infection.⁸In a prolonged course of experimental PV enteritis and in cases of naturally acquired disease in our study, however, unalteredand even hyperplastic bone marrow was present.^2,6,29 This findingfurther indicates the variable course of natural PV enteritis.In cats with EUE, a tendency for lymphoid depletion and increasedbone marrow activity was obvious, potentially reflecting therecruitment of inflammatory cells to the intestine.

Fig. 1. Jejunum; cat No. I-8. FeLV-associated enteritis. Fig. 1a. The majority of inflammatory cells in the mucosa are CD3-positive T cells. Peroxidase–antiperoxidase method. Bar = 50 µm. Fig. 1b. Few CD45R-positive B cells (arrowhead) are seen. Bar = 50 µm. Inset: Higher magnification of CD45R-positive B cells. Avidin–biotin–peroxidase complex method. Bar = 20 µm. Fig. 1c. A minority of infiltrating cells in the mucosa are myeloid/histiocyte antigen–positive macrophages (arrowheads). Peroxidase–antiperoxidase method, Papanicolaou's hematoxylin counterstain. Bar = 50 µm.
Fig. 2. Jejunum; cat No. II-13. Parvovirus enteritis Fig. 2a. The majority of the few infiltrating cells are CD3-positive T cells. Peroxidase–antiperoxidase method. Bar = 50 µm. Fig. 2b. Few CD45R-positive B cells (arrowheads) are found. Bar = 50 µm. Inset: Higher magnification of CD45R-positive B cells. Avidin–biotin–peroxidase complex method. Bar = 20 µm. Fig. 2c. Single myeloid/histiocyte antigen-positive macrophages (arrowhead) are seen. Bar = 50 µm. Inset: Higher magnification of myeloid/histiocyte antigen-positive macrophage. Peroxidase–antiperoxidase method, Papanicolaou's hematoxylin counterstain. Bar = 20 µm.
Fig. 3. Jejunum; cat No. III-8. FeLV-negative cat with EUE. Fig. 3a. Numerous CD3-positive T cells are found among infiltrating cells of the mucosa. Peroxidase–antiperoxidase method. Bar = 50 µm. Fig. 3b. Single CD45R-positive B cells (arrowheads) are found. Bar = 50 µm. Inset: Higher magnification of CD45R-positive B cells. Avidin–biotin–peroxidase complex method. Bar = 20 µm. Fig. 3c. Myeloid/histiocyte antigen-positive macrophages are numerous among infiltrating cells. Peroxidase–antiperoxidase method, Papanicolaou's hematoxylin counterstain. Bar = 50 µm.

In cats with FAE and EUE, PV infection was excluded by immunohistologyand ISH.^26,42,54 Therefore, failure to confirm PV infection,as encountered in a natural PV enteritis outbreak in a colonyof experimentally FeLV-infected specific-pathogen-free cats,is unlikely.^31,42,54 In general, FeLV and PV co-infections arerare.^44–46 In the two cats in our study with FeLV andPV co-infection, lesions were dominated by alterations typicalof PV enteritis. The FeLV staining pattern corresponded to thatof FeLV-positive cats without intestinal alterations.^26,27 Incats with FAE and in cats with PV/FeLV co-infection, lesionswere distinct from the erosion of villous tips in the small intestine as they have been described in the "panleukopenia-like syndrome" (myeloblastopenia) in FeLV-infected cats.¹⁶ Furthermore,the lymphoid depletion and severe granulocytic hypoplasia ofthe bone marrow described for this syndrome were also absent.¹⁶

In our study, the lack of both typical lesions of villous enterocytesand CoV antigen expression excluded CoV enteritis in cats withFAE and EUE.^20,25,38 As observed in one cat, lesions typicalof FAE and CoV enteritis may occur simultaneously.²⁵

FeLV infection was confirmed by immunohistology and by PCR fora 166-bp DNA fragment of the exogenous FeLV U3-LTR.^9,21 LatentFeLV infection was unlikely in all FeLV-negative cats, includingall cats with EUE.²¹ Occasional negative PCR results in catsimmunohistologically positive for FeLV may be due to destructionof DNA by tissue processing factors.²¹

In cats with EUE, infection with other enteric viruses, suchas astrovirus, rotavirus, or torovirus, cannot be definitivelyexcluded; ultrastructural examination of the intestinal contentwas not performed in all cats. However, these infections seemunlikely because they are generally rare and of minor pathologicsignificance.¹⁵ Intestinal changes in cats with EUE do not suggestfeline immunodeficiency virus (FIV) infection. However, intestinallesions associated with FIV range from nonexistent to extensivemucosal inflammatory cell infiltration, mucosal erosions orulceration, and transmural typhlitis.^3,7,36,51 Furthermore,lymphatic tissues and bone marrow do not show features indicativeof FIV infection, such as large and often depleted secondarylymphoid follicles and a distinctly increased bone marrow cellularity.^3,6,7,51However, because serology for FIV infection was not performed for cats with EUE, FIV infection cannot be definitively excluded.

Histopathology did not reveal involvement of bacterial, protozoal,or fungal pathogens in any cats. Bacterial adhesion or invasionof intestinal epithelial cells was not evident. Therefore, thenumerous gram-negative rod-shaped bacteria observed histologicallyand the E. coli growing heavily in a few cultures cannot beconsidered pathogens. Abundant bacterial colonization with almostequal amounts of aerobes and anaerobes has been identified asnormal in the small intestine of healthy cats.^37,52

In cats with EUE, exclusion of other causes of gastrointestinalinflammation renders the diagnosis of feline inflammatory boweldisease (IBD) acceptable. However, the cats in this group donot fulfil the criteria of lymphocytic-plasmacytic enteritis,the most common form of IBD in cats.^18,22,55 EUE is somewhatsimilar to human IBD, which is characterized by infiltrationof the lower lamina propria by newly recruited calprotectin-positivehistiocytes.^48,50 In human IBD, type IV hypersensitivity responseto chronic antigenic challenge and dysregulation of cytokinesecretion have been observed.^33,47 Calprotectin-positive macrophagesseem to have a pro-inflammatory potential; they are primed fortumour necrosis factor (TNF-alpha) and interleukin 1 production.⁴⁹Furthermore, calprotectin has an antimicrobial effect in vitro and might therefore represent a defence mechanism against microbial invasion.^5,48 These findings suggest that the pathogenesis oflesions in EUE is similar to that in human IBD; in most casesof EUE, myeloid/histiocyte antigen (calprotectin)-positive macrophages dominated the inflammatory cell population in the jejunal mucosa. These macrophages may release cytotoxic substances such as reactive oxygen species and TNF-alpha, thereby inducing the observed crypt epithelial changes.^32,49

Feline FeLV-associated enteropathy