Flashcards in Patterns of Disease: Gastrointestinal Tract Deck (32):
NORMAL GI TRACT STRUCTURE AND FUNCTION
Mucosa, submucosa, associated glands, muscularis (inner circular, outer longitudinal layer), adventitia/serosa.
Myenteric and Meissner's (submucosal) plexus make up the enteric nervous system.
Peyer's patches- lymphoid tissue, undertake immune surveillance.
Mucosa is specialised in different ways depending on location in the tract.
-PROVIDE A SELECTIVELY PERMEABLE BARRIER- allowing water, nutrient and electrolyte absorption and excluding pathogens and toxins. Distinguishing harmful and harmless antigens.
-Provided by interactions between epithelial cells in mucosa, mesenchymal cells and leukocytes in lamina propria and enteric nervous system.
DEFENCE MECHANISMS AND MUCOSAL IMMUNITY
PHYSICAL BARRIER- epithelial tight junctions, rapid epithelial cell turnover (at villus tips), peristalsis, secreted products (mucins, defensins, lactoferrin*), pancreatic and biliary secretions (bacteriostatic)
COMMENSAL BACTERIA- modulate pH to provide an unfavourable environment for pathogens.
IgA/IgE ANTIBODY SECRETION- adaptive immunity. IgA protects mucosal surfaces.
*Mucins- bind and immobilise pathogens
Defensins- inactivate pathogens
Lactoferrin- iron sequestration.
M cells are found amongst the enterocytes that make up the mucosal lining of the gut.
They have no mucous covering, so are exposed directly to the GI tract.
They take up large molecules and present them to Peyer's Patches, allowing release of immune cells.
M cells are a good point of entry for pathogens.
EPITHELIUM- pattern recognition receptors- TLRs on apical membrane, NOD in cytosol. These recognise PAMPs, bind to pathogens and activate cell signalling pathways to release cytokines, chemokines etc.
MHC II expression at basolateral membrane.
MUCOSAL ASSOCIATED LYMPHOID TISSUE
1. Diffuse MALT- intraepithelial and lamina proprial compartments, CD8+ T cells predominate.
2. Peyer's patches- increase in density in distal small intestine. B cells (lymphocytes) predominate.
DENDRITIC CELLS- present antigen to lymphocytes within Peyer's patches and mesenteric lymph nodes, resulting in formation of an immune response
METHODS OF ENTRY IN TO GI TRACT
1. Pathogens bind to elements in MUCOUS LAYER eg. Brachyspira hyodysenteria
2. Bind to CILIA and alter enterocyte function eg. enterotoxigenic E. coli- toxin production; enteropathogenic E. coli- alter enterocyte structure and function.
3. Infect and thrive within MACROPHAGES eg. Mycobacterium avium sspp. pseudotuberculosis.
4. Enter via infection of DENDRITIC cells.
5. Enter via spread through TIGHT JUNCTIONS eg. Leptospira, feline calicivirus.
6. Enter via M CELL (no mucous coating) macropinocytosis eg. Salmonella.
7. Target MUCOSAL NEURONS and spread to CNS eg. Listeria monocytogenes.
MECHANISMS OF PATHOGEN INDUCED GI DISEASE
-NON INFLAMMATORY- pathogen-induced enterocyte hypersecretion eg. ETEC.
-Increased cellular turnover; immature enterocytes are less functional.
-INFLAMMATORY- pathogen induces inflammatory response, enterocytes are damaged as 'bystanders' eg. Salmonella.
-direct damage to enterocytes by bacterial toxins eg. Clostridium.
Functional/architectural changes can be present with little or no histological change- clinical signs can still be severe.
ACUTE GI DISEASE
1. Parvoviral enteritis of dogs and cats
2. Equine colitis
3. Malignant catarrhal fever
4. Mucosal disease.
PARVOVIRAL ENTERITIS OF DOGS AND CATS
Caused by two closely related viruses- Feline Panleukopaenia Virus (FPV) and Canine Parvovirus 2 (CPV2).
Mink Enteritis Virus is closely related as well.
These viruses replicate most efficiently in actively dividing cells.
Enteritis caused is similar in dogs and cats- infection of crypt epithelium destroys stem cells/proliferative compartment; replication decreases.
Produces 'radiomimetic' lesions- mimic effects of radiation, producing large, bizarre cells which take a long time to recover.
Gross lesions- segmental haemorrhagic enteritis (CLASSIC PRESENTATION), granular appearance of serosa +/- serosal petechiae, evidence of dehydration, evidence of Gram negative sepsis (often cause of death).
PARVOVIRUS- EXTRAINTESTINAL LESIONS
DOG- 3 syndromes:
1. Generalised disease (intestine, other organs)- seen in neonates.
2. Myocarditis and enteritis (rapid turnover causes systemic disease)
3. Enteritis- older animals.
CAT- Cerebellar hypoplasia, bone marrow suppression, lymphoid necrosis
Seen in USA, Canada.
Salmonellosis or Clostridiosis (or Neorickettsia- Potomac Horse Fever)
Risk factors are similar for both- asymptomatic carriage, stress or antibiotic treatment producing bacterial overgrowth and thus clinical disease.
Gross and histological lesions do not differentiate between causative bacteria.
GROSS- oedematous, thickened, green fibrinonecrotic/pseudomembranous adherent material.
S. TYPHIMURIUM is the most commonly isolated.
3 syndromes are associated with infection:
1. PERACUTE- septicaemic, affects animals 1-6 months old. Similar to Dublin necrosis in calves.
2. ACUTE- fibrinonecrotic typhlocolitis (affects caecum and colon)
3. CHRONIC- gross lesions highly variable.
Bacteria enter via enterocytes or M cells (specialised cells, can phagocytose large molecules).
Virulence factors include- flagella (motility), fimbriae (epithelial binding), LPS cell wall (resists degradation)
Infect and survive within macrophages, inhibiting phagolysosome fusion and stimulating neutrophil chemotaxis.
Diarrhoea is caused by- mucosal damage by neutrophils, secondary to inflammation; bacterially mediated chloride hypersecretion.
Bacterial culture- beware false positives (asymptomatic carrier) and negatives (post antibiotic treatment).
Salmonella have fastidious growth requirements- not seen on normal aerobic culture; request Salmonella culture from lab.
Compatible histopathology in post mortem cases.
CLOSTRIDIAL COLITIS- COLITIS X
Adult horses, associated with stress (movement) or antibiotic treatment.
C. perfringens A- adult, C. perfringens C- foal are most commonly associated.
Cause diffuse fibrinonecrotic or haemorrhagic and ulcerative typhlocolitis (adults).
Virulence factors- TOXINS (bacteria alone are apathogenic)- bacteria proliferate within the gut lumen and release endotoxin.
Diarrhoea caused by- direct damage to enterocytes with secondary neutrophil chemotaxis.
C. perfringens- B and B2 toxin- pore forming. B2 toxin has been induced in vitro by aminoglycoside treatment- do NOT treat with antibiotics.
C. difficile- A and B toxin, act to disrupt cytoskeleton.
Different types of C. produce different toxins.
CLOSTRIDIAL COLITIS- DIAGNOSIS
-Culture- clostridia can be normal gut commensals; asymptomatic carriage is normal. Positive culture is not significant.
-Toxin detection- IS significant, allows determination of type of Clostridia. Faecal samples are submitted to lab for ELISA.
POTOMAC HORSE FEVER
Neorickettsia risticii- obligate intracellular bacteria. Causes Equine Monocytic Ehrlichiosis aka. Potomac Horse Fever.
Highly geographically localised- river valleys in N.E USA.
Trematode intermediate host, passes to mayfly- accidental ingestion of mayfly by horse can result in infection of monocytes and disease:
Fibrinonecrotic to ulcerative colitis, abortion in pregnant mares, secondary sepsis/laminitis common, mortality up to 30% in untreated cases.
BOVINE VIRAL DIARRHOEA VIRUS
Pestivirus, 2 genotypes- BVDV type I (UK) and II (USA).
Non-cytopathic (NCP) and cytopathic (CP) biotypes can be seen within each genotype- assessed by effect on cell culture.
Recombination of non-structural protein NS2-3 results in biotype switch from NCP to CP.
-Non pregnant, immunocompetent animal- transient diarrhoea, leukopaenia, fever. Non-cytopathic.
-Type II disease- acute, fatal ulcerative disease in immunocompetent. Most often associated with genotype II. Indistinguishable from mucosal disease, but is seen in adults.
-Thrombocytopaenic syndrome- seen in calves, superimposed on to or separate from type II disease. Petechiae, bleeding at injection sites etc. seen due to natural infection with BVDV.
BOVINE VIRAL DIARRHOEA VIRUS contd.
IN UTERO infection with NCP biotype- outcome depends on stage of pregnancy:
< 4 MONTHS GESTATION- embryonic resorption, abortion or PERSISTENT INFECTION (of calf).
4-6 MONTHS GESTATION- congenital malformations of the eye, CNS- microphthalmia, cerebellar hypoplasia, hydrocephalus etc.
>6 MONTHS GESTATION- calf born alive, clinically normal but seropositive.
BVDV persistently infected (PI) animals are a sourve of infectious virus in a herd.
NCP to CP transformation in the animal causes acute, fatal MUCOSAL DISEASE betwen 6 months and 2 years of age.
BVDV is pancytotropic- it affects many cells- virus can be detected in a wide variety of tissues by immunohistochemistry.
Gross lesions are generally confined to the GI tract (oral cavity to anus), can be associated with Peyer's patches in the small intestine.
MUCOSAL DISEASE- DIAGNOSIS
Disease occurs in virus positive, seronegative animals with compatible gross and histological lesions.
Viral detection- immunohistochemistry- pancytotropic so submission of fixed skin sample is sufficient.
MALIGNANT CATARRHAL FEVER
Multisystemic disease, seen in a wide variety of animals; most commonly cattle (deer, bison, water buffalo, pigs also)
Gamma herpes virus- shed by asymptomatic carrier.
Ovine herpesvirus 2- sheep associated malignant catarrhal fever (MCF)
Caprine herpesvirus 2- goat associated MCF
Acelaphine herpesvirus 2- wildebeest associated MCF.
MALIGNANT CATARRHAL FEVER- PATHOGENESIS
Virus infects CD8+ (cytotoxic) and large granular T lymphocytes.
Lesions are associated with vasculitis in GI tract, kidney, eye, brain etc; and with lymphoproliferation (vessels filled with activated lymphocytes).
GROSS- wide lesion variation, potentially pansystemic.
-GI tract- oral cavity, forestomachs, less frequent in intestine and colon.
-Genitourinary tract- ulcerative cystitis, nephritis.
-Ophthalmitis and conjunctivitis, pneumonia, portal vasculitis in liver etc.
MALIGNANT CATARRHAL FEVER- DIAGNOSIS
Differentiation from mucosal disease can be difficult.
MCF is characterised by- lesions outwith the GI tract are often present (cf. only GI lesions in MD),
lymphoid hyperplasia IS present in MCF, NOT present in MD (lymphoid atrophy/necrosis)
CHRONIC GI DISEASE
1. Johne's Disease
2. Histiocytic ulcerative colitis of Boxer dogs.
Chronic enteritis of ruminants caused by Mycobacterium avium sspp PSEUDOTUBERCULOSIS.
Clinical signs- chronic ill-thrift, weight loss, watery diarrhoea.
GROSS- diffuse thickening of mucosa and submucosa, corresponds to a granulomatous enteritis.
Granulomatous lymphangitis and lymphadenitis.
JOHNE'S DISEASE- PATHOGENESIS
Infection occurs in the neonate- macropinocytosis in the immature gut facilitates infection.
Myobacteria are phagocytosed by macrophages.
Once inside macrophages, they inhibit phagolysosome function and persist.
Persistent macrophage stimulation incites CHRONIC GRANULOMATOUS RESPONSE.
Diarrhoea is caused by alteration in mucosal function by inflammatory process, and alteration of lymph flow in occluded lymphatics causing protein losing enteropathy.
JOHNE'S DISEASE- DIAGNOSIS
1.Detection of infectious agent- faecal culture (slow growing and fastidious)
-faecal or mucosal smear- acid fast stain. Low sensitivity.
-PCR- similar sensitivity to culture.
2. Serology- ELISA on milk or blood.
HISTIOCYTIC ULCERATIVE COLITIS
Predominantly a disease of Boxers (and Boston terriers), usually less than 2 years old. Rarely reported in non-Boxers.
Chronic large intestinal diarrhoea, haematochezia, with or without ill thrift.
Similar histologically to Johne's- large, foamy macrophages.
GROSS- Marked thickening of the colonic lamina propria and submucosa- corresponds to marked infiltration of foamy macrophages containing abundant Periodic acid-Schiff (PAS) positive granules. Raised, ulcerative nodules in mucosa.
Lesions are confined to submucosa, so often require a full thickness biopsy to investigate.
HISTIOCYTIC ULCERATIVE COLITIS- PATHOGENESIS
Mycoplasma and Chlamydia previously suspected.
PAS positive granules in macrophages identified as phagolysosomes, some containing bacteria.
INVASIVE E. COLI detected by FISH (Fluorescent In Situ Hybridisation).
Remission achieved with fluoroquinolone treatment, and correlated with eradication of E. coli in mucosa.
Macrophage dysfunction also suggested as a cause.
EQUINE GRASS SICKNESS
Acute, usually fatal idiopathic acquired dysautonomia (autonomic nervous system derangement).
Clinical signs are attributable to a derangement of the ANS, mostly manifested as GI obstruction- functional disturbance.
Acute, subacute and chronic presentations can be seen.
GROSS- lesions are often subtle to absent on PME. 'Mal de Seco'- dry disease- colonic contents is often very dry and adherent to colonic mucosa.
EQUINE GRASS SICKNESS- PATHOGENESIS
Ingested toxin is highly suspected- Clostridium botulinum?
Serum from affected horses will cause disease when give IV- serum toxin causes disease.
Degenerative changes detected in myenteric and submucosal plexus (neuronal necrosis) and cranial mesenteric and cranial cervical ganglia (non-GI associated ganglia- suggests toxin is not just in the GI tract; it is circulating).