Five-year-old male rhesus
macaque (Macaca mulatta).This animal was assigned to the
research project of alcohol, HIV infection &
host defense. Ethanol was administered via
the gastric catheter with 30% ethanol in
water (w/v) as a 0.5-hour prime, followed
immediately by a 4.5-hour maintenance
infusion. The concentration of ethanol in
blood was 50 to 60 mM. The animals
received ethanol four consecutive days per
week for the duration of the study. Three
months after ethanol administration, this
animal was intravenously inoculated with
simian immunodeficiency virus (SIV) 251
about one year before sacrifice. Streptococcus
pneumoniae was inoculated in
right lung seven months before sacrifice.
Six months after SIV inoculation, this animal began to show chronic, mild leukocytosis, mild neutrophilia, and moderate thrombocytopenia. The animal developed weight loss, loss of muscle mass, enlargement and restriction of stifles, enlarged lymphoid tissue, and mild splenomegaly and hepatomegaly.
Presented was a severely
thin animal with no body fat. A catheter tube
was inserted on the left dorsal-lateral back,
tunneled through subcutaneous, and ended at
the left side of stomach. The spleen was
markedly enlarged with prominent white
pulp. All peripheral lymph nodes were four
to six times enlarged. This animal had mild
to moderate thymic and muscular atrophy.
Multifocally the small and medium-sized
arteries are expanded and variably disrupted
by proliferation of the tunica intima, smooth
muscular hyperplasia, and infiltration of
inflammatory cells. The lumina of affected
arteries are partially to completely occluded
and lined by hypertrophic endothelial cells.
Usually, the tunica media are segmentally to
circumferentially thickened by smooth
muscle hyperplasia, fragmented collagen
bundles, and reactive fibroblasts. The tunica
adventitia is markedly expanded by numerous
neutrophils, lymphocytes, plasma
cells, and fewer macrophages and
eosinophils. Some subendothelial tunica
intima and tunica media are disrupted and
markedly expanded by thick bands of deeply
eosinophilic hyaline to fibrinoid material
admixed with cellular and karyorrhectic
debris and many erythrocytes (necrosis and
hemorrhage). Multifocally the renal tubules
are ectatic, lined by attenuated epithelial
cells, and contain hypereosinophilic homogenous
material (protein casts) and cellular
debris. Multifocally the interstitium is
infiltrated by many lymphocytes and plasma
cells. Occasionally the interstitium is expanded
by lymphoid aggregates (lymphoid
hyperplasia and dysplasia). Some
glomerular tufts are senescent and shrunken
with ectatic Bowmans spaces.
Kidney, medium and small arteries:
Arteritis, proliferative and necrotizing,
2. Kidney, lymphoplasmacytic interstitial
nephritis, multifocal, mild.
3. Kidney, interstitial lymphoid hyperplasia
Polyarteritis nodosa-like syndrome/SIV
also noted in the small to medium arteries of
the mesentery, testis, liver, gall bladder,
pancreas, urinary bladder, and bone marrow.
The systemic vascular lesions in this
monkey resemble those found in polyarteritis
nodosa (PAN)-like syndrome in
HIV patients. PAN-like syndrome has been
described in HIV patients in the literature.6,7
While target organs are usually muscles,
nerves, skin and gastrointestinal tract, renal
polyarteritis nodosa in HIV patients has also
been reported.2 PAN-like syndrome occurs
in fewer than 1% of HIV patients. The
underlying mechanism is thought to involve
cell or immune-complex-mediated inflammation,
like classic PAN in other
species. Although the histopathological
changes are similar between two entities,
there are several important differences
between PAN in HIV patients and so-called
classic or idiopathic PAN. First, the waxing
and waning clinical course of classic PAN is
not seen in patients with HIV infection.
Second, classic PAN can be associated with
hepatitis B virus infections, but in HIV
patients, the serology for HBV is always
negative. Third, the affected arteries in HIVassociated
PAN tend to be smaller than that
seen in classic PAN.4
PAN-like syndrome has been reported in
two SIV-infected rhesus macaques.11
Vasculopathy is prominent in kidney,
intestine, pancreas, liver, heart, lymph
nodes, spleen, and testis. Histologically, disseminated
arteriopathy is characterized by
intimal thickening and fibrosis with varying
degrees of vasculitis. Intranuclear inclusion
bodies were CMV positive by immunohistochemistry
in multiple organs in these
two monkeys. Intranuclear inclusion bodies
were not observed in the current case but
immunohistochemistry for CMV or other
viral agents was not performed in the current
case. Pulmonary arteriopathy is the
most common vasculopathy in
macaques infected with SIV.
Nineteen of 85 animals infected
with SIV developed pulmonary
arteriopathy characterized by
intimal thickening, luminal
occlusion, and internal elastic
laminae fragmentation and
hyperplasia and/or plexiform
arteriopathy were present in eight
of 13 (62%) SHIV-infected
macaques.5 However, the
pulmonary arteries were histopathologically
normal in the
current case. This observation is
consistent with the two published
cases, in which, arteriopathy was
mild or absent in the lungs.11
These observations suggested a
arteriopathy and PANlike
syndrome in SIV
Based on extensive experience on this model, it is unlikely that ethanol administration was associated with PAN-like syndrome in this monkey. There is no documentation of alcohol and arteriopathy in the literature. Although this animal was inoculated with Streptococcus pnenumonae, grossly and microscopically there was no current evidence of Streptococcus infection. Renal interstitial lymphoid hyperplasia and dysplasia are not uncommon findings in SIV-infected monkeys.
1. Kidney, small arteries
and arterioles: Arteriopathy, proliferative
and necrotizing, multifocal, mild to marked,
with adventitial inflammation, rhesus
macaque (Macaca mulatta).
2. Kidney: Interstitial nephritis, lymphoplasmacytic,
specific etiology and pathogenesis of this
lesion are unclear, the contributor provides
an excellent example of a polyarteritis
nodosa (PAN)-like syndrome in a nonhuman
primate. PAN-like syndromes are
thought to be a type III hypersensitivity
reaction secondary to antigen:antibody
complex deposition in medium to small
caliber arteries.1 Immune complex
deposition results in complement activation
leading to segmental, circumferential, and
proliferative arteritis. This syndrome has
been well described in the aged SpragueDawley
rat and beagles.9,10 In rats, lesions
most often occur in the muscular mediumsized
arteries of the mesentery, pancreas,
testis, hepatic, coronary, uterine, cerebral,
adrenal, and renal arteries.
10 This condition
in beagles is associated with beagle pain
syndrome. In these cases, the coronary and
meningeal arteries are most affected, and
clinically dogs are febrile, lose weight, and
have cervical pain.9 Typically in domestic
species, PAN-like syndrome spares the
pulmonary circulation, large arteries and
11 The association of SIV as part
of the pathogenesis of the arteriole lesions,
in this case, remains unclear.
The JPC strives to avoid using the suffix - opathy in a morphologic diagnosis due to its non-specific nature; however, in rare instances, this terminology may be appropriate, especially in cases where the primary process underlying the lesion is difficult to ascertain. While the SIV-positive status of this particular animal suggests a causal relationship, PAN has also been seen as a spontaneous finding in macaques, as well as a toxic lesion association with administration of cyclosporine and tacrolimus (WSC 2003-2004, Conference 20, Case 1). The term arteriopathy can be modified by other descriptors such as proliferative and necrotizing to further define the underlying process. Much of the literature on this disease uses the term arteriopathy to describe this finding in arteries and arterioles in SIV-infected rhesus macaques.
During a discussion of the vessel wall changes in this case, some conference participants preferred the term hyaline change to describe the circumferential homogenous, eosinophilic, proteinaceous material deposited within the external elastic membrane of arterioles rather than the wellensconced term fibrinoid necrosis. Fibrinoid necrosis has been classically used by both human and veterinary pathologists to describe the brightly eosinophilic changes in the injured vessel associated with immune complex, plasma protein, and complement protein deposition within vessels.1 Fibrinoid necrosis implies a pathogenesis that may or may not be present. The brightly eosinophilic homogenous protein accumulation obscures the structural detail of the blood vessel, thus making it difficult or impossible to determine if there is fibrin or necrosis present within the arteriole wall. Hyalinosis describes the accumulation of leaked eosinophilic proteinaceous material secondary to endothelial damage and increased vascular permeability without making assumptions about the pathogenesis.
Finally, several participants found multinucleated giant cells within the tubular epithelium and lumina of collecting ducts within their sections. Multinucleated giant cells have been described as a common incidental finding in macaques8 ; however, a number of participants ascribed them as a potential corroborating sign of lentivirus infection in this macaque.
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