AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2017

N-V08

 

Signalment (JPC#1690060): Chicken

 

HISTORY: This chicken developed flaccid paralysis of the legs and wings.

 

HISTOPATHOLOGIC DESCRIPTION: Peripheral nerves, longitudinal and cross sections: Multifocally separating and surrounding individual nerve fibers and small caliber vessels within the nerve are moderate numbers of lymphocytes with fewer plasma cells and macrophages. There are scattered aggregates of lymphocytes within the surrounding adipose tissue.

 

MORPHOLOGIC DIAGNOSIS: Peripheral nerves: Neuritis, lymphocytic, multifocal, minimal, chicken, breed not specified, avian

 

ETIOLOGIC DIAGNOSIS: Alphaherpesviral neuritis

 

CAUSE: Gallid herpesvirus 2

 

CONDITION: Marek's disease

 

CONDITION SYNONYMS: Fowl or range paralysis; polyneuritis; neurolymphomatosis; transient paralysis

 

GENERAL DISCUSSION

·     Marek's disease (MD) is a herpesvirus induced lymphoproliferative disease characterized by infiltration of nerves and other organs with pleomorphic lymphocytes, and is the most common lymphoproliferative disease of chickens worldwide

·       May be associated with development of atherosclerosis in young chickens

·       Incubation period and disease manifestation are dependent upon virus strain, dosage, route of infection, age, genetic strain, and sex of host

·       Formerly a gamma herpesvirus; however, genome architecture most closely resembles alpha herpesvirus (Genus Mardivirus)

·       Three serotypes:  1 (Gallid herpesvirus) , 2, 3 (2 and 3 are nononcogenic)

·       Serotype 1 is further divided into pathotypes: Mild (mMDV), virulent (vMDV), very virulent (vvMDV), or very virulent + (vv+MDV)

·       The pathogenesis of MD can be divided into 4 well characterized phases: (1) acute cytolytic infection; (2) latency phase; (3) secondary cytolytic phase, and (4) lymphoproliferative disease

 

PATHOGENESIS:

·     Four phases of infection (several phases may coexist in different cells in the same bird):

1.       Early productive-restrictive infection (cell to cell by contact only): Inhalation of feather dander containing cell-free virus (feather dander highly infectious) > respiratory epithelial cell infection and local macrophage infection > cell-associated viremia (spreads to lymphoid organs within 24-36 hrs) > cytolytic lymphoid cell infection (B-cells and activated T-cells) within thymus, bursa of Fabricius, bone marrow, and spleen > immunosuppression (transient or permanent)

2.       Latent infection:  Development in T-cells (primarily activated CD4+) 6-7 days post-infection coincides with development of cell-mediated immune response; may also occur in B-cells and CD8+ T-cells

3.       Feather follicle shedding / cytolytic infection in FFE (14 days PI):

1.   Feather follicle epithelium (FFE): The only site of complete virus replication; infected lymphocytes carry and transfer virus to FFE > viral replication > cell-free virus shed in dander and feather debris

2.   Lymphoid and visceral organs (epithelium of kidney, pancreas, liver, adrenal gland, proventriculus, etc.):  Development and extent of infection depends on host genetic resistance and strain virulence

4.       Proliferative phase (development of lymphomas): Persistent cell-associated viremia two weeks post-infection > proliferation (and possibly transformation) of lymphoblastoid T-cells (mainly CD4+) that may progress to lymphoma > regression or death after 3 weeks post-infection

·     Proposed that T-cells become susceptible to infection and undergo neoplastic transformation once activated during the initial immune response to viral antigen

·     Important MD-specific genes: Meq (transformation, one of the most important determinants of oncogenicity), pp38/pp24 (virus replication), v-IL8 (homologue of avian IL8 that attracts T-cells), important for switching infection from B to T-cells, deletion results in reduced incidence of tumors

·     Transformed MD-infected T-cells often overexpress an activated T-cell surface marker, MD tumor-associated surface antigen (MATSA) and a TNFR-II family antigen, AV37 (CD30 - Hodgkin's disease antigen)

 

TYPICAL CLINICAL AND GROSS FINDINGS: 

·     Most frequently occurs between 12 and 24 weeks of age; usually no earlier than 3-4 weeks of age

·     *Four overlapping clinical lymphoproliferative disease syndromes:

1.     Neurolymphomatosis (Classical Marek’s disease; fowl or range paralysis; polyneuritis):

·     Enlargement and/or yellowing with loss of cross striations of peripheral nerves; often unilateral

·     Lymphoma may also be present with this syndrome, most commonly in ovary, but also may be present in muscle, lungs, kidney, heart, and liver

·     Mortality rarely exceeds 10-15% and occurs over a few weeks or several months

·     Clinical signs depend on the affected peripheral nerves:  Asymmetric spastic paralysis of one or both wings or legs leading to straddle-leg paralysis (brachial and sciatic); torticollis (cervical); dilation of crop and respiratory signs (vagus and intercostal)

2.     Acute Marek’s disease:

·     Diffuse lymphomatous involvement and enlargement with visceral tumors of the liver ("big liver disease;” moderate in young birds, more severe in adults), gonads, spleen, lungs, kidneys, proventriculus, heart and other organs / tissues

·     Feather follicle and skeletal muscle lymphomas

·     Higher mortality rates ranging from 10-30% and occasionally up to 80%

·     Acute death without previous symptoms, death following depression, or paralysis similar to the classical disease

3.     Ocular lymphomatosis:

·     Discoloration of the iris

·     Unilateral or bilateral lymphoblastoid infiltration of iris causing a gray appearance with loss of pigmentation ("gray eye")

·     Irregular and eccentric pupils; partial or total blindness

4.     Cutaneous Marek’s disease:

·     Enlargement of feather follicles and reddening of the skin

·     Most common in broilers; most important cause of carcass condemnation

·     Round, up to 1 cm diameter, multifocal to coalescing nodular lesions involving feather follicles

·    Skin on legs may be erythematous ("Alabama redleg")

·     Other nonlymphoproliferative syndromes:

·     Lymphodegenerative disease with severe atrophy of thymus and bursa of Fabricius (transient, acute cytolytic changes in those organs)

·     Transient paralysis:  Due to vasogenic brain edema (vasculitis > vascular leakage of IgG and albumin > vacuolization of neuropil > edema)

·     Classic form:  Short duration ataxia and flaccid paralysis of neck or limbs with rapid and complete recovery

·     Acute form:  Flaccid paralysis rapidly progresses to death

·     Occlusive atherosclerosis:  Rare; occurs in large coronary arteries, aorta, major aortic branches, and other arteries

·     T lymphoblast leukemia occasionally reported

 

 

TYPICAL MICROSCOPIC FINDINGS: 

·     Peripheral nerves:  Lesions are termed Type A (proliferative/neoplastic with pleomorphic lymphoblastic cells), Type B (inflammatory, small lymphocytes and plasma cells), and Type C (chronic, minor lesions, few small lymphocytes); demyelination occurs in Type A and B lesions leading to paralysis

·     Brain:  Type B lesions most common; perivascular cuffs, or nodules of lymphocytes, vasculitis and endothelial hypertrophy; edema prominent in the white matter, Purkinje cell layer, and granular cell layer of the cerebellum

·     Spinal cord:  focal accumulations and regional infiltrates of lymphocytes with root ganglia intensely infiltrated, producing a disease primarily of peripheral nerves

·     Eye:  mononuclear infiltration of the iris is the most constant ocular change

·     Viscera:  lymphomatous visceral lesions have a cellular composition like type A nerve lesions; lymphoid tumors are most common and consist of a mixture of pleomorphic lymphocytes including malignantly transformed T-cells, reactive B-cells, T-cells, and macrophages

·     Skin:  Lesions are mostly inflammatory (primarily small lymphocytes and plasma cells), but may be lymphomatous (lymphocytes, lymphoblasts, and reticulum cells), and are localized around feather follicles

·     Compact, often perivascular, dermal aggregates of proliferating cells, scattered histiocytes and plasma cells may occur

·     Large lesions may be ulcerated

·     Eosinophilic intranuclear inclusion bodies may occur within feather follicle epithelium

·       Bursa and thymus:  Productive replication results in degeneration and atrophy

·       Necrotizing lesions reported in one week old chickens in bursa, intestine, lung and proventriculus (one report)

 

ULTRASTRUCTURAL FINDINGS:

·       Virions in nucleus, enveloped, 273-400nm in diameter

 

ADDITIONAL DIAGNOSTIC TESTS:

·       Virus isolation and serological procedures of immunodiffusion, fluorescent  antibody and viral neutralization have been used to confirm the diagnosis

·       PCR assay

·       Immunohistochemistry using antibodies against virus antigens pp38, gB, and Meq

 

DIFFERENTIAL DIAGNOSIS: 

Other causes of lymphoproliferative disease in chickens:

·     Lymphoid leukosis (avian leukosis):  May occur concurrently with Marek’s disease in the same flock and even in the same bird

 

 

FEATURES

 

LYMPHOID LEUKOSIS

 

MAREK'S DISEASE

 

Etiology

 

Type C  Retrovirus

 

Alphaherpesvirus

 

Age

 

> 16 weeks

 

> 4 weeks (usually 2-5 months)

 

Paralysis

 

Absent

 

Present

 

Bursa of Fabricius

 

Nodular tumor

 

Diffuse enlargement, or  atrophy (or no lesions)

 

Skin or Muscle Involvement

 

Absent

 

May be present

 

Peripheral Nerve Infiltration

 

Absent

 

Present

 

Bursal Proliferation

 

Intrafollicular

 

Interfollicular

 

Lymphoid Cells

 

Uniform blasts

 

Pleomorphic

 

Tumor Cell Type

 

Predominantly B-cells

 

Predominantly T-cells

 

Tumor Cell

 

> 90% IgM+

 

< 5% IgM+

 

MATSA (on tumor cells)

 

Absent

 

Present (5-40%)

Note:  MATSA (Marek's disease tumor-associated surface antigen) was once thought to be tumor specific but is now considered to be a host antigen (present on activated T-cells).

 

·     Reticuloendotheliosis virus (REV-retrovirus):  Cause of non-neoplastic runting syndrome (bursal and thymic atrophy), acute neoplastic disease resulting in T-cell lymphomas (resembles Marek’s disease) and chronic neoplastic disease resulting in B-cell lymphomas (resembles lymphoid leukosis),  in chickens, turkeys, ducks, quail, and geese after either experimental infection or accidental infection from contaminated vaccines

 

COMPARATIVE PATHOLOGY:

Oncogenic Viruses:

 

SPECIES

NEOPLASM

DNA Viruses

 

 

Adenoviridae

 

 

Various Strains

Hamster

Experimental Sarcomas

Hepadnaviridae

 

 

Hepatitis B Virus

(Orthohepadnavirus)

Human

Hepatocellular Carcinoma

Woodchuck Hepatitis Virus

(Orthohepadnavirus)

Woodchuck

Hepatocellular Carcinoma

Duck Hepatitis Virus

(Avihepadnavirus)

Duck

Hepatocellular Carcinoma

Herpesviridae

 

 

Marek's Disease Virus

(Alphaherpesvirus)

Chicken

Lymphoma

Epstein-Barr Virus (EBV)

(Gammaherpesvirus)

Human

Burkitt's Lymphoma, Nasopharyngeal Carcinoma

Macacine herpesvirus 4; Ateline herpesvirus 2,3; Saimirine herpesvirus 2

Callitrichine herpesvirus 3

(Gammaherpesviruses)

Nonhuman Primates

Lymphoma

Herpes sylvilagus

(Gammaherpesvirus)

Rabbit

Lymphoma

Ranid Herpesvirus

(Unclassified)

Leopard Frog

Renal Adenocarcinoma

Papovaviridae

 

 

Polyomaviruses

Mouse & Hamster

Experimental Carcinomas and Sarcomas; trichoepithelioma (hamster)

Simian Virus 40 (SV40)

Rodents

Experimental Sarcomas

Papillomaviruses

Many Species (including humans)

Papillomas, Carcinomas

Poxviridae

 

 

Yaba Virus (Yatapoxvirus)

Rhesus Macaque

Histiocytoma

Shope Fibroma Virus (Leporipoxvirus)

Rabbit

Fibroma, Myxoma

RNA Viruses

 

 

Flaviviridae

 

 

Hepatitis C Virus

Human

Hepatocellular Carcinoma

Retroviridae

 

 

Type B

 

 

Mammary Tumor Virus

Mouse

Mammary Adenocarcinoma

Mammalian Type C

 

 

Murine Leukemia & Sarcoma Viruses

Mouse

Leukemia, Lymphoma, & Sarcoma

Feline Leukemia & Sarcoma Viruses

Cat

Leukemia, Lymphoma, & Sarcoma

Avian Type C

 

 

Avian Leukosis Virus

Chicken

Lymphoma

Reticuloendotheliosis Virus

Chicken

Lymphoma

Lymphoproliferative Disease Virus (LPDV)

Turkey

Lymphoma

Type D

 

 

Jaagsiekte Retrovirus (JSRV)

Sheep

Pulmonary Carcinoma

Ovine and Caprine Nasal Adenocarcinoma Retrovirus

Sheep and Goats

Nasal Adenocarcinoma

Type E (?)

 

 

Bovine Leukemia Virus (BLV)

Cattle

Lymphoma and Leukemia

Human T-Lymphotropic Virus Type 1 (HTLV-1)

Human

T-Cell Leukemia and Lymphoma

Simian T-Lymphotropic Virus (STLV)

Nonhuman Primates

T-Cell Leukemia and Lymphoma

 

References:

1.    Ajithdoss AD, Reddy SM, and Lupiani B. The DNA binding domain of Meq, a Marek’s disease virus oncoprotein plays a major role in the transformation ability of the virus [abstract]. Vet Pathol. 2011;48(E1):192.

2.    Barthold SW, Griffey SM, Percy DH. Hamster. In: Barthold SW, Griffey SM, Percy DH, eds. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley and Sons Inc.; 2016:176-178.

3.    Barthold SW, Griffey SM, Percy DH. Mouse. In: Barthold SW, Griffey SM, Percy DH, eds. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley and Sons Inc.; 2016:39-44.

4.    Barthold SW, Griffey SM, Percy DH. Rabbit. In: Barthold SW, Griffey SM, Percy DH, eds. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley and Sons Inc.; 2016:262-264.

5.    Boulianne M, et al.  Avian Disease Manual.  7th ed.  Jacksonville, FL: AAAP;2013:30-34.

6.    Bhaskaran M and Mohan M. MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. Vet Pathol. 2013;50(5):1-17.

7.    Burgess SC, Basaran BH, Davison TF. Resistance to Marek's disease herpesvirus-induced lymphoma is multiphasic and dependent on host genotype. Vet Pathol. 2001;38:129-142. 

8.    Carvallo FR, French RA, Gilbert-Marcheterre, et al. Mortality of one-week-old chickens during naturally occurring Marek’s disease virus infection. Vet Pathol. 2011;48(5):993-998.

9.    MacLachlan NJ, Dubovi EJ. Fenner’s Veterinary Virology. 4th ed. San Diego, CA: Academic Press; 2011:192-193.

10. Nair V.  Latency and tumorigenesis in Marek’s Disease. Avian Dis. 2013;57(2s1):360-365.

11. Nair V, Jones RC, Gough RE. Herpesviridae. In: Pattison M, McMullin PF, Bradbury JM, Alexander DJ, eds. Poultry Diseases. 6th ed. Philadelphia, PA: Saunders Elsevier; 2008:258-267.

12. Schat KA, Nair V.  Marek’s disease. In: Swayne DE, et al, eds. Diseases of poultry. 13th ed. Ames, IA: Iowa State University Press; 2013: 515-552.

13. Seimon TA, McAloose D, Raphael B, Honkavuori KS, Chang, Hirschberg DL, and Lipkin WI.  A novel Herpesvirus in 3 species of pheasants: Mountain peacock pheasant (Polyplectron inopinatum), Malayan peacock pheasant (Polyplectron malacense), and Congo peafowl (Afropavo congensis). Vet Pathol.  2012; 49(3):482-491.

14. Watchman L, Mansfield, K.  Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, et al., eds. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed, Vol 2. San Diego, CA: Academic Press; 2012:7-26.

 

 

 


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