Discrimination of Classical and Atypical BSE by a Distinct Immunohistochemical PrPSc Profile
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Statement
2.2. Intracerebral BSE Challenge
2.3. Oral Animal BSE Challenge (FLI)
2.4. Tissue Selection
2.5. Histopathological and Immunohistochemical Analysis
2.5.1. Histopathology/Lesion Profile
2.5.2. Immunohistochemistry/PrPSc-Profile
3. Results
3.1. Lesion Profile
3.2. PrPSc-Profile/General Remarks
- The most characteristic pattern of C-type BSE is the higher variability of staining reactions as compared to atypical BSE cases. In several brain regions C-type animals showed a STEL reaction pattern which is only rarely seen in H-type cases and is absent in L-types. Additionally, C-type animals frequently show, mostly associated with high PrPSc levels, a coarse PART PrPSc deposition often accompanied by distinct LIN staining reactions and occasionally even PL pattern.
- Cattle infected orally with C-type BSE show little difference in the PrPSc profile as compared to intracerebrally inoculated animals. This particularly concerns the PART staining reactions which, in some regions (hypoglossal nucleus, molecular layer of cerebellum, septal area), also show a coarse deposition in intracerebrally infected animals, whereas in orally infected animals only fine PART distributions are seen. Additionally, in the hilus of hippocampus and white matter of frontal cortex, a STEL pattern was only visible in intracerebrally inoculated animals.
- Animals infected with L-type BSE show a fine and equally distributed PART PrPSc accumulation in several regions which always, even in advanced cases, i.e., in moderately to severely affected animals, has a regular appearance. LIN staining reactions are frequently seen, but not as distinct or typical as in C-type BSE cases. In contrast, PL are rarely seen and confined to certain regions (external grey matter and white matter of cerebrum).
- The most typical pattern of H-type animals is an extensive ITMG staining reaction most often in combination with a fine PART neuropil accumulation of PrPSc, which allows the reader to recognize this pattern even in low magnification. LIN staining reactions are rarely seen, but PL patterns are common, often in the form of very small plaque-like accumulation.
3.3. Hypoglossal Nucleus
3.4. Cerebellum
- In the molecular layer (Figure 1B1–B4), the most characteristic feature in C-type infected animals was the variability in the reaction patterns. A distinct STEL staining was detected in combination with an ITMG deposition, a fine to coarse multifocal PART, and a randomly distributed LIN staining reaction. In contrast, a STEL reaction pattern was not seen in L-type animals. Instead, the characteristic pattern included a fine homogenous PART reaction pattern plus some fine LIN staining. With one exception (see below), H-type animals revealed a mild ITMG reaction pattern close to the granular layer and mostly combined with randomly distributed fine, rarely coarse, PART accumulations.
- In the granular layer, the most obvious difference was the PNER reaction pattern in L-type infected animals, in which an ITNR PrPSc deposition was rarely seen. This is quite the opposite to C-type BSE, which induced a distinct ITNR, but never a PNER staining reaction. In H-type cases, both variants were seen. In all BSE cases, granular cells showed intracellular PrPSc accumulation, which was most distinct in H-type cases. Only C-type-affected animals displayed a widespread net-like staining reaction following the dendrites of the granular cells and resembling a STEL reaction pattern. L-type BSE induced a fine, homogeneously distributed PART PrPSc accumulation that involved almost the entire layer in advanced cases, whereas C- and H-type animals showed fine to coarse PART depositions that were randomly distributed. Additionally, PL patterns were seen in C- and H-types only but were most prominent in C-types.
- In atypical BSE cases, an ITMG staining reaction was widely distributed in the white matter of the cerebellum and involved in moderate to severe cases almost all glial cells. This is in clear contrast to C-type BSE, in which this region is never more than mildly affected. More distinctly, a PNER staining reaction was only seen in L-type cases.
- In cerebellar nuclei and adjacent white matter (Figure 2A1–A4), a high variability of staining reactions was seen with C- and L-type BSE. In contrast, H-type BSE revealed a prominent ITMG PrPSc deposition in combination with a fine PART PrPSc background.
3.5. Red Nucleus
3.6. Hippocampus
3.7. Septal Area
3.8. Frontal Cortex
- A PrPSc “tape-like pattern” in the most external parts of the molecular layer, most likely associated with horizontal projections of Cajal cells, was characteristic of C- and H-type BSE infected animals. This “tape” consisted of fine to coarse PART, as well as ITMG deposits. In contrast, in L-type BSE a mostly fine PART staining reaction in combination with a ITMG accumulation was homogeneously covering all parts of the layer. An ITNR staining reaction was seen with all types, but it was seen in L-type BSE to a higher degree, even in very mild cases. A STEL reaction pattern was clearly seen with C-type infected animals. A characteristic for H-type BSE was the detection of very small but prominent and homogeneously distributed PL staining reactions. In C- and L-types this reaction pattern was seen to a much lesser degree and was confined to single locations. In Figure 4A1–A4 representative cases from each BSE type are presented.
4. Discussion
5. Conclusions
- C-type BSE showed the most variable PrPSc profile with a distinct tendency for a stellate pattern, which is particularly obvious in the multifocal distribution pattern found in the cerebellar cortex. In addition, hypoglossal nucleus revealed clear intraneuronal PrPSc accumulation, the central parts of the hippocampal hilus were massively affected even with unique plaque-like formations, and in the molecular layer of the cerebrum, PrPSc accumulations seemed to be associated with Cajal horizontal cells, forming a tape-like pattern.
- H-type BSE showed a characteristic strong intramicroglial PrPSc accumulation pattern throughout the brain, which is mostly associated with a fine particular staining reaction of the neuropil. In the hypoglossal nucleus an intraneuronal staining reaction was obvious, while in the hilus of the hippocampus, PrPSc accumulation was mostly confined to peripheral neuronal cells. Moreover, in the molecular layer of cerebrum, a PrPSc tape-like pattern is evident.
- L-type BSE revealed a mostly fine particulate and diffuse PrPSc accumulation in the neuropil in the molecular layers of the cerebellum and cerebrum. In the cerebrum, large plaque-like formations were frequently found, and in the granular layer of cerebellum, a unique perineuronal staining reaction was visible, while an intraneuronal PrPSc deposition in hypoglossal nucleus was missing.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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BSE | Animal ID | Incubation Time (mpi) | Lesions (H&E) | Obex/PrPSc Deposition | Age at Inoculation | Inoculation | Site of Inoculation |
---|---|---|---|---|---|---|---|
C-type (CFIA) | 25015 | 26 | ++ | +++ | 2–3 months | 1 mL of a 10% brain homogenate | Midbrain |
25022 | 27 | ++ | +++ | ||||
25023 | 27 | ++ | +++ | ||||
25032 | 26 | + | +++ | ||||
25034 | 24 | ++ | +++ | ||||
29024 | 20 | + | ++ | 5–6 months | 1 mL of a 10% brain homogenate | Midbrain | |
29026 | 18 | (+) | ++ | ||||
H-type (CFIA) | 29018 | 18 | + | ++ | |||
29033 | 17 | + | ++ | ||||
L-type (CFIA) | 29012 | 18 | ++ | ++ | |||
29030 | 17 | ++ | + | ||||
H-type (FLI) | RA10 | 12 | (+) | + | 6 months | 1 mL of a 10% brain homogenate | Rostral midbrain |
RA13 | 15 | ++ | +++ | ||||
RA14 | 14 | + | ++ | ||||
RA15 | 16 | + | +++ | ||||
RA16 | 16 | ++ | +++ | ||||
L-type (FLI) | RA02 | 17 | +++ | +++ | 6 months | 1 mL of a 10% brain homogenate | Rostral midbrain |
RA03 | 16 | ++ | ++ | ||||
RA04 | 16 | +++ | +++ | ||||
RA05 | 11 | (+) | (+) | ||||
RA06 | 14 | ++ | + | ||||
C-type (FLI-oral) | IT18 | 50 | +++ | +++ | 4–6 months | 100 g BSE brainstem homogenate | Oral |
IT23 | 36 | ++ | +++ | ||||
IT49 | 36 | +++ | +++ |
Brain Area | Brain Regions Examined |
---|---|
Brain stem (Obex) | Hypoglossal Nc. (1), DMNV (2), Nc. of the solitary tract (3), Nc. of the spinal tract of the trigeminal nerve (4), Reticular formation (5) |
Cerebellum | Molecular layer (6), Granular layer (7), White matter (8), Deep cerebellar Ncc. (9) |
Mid brain | Red Nc. (10) |
Hippocampus | Hilus (11), Str. oriens (12), Str. pyramidale (13), Str. radiatum (14) |
Frontal Cortex | Molecular layer (15a), External layer (15b), Internal layer (15c), White matter (16) |
Telencephalon | Septal area (17) |
Brain Region | Profile | C-Type BSE | H-Type BSE | L-Type BSE |
---|---|---|---|---|
Brainstem/Hypoglossal Nucleus | ITNR | X | X | -- |
ITMG | X | XX | (x) | |
PART | Fine to coarse | Fine | Fine | |
STEL | X | -- | -- | |
LIN | X | (x) | -- | |
Cerebellum/Molecular Layer | ITMG | X | XX | X |
PART | Fine to coarse | Fine | Fine | |
STEL | X | (x) | -- | |
LIN | (x) | (x) | X | |
Remarks | Multifocal | Multifocal | Diffuse | |
Cerebellum/Granular Layer | PNER | -- | -- | X |
STEL | X | -- | -- | |
Remarks | Multifocal | Multifocal | Diffuse | |
Cerebellum/White Matter | ITMG | X | XX * | X |
PART | Fine | Fine | Fine | |
Remarks | Weakly affected | Distinctly involved | Distinctly involved | |
Midbrain/Red Nucleus | ITNR | X | X | X |
ITMG | X | XX | X | |
PART | Coarse | Fine | Fine | |
LIN | X | (x) | (x) | |
Hippocampus/Hilus | ITNR | X | X | X |
ITMG | X | XX | X | |
PART | Mostly coarse | Fine | Fine | |
STEL | X | -- | -- | |
PL | X | -- | -- | |
Remarks | Central parts | Peripheral parts | Peripheral parts | |
Hippocampus/in general | PrPSc | Str. radiatum and preference for Hilus | Str. radiatum and preference for Str. pyramidale | Str. radiatum and preference for Str. pyramidale |
Septal area | ITNR | X | X | X |
ITMG | X | XX | X | |
PART | Fine to coarse | Fine | Fine | |
STEL | X | -- | -- | |
Cerebrum/Molecular Layer | ITNR | (x) | (x) | X |
ITMG | X | XX | X | |
PART | Fine to coarse | Fine to coarse | Fine to coarse | |
STEL | X | (x) | (x) | |
Remarks | PrPSc tape-like | PrPSc tape-like | -- | |
Cerebrum/White Matter | ITMG | (x) | XX * | (x) |
PART | Fine to coarse | Fine | Fine to coarse | |
STEL | X | -- | -- | |
PL | Small | Small | Frequent and large |
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Fast, C.; Graham, C.; Kaatz, M.; Santiago-Mateo, K.; Kaatz, T.; MacPherson, K.; Balkema-Buschmann, A.; Ziegler, U.; Groschup, M.H.; Czub, S. Discrimination of Classical and Atypical BSE by a Distinct Immunohistochemical PrPSc Profile. Pathogens 2023, 12, 353. https://doi.org/10.3390/pathogens12020353
Fast C, Graham C, Kaatz M, Santiago-Mateo K, Kaatz T, MacPherson K, Balkema-Buschmann A, Ziegler U, Groschup MH, Czub S. Discrimination of Classical and Atypical BSE by a Distinct Immunohistochemical PrPSc Profile. Pathogens. 2023; 12(2):353. https://doi.org/10.3390/pathogens12020353
Chicago/Turabian StyleFast, Christine, Catherine Graham, Martin Kaatz, Kristina Santiago-Mateo, Tammy Kaatz, Kendra MacPherson, Anne Balkema-Buschmann, Ute Ziegler, Martin H. Groschup, and Stefanie Czub. 2023. "Discrimination of Classical and Atypical BSE by a Distinct Immunohistochemical PrPSc Profile" Pathogens 12, no. 2: 353. https://doi.org/10.3390/pathogens12020353