BK virus encephalopathy and sclerosing vasculopathy in a patient with hypohidrotic ectodermal dysplasia and immunodeficiency
© The Author(s). 2016
Received: 13 May 2016
Accepted: 26 June 2016
Published: 13 July 2016
Human BK polyomavirus (BKV) is reactivated under conditions of immunosuppression leading most commonly to nephropathy or cystitis; its tropism for the brain is rare and poorly understood. We present a unique case of BKV-associated encephalopathy in a man with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) due to IKK-gamma (NEMO) mutation, who developed progressive neurological symptoms. Brain biopsy demonstrated polyomavirus infection of gray and white matter, with predominant involvement of cortex and distinct neuronal tropism, in addition to limited demyelination and oligodendroglial inclusions. Immunohistochemistry demonstrated polyoma T-antigen in neurons and glia, but expression of VP1 capsid protein only in glia. PCR analysis on both brain biopsy tissue and cerebrospinal fluid detected high levels of BKV DNA. Sequencing studies further identified novel BKV variant and disclosed unique rearrangements in the noncoding control region of the viral DNA (BKVN NCCR). Neuropathological analysis also demonstrated an unusual form of obliterative fibrosing vasculopathy in the subcortical white matter with abnormal lysosomal accumulations, possibly related to the patient’s underlying ectodermal dysplasia. Our report provides the first neuropathological description of HED-ID due to NEMO mutation, and expands the diversity of neurological presentations of BKV infection in brain, underscoring the importance of its consideration in immunodeficient patients with unexplained encephalopathy. We also document novel BKVN NCCR rearrangements that may be associated with the unique neuronal tropism in this patient.
Here we report the first histological description of BK virus encephalopathy with cortical predominance in a male patient with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID), a rare X-linked disorder due to mutation in the NFkB signaling pathway. Ectodermal dysplasias are a group of inherited disorders characterized by absence or dysplasia of ectodermal appendages. In the hypohidrotic form, there is abnormal development of eccrine sweat glands, teeth, and hair . Mutations within a regulatory subunit of the NFkB pathway, IKK-gamma/NF-kappa-B essential modulator (NEMO), are known to cause two distinct X-linked forms of ectodermal dysplasia: X-linked dominant familial incontinentia pigmenti (IP), which is typically fatal prenatally in males; and X-linked recessive disorder with rare combination of HED and immunodeficiency (HED-ID), in which incomplete loss of NEMO function leads to impaired immune response with recurrent bacterial and viral infections in addition to HED [2, 17, 21, 30, 46, 50, 59]. Herein, we demonstrate BKV encephalopathy by histology, immunohistochemistry, sequencing, and further characterize a novel BKV variant (BKVN), which harbors unique rearrangements in the noncoding control region (NCCR), potentially contributing to its neuronal tropism. Finally, we describe several other previously unreported neuropathological features in this patient in the context of his underlying HED-ID disorder.
Polyomaviruses are non-enveloped, small (~40 nm) viruses with a circular double-stranded DNA genome. BK polyomavirus (BKV) displays approximately 75 % DNA homology with JC polyomavirus (JCV) and 70 % homology with the simian polyomavirus SV40. Infection with BKV occurs during childhood and is usually asymptomatic. Thereafter, the virus enters a state of latency, predominantly in the renal tubular epithelial cells, during which BKV DNA can be detected, while viral proteins such as T-antigen, agnoprotein and capsid proteins, cannot. By adulthood, 80–90 % of the general population is persistently colonized with BKV [31, 32]. Reactivation of the latent virus occurs predominantly in patients with impaired immune function, including HIV-1/AIDS, lymphoproliferative disorders and other malignancies, and treatment with immunosuppressive drugs [10, 48]. The most common pathologic conditions associated with reactivation of BKV are polyomavirus-associated nephropathy or PVAN in kidney transplant recipients [13, 14, 52] and hemorrhagic cystitis in bone marrow transplant recipients [3, 31]. Less often, BKV is reported to cause fatal pneumonia, retinitis, native kidney nephritis, and only rarely meningoencephalitis in the severely immunocompromised [12, 16, 54]. JC polyomavirus, rather than BK, is by far the most commonly associated virus with a CNS tropism in the context of immunosuppression, causing a progressive multifocal demyelinating leukoencephalopathy (PML) .
A 29-year-old man had been diagnosed with immunodeficiency at the age of one year after developing recurrent bacterial and viral infections in the setting of dysgammaglobulinemia with low levels of IgG. He also displayed signs of ectodermal dysplasia, including conical-shaped incisors, hypodontia and inadequate sweating. After multiple recurrent infections, at the age of 12, the patient was diagnosed with HED-ID caused by NEMO deficiency. Genomic analysis revealed a missense mutation within the putative zinc-finger domain in the most 3′ exon of IKK-gamma - exon 10, causing a cysteine to arginine substitution [2, 59]. Notably, the patient’s older brother had very similar clinical presentation and passed away at the age of 17 with recurrent bronchiectasis after bilateral lung transplantation. Following diagnosis of HED-ID in the reported patient, lifelong IVIG treatment was initiated and maintained, leading to stabilization of IgG levels and a normal quality of life.
We also analyzed expression of the polyomavirus VP1 capsid protein using an antibody that cross-reacts with VP1 of JCV, BKV and SV40. Intriguingly, the number of cells positive for VP1 was significantly lower compared to T-antigen positive cells in the same region (Fig. 3c-d). Noticeably, VP1-immunoreactivity was associated with cells of oligodendroglial or astrocytic phenotype (Fig. 3d) but was largely absent in infected neurons (Fig. 3c). Electron microscopy confirmed the presence of 30–40 nm non-enveloped icosahedral viral particles within the nuclear chromatin, consistent with polyomavirus (Fig. 3e-f).
Detection of JC virus DNA by PCR, the most common polyomavirus to infect the brain, was unsuccessful both in CSF prior to the brain biopsy as well as in the pathological cortical tissue. We therefore considered the possibility of infection by other polyomavirus species, and performed targeted qPCR for BKV at the CLIA/NINDS laboratory , which detected a high titer of BK virus within the CSF and biopsy tissue.
Sequence analysis of the patient’s VP1-amplified fragment (Additional file 1: Figure S1) showed high homology (within a few single nucleotide variations) with BKV isolate RU15 (GenBank: FR720320.1; 2153 - 2583 nucleotides) and BKV Dunlop strain (GenBank: V01108.1; 2272 - 2697 nucleotides). The NCCR amplified fragment containing the initial portion of early genes (203 bp with start codon for large T-antigen) also showed high similarity to the Dunlop strain.
We also compared the sequence of our entire NCCR amplicon (432 bp) with the archetypal variant (non-rearranged, WW, GI:4838415). In the most frequently seen archetype BKV strain, NCCR has been arbitrarily divided into five sequence blocks denoted O-143, P-68, Q-39, R-63 and S-63 where the numbers indicate base pairs [40, 41]. Block O contains the origin of replication (ori) and binding sites for large T-antigen and TFs, including NFkB, CEBPβ and SP1 . The early and late gene promoters and enhancers are located in P, Q, R, and S blocks. The BKV NCCR in our patient harbored significant deviations from reported NCCR sequences, including four repeats of portions of block P (two ΔP41 and two ΔP26) in addition to a small insertion, deletions and single nucleotide variations. Block O, in contrast, was conserved (Fig. 4). The P blocks in our patient appeared in two variants consisting of 41 (ΔP41) and 25 (ΔP26) nucleotides. Each of these blocks encompassed the initial portions of P block of archetype. The P blocks were arranged in the alternating manner: ΔP41 + ΔP26 followed by small adenine-rich fragment and the second ΔP41 + ΔP26. After the second ΔP26, blocks Q and R were present, although with nucleotide variations and deletions. Block S was not identified, although we cannot exclude the possibility that this region failed to amplify (Fig. 4b). We also compared our sequence with previously reported rearranged BKV isolates and observed the highest homology with NCCR of BKV strains WWM13 (GenBank: JQ513604.1) and WWM9 (GenBank: JQ513600.1). Intriguingly, these strains were isolated from the CSF of patients with neurological symptoms , implicating a possible association between these BKV rearrangements and predilection for CNS infection.
We report a very unusual presentation of BK virus encephalopathy in a patient with rare immunodeficiency and ectodermal dysplasia due to NFkB dysfunction and provide the first documented neuropathological description of this rare disorder, including the presence of unique form of sclerosing vasculopathy.
To our knowledge, this is the first histological demonstration that BK virus can infect cortical neurons in man, causing overwhelming encephalopathy with minimal demyelination. CNS infection by BK virus is unusual and clinically under-recognized, although a review of the literature reveals descriptions of BKV-associated encephalitis [7–9, 24, 35, 38, 55], meningoencephalitis [12, 51, 53, 54], PML [15, 19], and retinitis [12, 26]. A single report describes the neuropathological alterations caused by BKV in the brain as marked perivascular and leptomeningeal lymphocytic infiltration and patches of demyelination and gliosis . These elements were also present in our patient. Previous reports based on neuroimaging studies suggest that BKV infection has a predilection for the periventricular and pial surfaces of the brain parenchyma, with the cortex being spared . Our case clearly demonstrates that BKV can also infect cortical neurons leading to progressive encephalopathic symptomatology, with only minimal demyelinating component at the time of biopsy. Indeed, numerous pyramidal cortical neurons in the occipital cortex of our patient showed strong positivity for polyomavirus T-antigen but lacked staining for VP1 capsid protein. Among polyomaviruses, the most common one to infect the brain is JCV, which typically causes a demyelinating disease with a productive and lytic infection of oligodendrocytes and less commonly astrocytes [10, 20, 44]. Although predominant neuronal infection is rare, it has been reported in cerebellar granule cell neurons as JC virus granule cell neuronopathy (JCV-GCN), which is associated with JCV variants harboring a small deletion in the VP1 capsid protein [22, 33], and in cortical pyramidal neurons as JCV encephalopathy (JCV-E), which is caused by JCV variants containing Agno deletions . Interestingly, in JCV-E more neurons are positive for T-antigen, than for VP1 capsid protein, and it has been suggested that this phenomenon is due to latent, recent, or abortive infection . Similar findings were reported in the occipital and temporal cortices of a 21-year-old patient with common variable immunodeficiency, where the presence of JCV T-antigen and P53, but not VP1 capsid protein, was detected in dysplastic ganglion-like cells . Overall, our findings corroborate that polyomaviruses can infect neurons, and underscore the importance of considering BKV infection in the differential diagnosis of immunosuppressed patients with clinical symptoms of encephalopathy with undetectable JCV in their CSF.
Furthermore, we have identified a new BKV isolate with significant rearrangements in its NCCR, which likely contributed to the reactivation of the virus, in agreement with numerous studies showing that the most rearranged strains with deletions, insertions and duplications in NCCR are associated with increased viral replication [25, 43]. We speculate that the activation of BKV in an unusual host compartment – here the neuronal cell - is dependent on these unique NCCR rearrangements. This novel strain has a quadruple enhancer element containing imperfect duplications of an archetypal P element. One possible mechanism for viral activation and/or neuronal tropism may be through selective amplification of TF motifs in this amplified P NCCR region, such as nuclear factor 1 (NF1) or SP1, leading to transcriptional activation of viral genes necessary for replication and/or neuronal infectivity. Further studies are needed to characterize the exact role NCCR rearrangements may play in BKV activation and neuronal tropism, and the regulatory networks involved, which are beyond the scope of this report.
Our detailed neuropathological analysis uncovered two additional unusual features in the brain of this patient with HED-ID, which may be related to his underlying ectodermal dysplasia. The first one was the widespread presence of dysplastic neurons throughout the occipital cortex biopsy specimen. Many of these neurons showed T-antigen immunoreactivity, suggesting that BKV infection may account for their dysmorphic appearance. Intriguingly, many neurons immunoreactive for large T antigen were also positive for p53, but not for capsid protein VP1. Previous studies have suggested a possible role of T-antigen in the dysplastic, ganglion cell-like change of the JCV infected cortical neurons . However, we found that more neurons appeared dysplastic than showed immunohistochemical evidence of infection, raising the additional possibility of an underlying cortical dysplasia superimposed on polyomavirus infection in this patient. In the absence of previous reports on the neuropathological effect of NEMO or BKV on neurons and without further mechanistic studies, it is not feasible to relate unequivocally the presence of abnormal/dysplastic neurons to either BKV–associated cytopathic effect or to HED-ID. The effect of NEMO deficiency on cortical neuronal development has not been previously scrutinized and it deserves further consideration.
We also uncovered a unique sclerosing vasculopathy. The fibrosing process had notable predilection for medium sized vessels in the white matter, and manifested with obliteration of the vessel lumen and deposition of perivascular collagen in a lamellated pattern, which extended into the surrounding brain parenchyma. As well, abnormal accumulation of lysosomal material was noted within the walls of some small-caliber vessels, which may be secondary to hypoxic stress or alternatively relate to a degenerative process. To our knowledge, the appearance of this angiocentric fibrotic scar has not been previously described in other CNS vasculopathic processes. We believe it represents unique dysplastic pathology related to the patient’s underlying ectodermal dysplasia and herein provide its first neuropathological depiction in a male patient with NEMO-deficiency.
There is very limited number of reports on the pathology of HED-ID. The first comprehensive study to describe pathological findings in 13 patients with HED-ID (biopsies and autopsies) did not disclose any neuropathological abnormalities or features specific to NEMO deficiency . CNS findings in this study included agenesis of the corpus callosum in one child, moderate-to-severe cerebral atherosclerosis and hipopigmented substantia nigra in one adult, a remote cerebral cortical infarct, cortical ribbon defect and invasive cerebral aspergillosis in another adult, and subacute and chronic inflammation in the white matter of one living adult patient, without further histological analyses. Skin biopsies were also analyzed in this study, describing mainly inflammatory pathological findings (granulomatous dermatitis with positive AFB staining, lobular panniculitis, seborrheic keratosis, folliculitis) as well as abnormal vascular calcification in two patients; there was no mention of fibrosing vasculopathy and the presence of abnormal lysosomal accumulations were not assessed. While our report is the first to describe fibrosing vasculopathy in the brain of a patient with HED-ID, abnormalities in CNS vessels have been previously observed in patients with the closely related NEMO-deficiency disorder in females, IP . Brain MR imaging studies in patients with IP have demonstrated findings suggestive of microangiopathy [27, 34, 39]. Interestingly, vascular sclerosis and occlusion with associated fibrotic perivascular changes were reported in the retina of patients with IP . The molecular mechanisms underlying these vascular changes are not known, but dysregulation of the NFkB signaling pathway is likely to play a role.
BK polyomavirus encephalopathy is not typically considered in the differential diagnosis of patients with neurological symptoms, and may be under-recognized in immunosuppressed patients. We suggest that screening for BKV in the CSF of patients with encephalopathy and undetectable JCV is of clinical importance. Our study provides detailed neuropathological description of the manifestation of BKV CNS infection with distinct neuronal tropism in a patient with NFkB-mediated immunosuppression, expanding its clinical recognition. The identified unique BKV sequence may be important for elucidating the mechanisms of BK viral reactivation and neurovirulence in future studies.
Materials and methods
Immunohistochemistry (IHC) was performed with the following antibodies: mouse monoclonal anti-NeuN (A60; MAB377; Chemicon), mouse monoclonal anti-Neurofilament (2 F11, 760-2661, Ventana Medical Systems, Inc.), rabbit polyclonal anti- Glial Fibrillary Acidic Protein (GFAP) (EP672Y; 760-4345, Ventana Medical Systems, Inc.), mouse monoclonal anti-p53 (DO-7, 790-2912, Ventana Medical Systems, Inc.), rabbit monoclonal anti-CD3 (2GV6, 790-4341, Ventana Medical Systems, Inc.), mouse monoclonal anti-CD34 (QBEnd/10, 790-2927, Ventana Medical Systems, Inc.), mouse monoclonal anti-CD68 (KP-1, 790-2931, Ventana Medical Systems, Inc.), SV40 T Ag (v-300; sc-20800, Santa Cruz Biotechnology, Santa Cruz, CA) rabbit polyclonal antibody (raised against amino acids 4-30 mapping near the N-terminus of SV40 T Ag). Anti-VP1 antibody (mouse serum ab 597) was kindly provided by Dr. Kamel Khalili (Department of Neuroscience, Temple University School of Medicine, Philadelphia, US).
Paraffin embedded sections (4 μM) fixed in 10 % formalin were deparaffinized in xylene, with subsequent rehydration in a decreasing gradient of ethanol. Antigen retrieval was performed using cell-conditioning solution 1 (Ventana Medical Systems, AZ) for 60 min at 95 °C. After blocking, sections were incubated with primary antibodies according manufacturer protocols. Sections were washed and incubated with mouse or rabbit secondary antibodies depending on the type of the primary antibody on automated strainers at room temperature (Ventana XT). Immunoreactivity was detected by means of the IVIEW or Ultraview Universal DAB Detection Kits (760-500, Ventana Medical Systems, AZ).
Small pieces of brain tissue were received fixed in 3 % glutaraldehyde in a 0.2 M sodium cacodylate buffer at pH 7.4. The tissue was treated with osmium tetroxide for one hour rinsed in 0.2 M sodium cacodylate buffer and then subjected to dehydration in increasing steps of ethanol through propylene oxide and embedded in embed 812. One-micrometer plastic sections were cut, stained with methylene blue and Azure II, and observed by light microscopy. Representative areas were chosen for ultrathin sectioning. The thin sections were stained with uranyl acetate and lead citrate and photographed with a Hitachi H7650 transmission electron microscope equipped with an SIA digital imaging system.
DNA isolation and sequencing
DNA extraction was performed from 40 μl of fresh frozen brain tissue using Qiagen QIAamp DNA kit (Cat. #51304) and Qiagen ATL Buffer (Cat. #19076) according to the manufacturer’s instructions. RNA Carrier (Qiagen Cat. 1068337) was added to the sample to optimize DNA yield. The DNA was eluted in a volume of 45 μl AE Buffer and its concentration was measured using NanoDrop 2000.
Nested PCR amplification of VP1 and NCCR sequences of BKV was performed as previously described [4, 5], with slight modifications. Positions of nucleotides for all primers are shown based on nucleotide sequence in BKV Dunlop strain, V01108.
Amplification of the BKV VP1 region (nt 1456-2744)
In the first reaction, the following primers were used: forward VP1-F1 5′-AAACTATTGCCCCAGGAGGT-3′ (nucleotides (nt) 1456–1475) and reverse VP1-R4 5′-CTAAAACACCACCCCCAAAA-3′ (nt 2725–2744). A 1289 bp PCR products were purified by gel extraction using Qiagen QIAquick gel extraction kit (Qiagen, Cat. 28704) and used for nested PCR with the following primers: forward VP1-F4 5′-CTAATCAAAGAACTGCTCCTCAATG-3′ (nt 1477–1501) and reverse VP1-R8 5′-ACCACCCCCAAAATAACACA-3′ (nt 2718–2737), producing an amplicon of 1261 bp. Both reactions were performed in a volume of 50 μl with 500 nM of each primer, 5 mM MgCl2, 500 μM dNTP’s, and 1.25 U of AmpliTaq Gold (ThermoFisher, Cat. N8080248) and nuclease-free water. The first PCR was performed on 2 μl eluted DNA. A 4 μl of the first PCR product was used in the nested PCR. PCR conditions: denaturation - 15 min at 94 °C, 40 cycles of 30 s at 94 °C, 30 s at 55.7 °C (65 °C for the nested PCR), and 60 s at 72 °C with a final extension of 7 min at 72 °C.
Amplification of the BKV NCCR region (nt 4881-680)
In the first reaction, the following primers were used: forward ORIBK1 5′-ATCTGGGCAAAGAGGAAAATCA-3′ (nt 4881–4902) and reverse ORIBK2 5′-AGCAGCCTCAGATACACTGG-3′ (nt 661–680). Nested PCR was performed with Forward ORIBK3 5′-CAGGTTCCAAAATCAGGCTG-3′ (nt 4924–4943) and reverse ORIBK 5′-CTAGGAGTCTTTTACA-GAGTCT-3′ (nt 567–588) primers. For both amplification reactions, AmpliTaq DNA polymerase with GeneAmp kit (ThermoFisher Cat. N8080248) including 1.25U of the polymerase were employed. A final volume of 50 μl was completed with 500 nM of each primer, 500 μM of dNTPs, 5 mM of MgCl2, nuclease-free water and 2 μl of the DNA eluted (or 4 μl of the first PCR product for the nested PCR). PCR conditions: denaturation 15 min at 95 °C, 40 cycles of 30 s at 94 °C, 30 s at 56 °C (58 °C for the nested PCR), and 1 min at 72 ° with a final extension - 7 min at 72 °C. The amplicons were separated by electrophoresis on a 1 % agarose gel in the presence of ethidium bromide and were visualized under UV light. To avoid contamination, ultrapure reagents were added under a laminar flow hood and in a separate room.
Informed consent was obtained from all individual participants included in the study.
We thank the family, as well as the physicians who assisted in gathering clinical information and samples. We are grateful to Dr. Schein for the Neuropathology Endowed Fellowship award to Dr. Darbinyan A. We thank Dr. Kamel Khalili and Dr. Jennifer Gordon from the Department of Neuroscience and Center for Neurovirology, Temple School of Medicine, Philadelphia, PA for their insightful discussion and sharing of reagents.
AD participated in the neuropathological diagnosis, carried out viral DNA isolation from the frozen brain tissue and BKV genome characterization, analyzed the results of all studies, and wrote the manuscript. EOM, CR, and MCM first identified BKV in brain tissue by PCR. SM contributed to conceptualizing BKV encephalopathy and participated in the comprehensive analysis of the results. EOM and SM contributed significantly to the final manuscript. TPN analyzed the neuro-imaging studies. RG carried out electron microscopy studies. MF participated in the histopathology analysis. JM and FY helped with BKV isolation and downstream molecular studies. CC-R, JB and SH participate in the clinical care of the patient and provided clinical follow up. NMT formulated the neuropathological diagnosis, led the analysis of the results, designed the report, and constructed the final manuscript. All authors contributed to and approved the final manuscript.
The authors declare that they have no competing interests.
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