Human herpesvirus 8 variants in sarcoid tissues

doi:10.1016/S0140-6736(97)10102-7

The Lancet

Volume 350, Issue 9092, 6 December 1997, Pages 1655-1661

https://doi.org/10.1016/S0140-6736(97)10102-7 Get rights and content

Summary

Background

The cause of sarcoidosis is unknown, although mycobacteria have been implicated. We examined sarcoid tissues for human herpesvirus 8 (HHV-8) in addition to mycobacterial genomic sequences.

Methods

Biopsy samples from 17 patients with sarcoidosis were studied (eight transbronchial, 27 lymph node, two skin, and two oral mucosa). We used tissues (n=137) from 96 patients without sarcoidosis as negative controls. A nested PCR was applied to amplify a segment of open reading frame (ORF) 26 of the HHV-8 genome, and a heminested PCR was used to amplify a segment of ORF 25 of HHV-8 and of the 16 S rRNA gene of mycobacteria. Differences in base sequences of the amplified fragments were resolved with single-strand conformation polymorphism and dideoxy sequencing.

Findings

HHV-8 ORF 26 DNA was detected in significantly higher proportions of sarcoid than of non-sarcoid tissue samples from lung (8/8 vs 0/54; p·0·0001), lymph nodes (26/27 vs 6/29; p·0·0001), skin (2/2 vs 0/17; p=0·006), and oral tissues (2/2 vs 1/13; p=0·029). 31 (82%) of the 38 ORF 26 DNA-positive sarcoid specimens were also positive for ORF 25 DNA. For mycobacteria-like 16 S rRNA DNA, the proportion positive was significantly higher in sarcoid than non-sarcoid tissues for lymph node samples (11/27 vs 2/29; p=0·003) but not for other tissues (lung 3/8 vs 22/54; skin 2/2 vs 15/17; and oral tissues 1/2 vs 0/13). Overall, the prevalence of HHV-8 ORF 26 sequences was higher in sarcoid tissues than in non-sarcoid tissues (p<0·0001). When patients whose tissues were included in a masked phase of the study were treated as units of analysis, eight of eight sarcoidosis patients were positive for HHV-8 ORF 26 DNA, compared with three of 56 control patients (p<0·0001); for mycobacteria-like sequences, three of eight sarcoidosis patients were positive, compared with four of 56 controls (p=0·0464). The HHV-8 ORF 26 sequences, ten of which were unique, could be segregated into four groups according to peptide motifs. In seven of nine patients from whom biopsy samples were taken from various sites, different sequences were recovered. The mycobacterial sequences amplified from sarcoid tissues were also varied, but none was homologous to those of known species.

Interpretation

Variant HHV-8 DNA sequences are found in a wide range of sarcoid but not non-sarcoid tissues.

Mycobacteria-like 16 S rRNA sequences are more frequently present in sarcoid lymph nodes and not in other tissue types, but do not indicate infection by a particular mycobacterial species.

Introduction

Sarcoidosis has been described as a systemic disorder characterised by the presence in multiple tissues of non-caseating epithelioid-cell granulomas, which may spontaneously resolve or convert to hyaline connective tissue.¹ In the active phase of the disease, activated macrophages aggregate at several tissue sites and coalesce as giant and epitheloid cells.² Also accumulating at these sites are CD4 cells, which show restriction in their use of T-cell-receptor genes,³ indicating stimulation by a limited range of antigens. Clinical expression of sarcoidosis is variable and can be protean, but the disease frequently presents on chest radiograph as bilateral hilar lymphadenopathy with or without pulmonary mottling.²

The aetiology of sarcoidosis is uncertain. Many agents have been implicated as possibly providing the antigens that elicit the sarcoid granulomatous response.² In particular, the role of Mycobacterium tuberculosis and other mycobacteria is the subject of many studies and much debate.4, 5, 6, 7 Granuloma formation has been shown to follow infection by herpesviruses such as varicella zoster virus and herpes simplex virus type 1, and, in some cases, sarcoid-type granulomas are seen.8, 9, 10 Specific associations between granulomatous diseases and herpesviruses, however, are very rare. In this study, we looked for the presence of a newly discovered herpesvirus, human herpesvirus 8 (HHV-8; also known as Kaposi's sarcoma-associated herpes virus),11, 12 in sarcoid tissues.

Section snippets

Methods

Tissue samples

We studied paraffin-embedded formalin-fixed tissues obtained by transbronchial, lymph-node, and skin biopsies that were done to confirm sarcoidosis in 15 patients attending the University Hospital of Chieti, Italy. In addition, we examined two oral-biopsy specimens, one from each of two patients with oral ulceration presenting to the University Hospital of Bari, Italy. All 17 patients had chest changes, detected by radiography, suggestive of intrathoracic sarcoidosis, were

Results

The majority of tissues from patients with sarcoidosis-like changes showed no or negligible necrosis, and the extent of fibrosis was variable (table 1). 17 (44%) and 15 (38%) of the 39 specimens contained asteroid and Schaumann bodies, respectively.

Of the 38 specimens found positive for ORF 26 DNA, 31 (82%) were also positive for ORF 25 DNA (table 2). The 12 specimens from eight patients that were found positive by nested PCR for ORF 26 in the second phase also tested positive in the third

Discussion

The sarcoid granulomatous response has been thought to result from an immune action mounted to sequestrate foreign agents.² Our finding of a very high detection rate of HHV-8 ORF 26 DNA in sarcoid tissues, but not in non-sarcoid tissues (including those with intense inflammatory infiltration), points to a close association between HHV-8 and sarcoidosis. Whether this association is causal or not requires further study. Nevertheless, our study has not formally excluded a general association

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ArticlesHuman herpesvirus 8 variants in sarcoid tissues

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Blood

Lancet

Blood

Lancet

Lancet

Sarcoidosis: histopathological definition and clinical diagnosis

J Clin Pathol

Limited heterogeneity or biased T-cell receptor V gene usage in lung but not blood T cells in active pulmonary sarcoidosis

Immunology

Pulmonary sarcoidosis: could mycoplasma-like organisms be a cause?

Sarcoidosis Vasc Diffuse Lung Dis

Mycobacteria and sarcoidosis: an overview and summary of recent molecular biological data

Sarcoidosis

Growth of acid fast L forms from the blood of patients with sarcoidosis

Thorax

Identification of Mycobacterium avium complex in sarcoidosis

J Clin Microbio

Cutaneous sarcoid granuloma formation in herpes zoster scars

Arch Dermatol

Granuloma formation in herpes zoster scars

Dermatologica

Sarcoid-like granulomas secondary to herpes simplex virus infection

Dermatology

Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma

Science

Towards a phylogeny and definition of species at the molecular level within the genus Mycobacterium

Int J Syst Bacteriol

Articles
Human herpesvirus 8 variants in sarcoid tissues