Introduction

Top Introduction Virology Immunology of B19 infection Pathogenesis of disease... Natural history of B19... Clinical syndromes commonly... Clinical syndromes less... Conclusion References

Human parvovirus B19, discovered in 1975¹ and first linked with human disease in 1981,² is a small single stranded DNA virus classified within the family Parvoviridae, and the genus Erythrovirus, having tropism primarily for erythroid precursors. B19 is the only parvovirus which has been clearly linked with disease in humans. It replicates only in human cells and is autonomous, not requiring the presence of a helper virus.

Acute B19 virus infection is classically associated with the childhood rash illness, erythema infectiosum (EI), arthralgia, fetal death, and transient aplastic crisis (TAC) in those with shortened red cell survival. However, it has been assumed that in those with a normal immune system, the virus has a relatively simple pathogenesis and that after the acute phase the virus is cleared by a specific humoral immune response. However, increasingly B19 virus and B19 infection have been reported in association with quite atypical and unpredictable findings based on previous assumptions. For example, persistence of the virus in various tissues after acute infection in apparently normal subjects and the association of B19 infection with various connective tissue and autoimmune diseases. This paper will therefore summarise present knowledge of the virus, its known and potential pathogenetic mechanisms, and its associations with human disease, with an emphasis on rheumatic disease.

	Virology

Top Introduction Virology Immunology of B19 infection Pathogenesis of disease... Natural history of B19... Clinical syndromes commonly... Clinical syndromes less... Conclusion References

The B19 genome consists of a single stranded linear molecule of 5596 nucleotides, which is composed of an internal coding sequence of 4830 nucleotides flanked by terminal repeat sequences of 383 nucleotides each.³ These terminal repeat sequences are imperfect palindromes and fold back on themselves to form hairpin loops.⁴ Viral replication is thus self primed by the 3' terminus,⁵ and in minute virus of mice, a related parvovirus, has recently been shown to require the host cell transcriptional modulator, parvovirus initiation factor.⁶ This is a site-specific DNA-binding complex consisting of p96 and p79 subunits, which have 40% amino acid identity focused particularly within a 94 residue region containing the sequence KDWK, and may modulate transcription of many genes.

The P6 promoter at the far left side of the genome initiates transcription of all B19 proteins.⁷ The non-structural protein, NS1, is encoded by the left side of the genome (nucleotides 435-2448) and is approximately 77 kDa.⁸ Parvovirus non-structural proteins are fairly homologous between species, consistent with their role in virus propagation, and B19 NS1 contains two phosphorylation sites, an amidation site and a nucleotide binding site.⁹ NS1 is localised to the nucleus of infected cells,⁸ is found covalently bound to mature virions,¹⁰ and may nick its replicative DNA intermediates to facilitate viral packaging.⁵ NS1 is cytotoxic to various host cells¹¹ possibly owing to host DNA nickase activity, which is abrogated by mutations within the nucleoside triphosphate-binding domain.¹² B19 NS1 has also been shown to upregulate human interleukin 6 (IL6) gene expression¹³ and to induce apoptosis in cells of the erythroid lineage.¹⁴

Structural proteins, VP1 and VP2, are encoded in the same open reading frame by nucleotides 2444-4786 and 3125-4786 with production of proteins of 84 and 58 kDa, respectively.^7 15 VP1 and VP2 are identical except for an additional 227 amino acids at the amino terminus of VP1. Antibody to this unique VP1 region precipitates and neutralises the virus in erythroid culture and therefore this region is thought to protrude from the external virion surface into the milieu and may have a role in attachment.¹⁶ Parvovirus B19 particles are icosahedral (20-sided) and made up of 60 copies of the capsid proteins: 96% VP1 and 4% VP2,¹⁷ a ratio resulting from the relative inefficiency of VP1 translation.

Study of the molecular epidemiology of B19 virus has shown variation of certain regions of the virus with time and geographical location and is increased in conditions where the virus persists and is allowed to undergo multiple rounds of replication, such as in fetal infection.¹⁸ Although considerable effort has focused on a possible relation between particular genetic subtypes of the virus and particular clinical manifestations,¹⁸ only in the case of B19 encephalopathy has there been a suggestion that this actually occurs.¹⁹

Culture of B19 virus is not possible using routine diagnostic methods but requires erythroid progenitor cell culture, and this is probably an important factor in the relatively late discovery of the virus and of its role in human disease. Erythroid progenitors from a number of different sources have been shown to support B19 replication, all of which require erythropoietin, presumably to maintain the cells in rapid division; these include human bone marrow,^20 21 fetal liver,^22 23 erythroid cells from a patient with erythroleukaemia,²⁴ human umbilical cord blood,^25 26 and peripheral blood.^27 28

The receptor for the B19 virus has been shown to be blood group P antigen or globoside (Gb4),^29 30 a glycosphingolipid. Glycosphingolipids are molecules present in the plasma membrane of all animal cells which modulate membrane receptors, act as microbial receptors, and are used to differentiate erythrocytes on the basis of ABH, I, and P blood group antigens.³¹ Gb4 is expressed on erythrocytes, platelets, granulocytes, lung, heart, synovium, liver, kidney, endothelium, and vascular smooth muscle,³² and may explain the tissue tropism observed clinically in B19 infection.

	Immunology of B19 infection

Top Introduction Virology Immunology of B19 infection Pathogenesis of disease... Natural history of B19... Clinical syndromes commonly... Clinical syndromes less... Conclusion References

Both virus capsid-specific IgM and IgG are produced after experimental³³ and natural³⁴ B19 infection. In TAC, IgM may be present at the time of reticulocyte nadir and during the subsequent 10 days. However, specific IgG does not appear until the time of recovery. IgM may persist in serum several months after exposure.³⁵ IgA can also be detected and presumably plays a part in resistance to natural infection by the nasopharyngeal route.³⁶ Antibodies to the NS1 protein are produced during infection in approximately 30% of subjects and have been associated with acute³⁷ and chronic³⁸ B19 arthritis, and persistent B19 infection.³⁹ In normal subjects, resolution of B19 infection is associated with specific antibody production, which neutralises the virus in erythroid cell culture.⁴⁰ The humoral response is known to be crucial in disease resolution and was for many years thought to be the only important factor in protection. However, a cellular response to the capsid proteins was reported recently,⁴¹ the significance of which is unclear.

	Pathogenesis of disease associated with B19 infection

Top Introduction Virology Immunology of B19 infection Pathogenesis of disease... Natural history of B19... Clinical syndromes commonly... Clinical syndromes less... Conclusion References

The pathogenesis of B19 virus infection is complex, particularly when the less common clinical manifestations/associations are included. Although this review discusses each potential pathogenetic mechanism separately, it should be remembered that these do not occur separately in vivo, and during the pathogenesis of a single B19 infection a combination of these mechanisms may come into play. However, clearly, the importance of each will vary depending on the particular virus/host interaction (table 1).

It is believed that the virus usually gains access to the human host by aerosol droplet transmission and that infection is usually by inhalation of these infected droplets into the respiratory tract.³³ However, B19 may also be transmitted parenterally by infected blood and blood products.^42 43

LOCAL VIRAL REPLICATION
During the incubation period, the virus seems to multiply in the throat, leading to viraemia on day 6,³³ with infection of erythroblasts in the bone marrow,⁴⁴ after attachment to these cells through the Gb4 receptor.^29 30 Gb4 is expressed on erythrocytes, platelets, granulocytes, lung, heart, synovium, liver, kidney, endothelium, and vascular smooth muscle,³² and may explain the tissue tropism observed clinically in B19 infection. Local viral replication may therefore represent a primary pathogenetic mechanism in EI, TAC, chronic bone marrow failure, congenital red cell aplasia, vasculitis, and hepatitis. In EI, B19 replication occurs in erythroblasts with temporary cessation of reticulocyte production and reduction of the haemoglobin level by about 10 g/l.^33 44 This is a temporary phenomenon and usually subclinical owing to the normal red cell survival and the rapid development of a neutralising humoral immune response.^33 44 Local viral replication has also been shown in epidermal cells in the stratum basale in EI.⁴⁵ In TAC, B19 replication occurs in the erythroblasts with haemolysis and anaemia owing to the inability of red cell development to keep pace with haemolysis.⁴⁶ However, if survival of the acute phase is assumed, virus is cleared by neutralising antibodies, and the erythroid progenitors are regenerated from earlier haemopoietic cells. Chronic pure red cell aplasia (PRCA) occurs in immunocompromised subjects who do not mount an adequate immune response with ongoing replication of the virus in erythroblasts.⁴⁷ In fetal infection, B19 replication is thought to be important and may occur in several organs, including the bone marrow, liver, and heart.⁴⁸ B19 protein expression has also been shown in macrophages, follicular dendritic cells, and T and B lymphocytes from patients with RA.⁴⁹ Although human synoviocytes do express Gb4,³² they seem to be non-permissive to B19 virus.⁵⁰

NS1 CYTOTOXICITY
Cytotoxicity due to parvovirus B19 is directly related to the cytotoxicity of the NS1 protein,¹¹ and NS1 cytotoxicity is thought to account for thrombocytopenia and leucopenia occurring during B19 infection.^44 51 NS1 cytotoxicity has also been suggested as a possible mechanism in the arthralgia/arthritis of B19 infection.

IMMUNE COMPLEX DEPOSITION
Immune complex deposition is thought to occur in EI and in the acute polyarthropathy of B19 infection. In volunteer studies, appearance of rash and joint symptoms coincided with disappearance of viraemia and appearance of specific IgG.³³ In addition, rash and joint symptoms are known to occur in chronically infected subjects after treatment with immunoglobulin.⁵² The coincidence of peripheral nerve abnormalities with the appearance of anti-B19 IgG is also consistent with an immune mediated pathogenesis.^53 54

ERYTHROBLAST APOPTOSIS
B19 infection of erythroid lineage cells is characterised by a gradual cytocidal effect mediated by NS1 protein,²⁰ and by features of apoptosis.⁵⁵ It has recently been shown that NS1 is responsible for apoptosis of erythroid cells, an activity which was abolished by nucleotide mutation within the nucleoside triphosphate binding site of NS1.¹⁴ NS1 mediates apoptosis by a pathway that involves caspases 3, 6, and 8 and seems to be mediated by an increase in sensitivity to apoptosis induced by tumour necrosis factor  (TNF ).⁵⁶

PRODUCTION OF AUTOANTIBODIES
Some clinical features of B19 infection are similar to those of autoimmune connective tissue diseases. However, the relation between B19 infection and these conditions is unclear. B19 infection has been associated with development of rheumatoid factor,^57-59 antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and gastric parietal cell antibody.⁶⁰ Antiphospholipid antibodies produced during acute B19 infection seem to have the same specificity as those produced in systemic lupus erythematosus (SLE).⁶¹ Lunardi and colleagues have shown that in patients with skin rashes, rheumatoid arthritis (RA), and chronic B19 arthritis, anti-VP1 IgG, which has been affinity-purified using a synthetic B19 VP1 peptide, reacted specifically with human keratin, collagen type II, single stranded DNA, and cardiolipin.⁶² The main reactivity was against keratin and collagen type II, and there was a correlation between the clinical features and the main autoantigen specificity; immunoglobulin from patients with arthritis reacted preferentially with collagen II, whereas immunoglobulin eluted from patients with skin rashes reacted preferentially with keratin.⁶² As type II collagen is a target antigen of autoantibodies and clonally expanded T cells in the RA synovium,⁶³ this finding may have considerable significance in the proposed link between B19 infection and RA.

CYTOKINE UPREGULATION
Using human haemopoietic cell lines, K562, Raji, and THP-1, stably transfected with DNA encoding the NS1 protein and expressing NS1 on induction, it was shown that upon induction of NS1 expression the cells secreted IL6.¹³ Transient induction of IL6 was also shown in human endothelial cells. This effect of NS1 was mediated by the NF- B site in the IL6 promoter region, implying that NS1 functions as a trans-acting transcriptional activator on the IL6 promoter. This finding supports the possible association between B19 infection and polyclonal B cell activation in RA and suggests that NS1 mediated induction of host cell genes may have a role in clinical manifestations of B19 infection.¹³

Human T cell leukaemia type 1 (HTLV-1) tax protein is necessary for viral propagation and activates IL6 production, probably through the NF- B binding site in the IL6 promoter.^64 65 Human immunodeficiency virus type 1 (HIV-1) tat protein also trans-activates IL6 production.⁶⁶ These two proteins resemble B19 NS1 in that they play a part in replication and activation of viral and host genes. HTLV-1 is known to cause a chronic inflammatory arthropathy in humans,⁶⁷ and HTLV-1 transgenic mice develop an arthropathy resembling RA.^68 69 HTLV-1 tax protein leads to overgrowth of human synovial cells.⁷⁰

There is scanty documentation of serum cytokine levels occurring in B19 infection. One report documents a 63 year old woman with acute B19 infection and polyarthritis with transcript mRNA concentrations of IL1 , IL6, and interferon  which were increased by factors of 32, 8, and 16, respectively. This suggests that acute B19 infection is associated with widespread and systemic activation of monocytes, T cells, and natural killer cells, which may have a role in disease manifestations.⁷¹ Raised serum TNF

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