Infections, and virus infections in particular, have long been suspected of having a primary role in RDD.3
Human herpes virus‐6 infection has been reported in a small set of cases with RDD.7,8
However, conclusive evidence on the cause of RDD is still unavailable. B19 has more recently been implicated in inflammatory or autoimmune diseases.16,18
We analysed tissue sections of two patients with nodal RDD or SHML and two patients with ENSHML for the presence of B19 capsid proteins VP1 and VP2. We showed remarkable amounts of B19‐infected cells in the two nodal and the two extranodal RDD manifestations. This is the first report of B19 infection in RDD tissue indicating that B19 may be associated with the pathogenesis of RDD.
Several features of RDD, such as arthropathy and arthritis, autoimmune haemolytic anaemia and the association with autoimmune phenomena such as findings of rheumatoid factor are well‐known symptoms related to B19 infection, and are thus compatible with a virus‐induced origin of RDD.2,3,16,18
Interestingly, histiocytes, the characteristic and pathognomonic cells in SHML, did not show B19 infection. B19 capsid protein‐positive cells histomorphologically appeared as lymphocytic cells; B cellular and T cellular origin of infected cells was seen in both RDD lymph node tissues by immuno double labelling for CD20 and CD3.
This may indicate that primarily virus‐infected lymphocytes give rise to a secondary histiocytic reaction that eventually causes the typical histomorphology of RDD.
The observation of B19‐positive lymphocytes is unexpected, as B19 infection is known to occur mainly in the red blood cell lineage, using the erythrocyte P antigen (glycosphingolipid globoside Gb4) as a receptor.11
However, B19 infection has also been seen in several other cell types such as the T lymphocytes and B lymphocytes.24
Gb4 was identified as a major neutral glycosphingolipid in 11 tissues, particularly those of mesodermal origin.25
Furthermore, B19 capsid binding to several tissue‐specific glycosphingolipids was seen in various tissues, including granulocyte, kidney, liver and bowel tissue.25
The finding of B19 capsid proteins in lymphocytic cells thus further indicates that B19 infection is not restricted to the erythroid lineage and that different cellular receptors may also be used for B19 infection of other cell types.25
Likewise, besides anaemia, thrombopenia and lymphocytopenia have been reported as clinical findings associated with B19 infection, suggesting that these cell types may somehow be affected by B19.26
To rule out antibody‐specific staining failures, two different monoclonal B19 VP1/VP2 antibodies were used, showing qualitatively identical results; a cross reactivity with, for example, activated lymphocytes of the antibodies, however, may still be possible.
In synovial tissues of patients with rheumatoid arthritis, which like RDD often show massive lymphoplasmocytic infiltration, we showed B19 infection of lymphocytes in a recent study.19
Also, B19 infection was shown in a few other inflammatory synovial affections exhibiting a similar rheumatoid arthritis‐like histomorphology with lymphoplasmocytic proliferation.19
These observations hinted at a specific reactive histomorphological phenotype associated with B19 infection of specific cell types. It has to be mentioned, however, that huge masses of histiocytes are not observed in rheumatoid arthritis. The report of B19‐associated haemophagocytosis of histiocytes in the bone marrow of a patient with Evans syndrome is of interest in this regard.27
This report also links B19 infection to the distinctive histomorphological phenomenon of histiocytosis and emperipolesis. Even more remarkable is the nature of the underlying disease associated with B19 in this case. Evans syndrome is a haematological disorder defined by autoimmune destruction of at least two haematological cell types. Recently, it has been suggested that a subset of patients with Evans syndrome may have autoimmune lymphoproliferative syndrome (ALPS), a rare disorder of disrupted lymphocyte homeostasis showing lymphoproliferation and autoimmune features.28
In most patients with ALPS, defective Fas‐mediated apoptosis, caused by defects in the Fas
gene and Fas ligand gene, is reported.28,29
Recently, cases of RDD or SHML associated with ALPS were described.30
gene mutations were detected in a small subset of patients with SHML without ALPS.3
A primary genetic background as in ALPS, however, is not documented in RDD. Summarising these data, it has been hypothesised, that in most cases RDD or SHML may be an acquired disorder of deregulation of apoptotic signalling pathways.3
We detected B19 infection in high numbers of cells in nodal and extranodal RDD tissues in a small set of cases. This finding indicates that B19 may have an important role in the development of RDD or SHML, thus adding another disease to the spectrum of B19‐related conditions. The possible mechanisms by which B19 may contribute to the specific pathological reactions, however, especially when infecting non‐permissive cell types, are still little understood.
Further studies on B19 cellular interactions using larger numbers of cases with RDD or SHML are required to elucidate the role of B19 in RDD or SHML.