Kikuchi-Fujimoto Disease in the Setting of Systemic Lupus Erythematosus
Cynthia M. Magro
Weill Medical College of Cornell University
New York, New York
Case 1C: Kikuchi-Fujimoto Disease in the Setting of Systemic Lupus Erythematosus
Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a subacute inflammatory
disorder most often seen in young women with clinical and pathologic features suggestive of an infectious
etiology. Among the features are fever, neutropenia and localized lymphadenopathy. Approximately 10% of
patients develop a skin rash. The most commonly suspected infectious agents in KFD are the human
herpesviruses EBV, HHV6, HHV7 and HHV8. However there are many citations which suggest an autoimmune
based etiology whereby the condition may presage SLE, occur concurrently with SLE and or develop
subsequent to the initial diagnosis of SLE.
When one considers the phenotypic profile of LE it is not that difficult to understand how a cytokine
milieu can be generated that could produce a morphologic and phenotypic profile indistinguishable from so
called idiopathic or virally triggered KFD. There are clearly unique features of KFD that closely
parallels known pathogenetic mechanisms in SLE and perhaps one could use the phenotypic profile which
defines KFD as the more extreme expression of the distinctive phenotypic profile typical of SLE. In
particular a very unique aspect of the condition is one of extensive CD8 T cell and CD123 positive
plasmacytoid dendritic cell infiltration along with enhanced leukocyte apoptosis and engulfment of
nuclear debris by scavenger CD68 and lysozyme positive histiocytes. The strong MXA expression reflects
the interferon alpha rich microenvironment. Recent studies suggest that all apoptosis-associated genes,
especially caspases, are upregulated, while apoptosis inhibitory genes, including bcl-2 by
immunohistochemistry, are downregulated in KFD. As with TEN/SJS where excessive soluble Fas Ligand Fas
interaction at the level of the keratinocyte is associated with extensive and progressive apoptosis, the
serum soluble FAS ligand is also markedly elevated in patients with KFD, a point which will be discussed
In a recent study we completed examining the phenotypic profile of biopsies procured from patients
with classic features of dermatomyositis (DM), SLE, discoid lupus erythematosus(DLE) we found that
biopsies of SLE were characterized by a dominance of CD8 lymphocytes in the dermis and within the
epidermis with numerous CD123 plasmacytoid dendritic cells concentrated around vessels and at sites of
interface dermatitis with MXA, the signature protein indicative of an interferon alpha rich
microenvironment, being significantly expressed in the epidermis and amidst inflammatory cells.
Hence one can view KFD in the setting of SLE as really at the polar end of the normal phenotypic
profile of SLE. It is possible that in patients with KFD the apoptotic response is unusually marked and
serves as a substrate to trigger the induction and growth of interferon elaborating plasmacytoid
dendritic cells. The role of Fas ligand gene polymorphisms has not been explored in KFD although is
known to occur in patients with SLE. In addition an additional gene polymorphism controlling interferon
production may also play some role in the pathogenesis of KFD. Patients with SLE demonstrate an IFN gene
expression "signature" characterized by strong overexpression of IFN-responsive genes in leukocytes and
target tissues. One of the key genes of the IFN-alpha pathway, IRF5, was found to be strongly associated
with SLE. Various functional single nucleotide gene polymorphisms leads to upregulation of interferon
regulatory 5 expression the sequelae of which would be one of excessive interferon alpha production. A
very specific interferon gene polymorphism has been identified which could be operational in some cases
of KD. IRF5 encodes an IFN induced transcription factor. Polymorphism at SNP rs2004640 creates a novel
splice site in exon B allowing the expression of a novel IRF5 isoform. A second mutation rs 10954213
creates a functional polyadenylation site and hence a shorter and more stable gene transcript. Type I
interferons are typically produced in response to infection. Large amounts are produced by plasmacytoid
dendritic cells stimulated by viral RNA and DNA through toll receptors 7 and 9 . In SLE it
may also be triggered in response to nucleic acid antigens released from apoptotic cells. Type I
inteferons exert many downstream effects on the immune system stimulating the Th1 pathways and sustain
activated T cells and also lower the threshold for B cell activation through the B cell receptor and
promote B cell survival and differentiation.
Therefore in summarizing the events leading to KFD an antibody response directed
at either virus in the setting of idiopathic KFD or nucleosome in the setting of SLE may be the inciting
trigger. The CD8 cells could be responding to antigen or represent secondary effector cells via the
mechanism of antibody dependent cellular immunity. The soluble fas Ligand produced by these sensitized
CD8 T cells would then bind in a nonspecific manner to any cell expressing Fas which in the context of
skin would include not only keratinocytes but lymphocytes and histiocytes leading to upregulation of
casspases and cell death via the apoptotic pathway. The apoptosis would in turn stimulate plasmacytoid
dendritic cells to proliferate and produce more interferon alpha which in turn would enhance the local
cytotoxic CD8 and histiocytic immune response. Inherent gene polymorphisms in Fas Ligand and interferon
alpha regulation could produce higher levels of these critical factors which are conducive in producing
the apoptotic microenvironment that characterizes KFD.
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