A homozygous loss-of-function C1S mutation is associated with Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limited inflammatory disease of unknown pathogenesis. Familial cases have been described and defects in classical complement components C1q and C4 have been identified in some patients. MATERIAL AND METHODS: We describe genetic and immune investigations of a 16 years old Omani male, a product of consanguineous marriage, who presented with typical clinical and histological features of KFD. RESULTS: We identified a novel homozygous single base deletion in C1S (c.330del; p. Phe110LeufsTer23) resulting in a defect in the classical complement pathway. The patient was negative for all serological markers of SLE. In contrast, two female siblings (also homozygous for the C1S mutation), one has autoimmune thyroid disease (Hashimoto thyroiditis) and a positive ANA and the other sibling has serology consistent with SLE. CONCLUSION: We report the first association between C1s deficiency and KFD.

Kikuchi-Fujimoto disease is mediated by an aberrant type I interferon response.

Kikuchi-Fujimoto disease (KFD) is a reactive lymphadenitis of unclear etiology. To understand the pathogenesis of KFD, we performed targeted RNA sequencing of a well-characterized cohort of 15 KFD specimens with 9 non-KFD lymphadenitis controls. Two thousand and three autoimmunity-related genes were evaluated from archived formalin-fixed paraffin-embedded lymph node tissue and analyzed by a bioinformatics approach. Differential expression analysis of KFD cases compared to controls revealed 44 significantly upregulated genes in KFD. Sixty-eight percent of these genes were associated with the type I interferon (IFN) response pathway. Key component of the pathway including nucleic acid sensors, IFN regulatory factors, IFN-induced antiviral proteins, IFN transcription factors, IFN-stimulated genes, and IFN-induced cytokines were significantly upregulated. Unbiased gene expression pathway analysis revealed enrichment of IFN signaling and antiviral pathways in KFD. Protein-protein interaction analysis and a molecular complex detection algorithm identified a densely interacting 15-gene module of type I IFN pathway genes. Apoptosis regulator IFI6 was identified as a key seed gene. Transcription factor target analysis identified enrichment of IFN-response elements and IFN-response factors. T-cell-associated genes were upregulated while myeloid and B-cell-associated genes were downregulated in KFD. CD123+ plasmacytoid dendritic cells (PDCs) and activated T cells were noted in KFD. In conclusion, KFD is mediated by an aberrant type I interferon response that is likely driven by PDCs and T cells.

Identification of genes associated with Kikuchi-Fujimoto disease using RNA and exome sequencing.

Kikuchi-Fujimoto disease (KFD) is an extremely rare disease, and although it is reported to have a worldwide distribution, young Asian women are most likely to be affected. Although this disease is generally benign and self-limiting, distinguishing it from other diseases that cause lymphadenopathy (e.g., leukemia, lymphoma, and infectious diseases) is challenging. A lymph node biopsy is a definitive diagnostic technique for KFD and only requires skillful pathologists. There are no specific symptoms or laboratory tests for KFD, and more than 50% of KFD patients have suffered from being misdiagnosed with lymphoma, which leads to improper treatment. In this study, lymph node tissue samples from KFD patients were used to reveal their exomes and transcriptomes using a high-throughput nucleotide sequencer. Fourteen single nucleotide polymorphisms (SNPs) were identified as candidate KFD markers and were compared with a healthy lymph node exome dataset. The mutation of these genes caused disruptive impact in the proteins. Several SNPs associated with KFD involve genes related to human cancers, olfaction, and osteoblast differentiation. According to the transcriptome data, there were 238 up-regulated and 1,519 down-regulated genes. RANBP2-like and ribosomal protein L13 were the most up-regulated and down-regulated genes in KFD patients, respectively. The altered gene expression involved in the human immune system, chromatin remodeling, and gene transcription. A comparison of KFD and healthy datasets of exomes and transcriptomes may allow further insights into the KFD phenotype. The results may also facilitate future KFD diagnosis and treatment.

[Kikuchi-Fujimoto's disease or histiocytic necrotizing lymphadenitis: A report of two familial cases]. / Maladie de Kikuchi-Fujimoto ou lymphadénite histiocytaire nécrosante : à propos de deux cas familiaux.

INTRODUCTION: The histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto's disease is characterized by a lymph node inflammation whose similarity with systemic lupus is generally admitted. CASE REPORT: Our description of two familial cases aims at raising the hypothesis of the existence of a genetic background in this disease following the example of what is observed in the autoimmune diseases. CONCLUSION: Pathophysiology of Kikuchi-Fujimoto's disease is probably multifactorial and may include predisposing genetic background and a possible infectious triggering event.

Aberrant phenotypes in Kikuchi's disease.

Initial reports emphasized the immunophenotypic similarities between benign and malignant T cell populations, while some previous studies indicating that aberrant T-cell antigen loss is a good marker for detecting malignant T-cell proliferation. Recently, we found a very interesting and thought-provoking phenomenon: In benign disease-28 of 38 (73.7%) cases of Kikuchi's disease also showed aberrant phenotypes with loss of pan-T cell antigens, which makes the differential diagnosis between Kikuchi's disease and T cell lymphoma more challenging. In our study, 38 cases of Kikuchi's disease and 30 cases of reactive lymphoid hyperplasia (RLH) were studied by EliVision immunohistochemical staining. As well as TCR gene rearrangement using PCR was negative in 10 tested cases of the Kikuchi's disease. Among these cases, the most common antigen deficiency was CD5 (22 cases), then CD7 (11 cases), CD2 (8 cases) and CD3 (2 cases). Compared with proliferative and xanthomatous types of Kikuchi's disease, antigens tended to be lost in necrotizing type. Based on follow-up data, a correlation was not found between the occurrence of aberrant phenotypes and prognosis. In RLH, obvious pan-T cell antigen loss was also not found. In conclusion, this is the first study to demonstrate distinct patterns of antigen loss in Kikuchi's disease, suggesting that T cell antigen loss is not reliable as an auxiliary diagnostic standard for T cell lymphoma.

A non-invasive diagnosis of histiocytic necrotizing lymphadenitis by means of gene expression profile analysis of peripheral blood mononuclear cells.

Histiocytic necrotizing lymphadenitis (HNL), also called Kikuchi-Fujimoto disease, is a benign, self-limiting inflammatory disease with fever and painful cervical lymphadenopathy of unknown etiology. A lymph node biopsy is required for the definitive diagnosis because of no specific symptoms or laboratory findings for HNL. To establish the rapid non-invasive diagnostic method for this disease, we investigated genes specifically expressed in the patients by analyzing whole transcriptome using microarray analysis of peripheral blood mononuclear cells (PBMC). The top five up-regulated genes (IFI44L, CXCL10, GBP1, EPSTI1 and IFI27) in HNL were interferon-induced genes (ISGs). The expression levels of the up-regulated genes by microarray were verified by quantitative PCR. High levels of serum CXCL10 concentration were confirmed at the symptomatic phase of HNL patients. The expression levels of these 5 genes positively correlated with each other (r(2) = 0.28-0.60). The genes were also highly expressed in HNL lymph nodes. The discriminant analysis using the expression levels of these five genes distinguished HNL with 84% accuracy. The combination of up-regulated ISGs in HNL seemed to be a specific response induced by viral infections or autoantigens. An analysis of the gene expression profile of PBMC may provide a rapid non-invasive diagnosis of HNL.

The complete genome sequence of Corynebacterium pseudotuberculosis FRC41 isolated from a 12-year-old girl with necrotizing lymphadenitis reveals insights into gene-regulatory networks contributing to virulence.

BACKGROUND: Corynebacterium pseudotuberculosis is generally regarded as an important animal pathogen that rarely infects humans. Clinical strains are occasionally recovered from human cases of lymphadenitis, such as C. pseudotuberculosis FRC41 that was isolated from the inguinal lymph node of a 12-year-old girl with necrotizing lymphadenitis. To detect potential virulence factors and corresponding gene-regulatory networks in this human isolate, the genome sequence of C. pseudotuberculosis FCR41 was determined by pyrosequencing and functionally annotated. RESULTS: Sequencing and assembly of the C. pseudotuberculosis FRC41 genome yielded a circular chromosome with a size of 2,337,913 bp and a mean G+C content of 52.2%. Specific gene sets associated with iron and zinc homeostasis were detected among the 2,110 predicted protein-coding regions and integrated into a gene-regulatory network that is linked with both the central metabolism and the oxidative stress response of FRC41. Two gene clusters encode proteins involved in the sortase-mediated polymerization of adhesive pili that can probably mediate the adherence to host tissue to facilitate additional ligand-receptor interactions and the delivery of virulence factors. The prominent virulence factors phospholipase D (Pld) and corynebacterial protease CP40 are encoded in the genome of this human isolate. The genome annotation revealed additional serine proteases, neuraminidase H, nitric oxide reductase, an invasion-associated protein, and acyl-CoA carboxylase subunits involved in mycolic acid biosynthesis as potential virulence factors. The cAMP-sensing transcription regulator GlxR plays a key role in controlling the expression of several genes contributing to virulence. CONCLUSION: The functional data deduced from the genome sequencing and the extended knowledge of virulence factors indicate that the human isolate C. pseudotuberculosis FRC41 is equipped with a distinct gene set promoting its survival under unfavorable environmental conditions encountered in the mammalian host.

Kikuchi's disease displaying a t(2:16) chromosomal translocation.

Kikuchi's disease is a rare self-limiting lymphoproliferative condition of unknown aetiology, characterised by acute or subacute necrotising lymphadenitis. It is a benign condition that can mimic malignant lymphoma. In this report, a case of Kikuchi's disease associated with a chromosomal abnormality is described. This is the first report in the literature of such a case and it highlights an important learning point; benign lymphoproliferative conditions can be associated with chromosomal abnormalities that are more typically associated with malignant lymphoproliferative conditions such as malignant lymphoma. The report illustrates the necessity for interpreting cytogenetic data in the relevant clinical and histopathological context in a multidisciplinary setting to avoid misdiagnosis and inappropriate treatment.

Apoptosis- and cell cycle-associated gene expression profiling of histiocytic necrotising lymphadenitis.

Cell death is of two types; necrosis and apoptosis. In histiocytic necrotising lymphadenitis (HNL), apoptosis is the main form of cell death. Apoptosis results in the formation of nuclear debris, which is one of the characteristic features of HNL. We previously reported that in HNL it is predominantly CD8-positive cytotoxic T cells that undergo apoptosis; however, the majority of proliferating cells are also CD8-positive T cells. Recent advances in technical and analytical methods have facilitated the parallel quantitation of expression of numerous genes using DNA microarrays. The technology is particularly well suited to compare differences in gene expression between normal tissues and inflammatory disease. To investigate the apoptosis- and cell cycle-associated gene expression in HNL, we analysed five cases each of HNL and non-specific lymphadenitis (NSL), using ready-made microarrays, including cyclins and caspases, and immunohistochemical staining of caspase-3, ssDNA, bcl-2 and NF-kappaB. Caspase-3- and ssDNA-positive apoptotic cells were frequently detected in HNL, but were rare in NSL. However, bcl-2- and NF-kappaB-positive cells were rare in HNL. Gene expression tree analysis of DNA microarrays showed different clustering of HNL and NSL. In comparison with NSL, HNL exhibited diffuse upregulation of these gene profiles, particularly of cyclins and caspases (ratio; cyclin A2, 2.72; caspase-6, 2.43; caspase-3, 2.02); whereas, Mcl-1, which has been shown to delay apoptosis, was downregulated (ratio, 0.71), as confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Almost all apoptosis-associated genes, especially caspases, were upregulated, and apoptosis inhibitory genes, including bcl-2 by immunohistochemistry, were downregulated in all five cases with HNL. In addition, cell cycle-associated genes were upregulated in all. These findings confirm that both apoptosis and proliferation are simultaneously present in HNL lesions.

Kikuchi-Fujimoto's disease: report of familial occurrence in two human leucocyte antigen-identical non-twin sisters.

Kikuchi-Fujimoto's disease (KFD) is a self-limiting condition usually presenting as cervical lymphadenopathy, with fever and leukopenia, in young adult females. No specific aetiology has been identified yet, although some authors believe that KFD is a 'forme fruste' of systemic lupus erythematosus. Certain human leucocyte antigen (HLA) types have also been associated with KFD. We herein report KFD in two non-twin sisters with HLA-identical phenotype, who presented 10 years apart. Neither patient had evidence of recent infection or connective tissue disease. The familial occurrence emphasizes the possibility of genetic predisposition and calls for a more extensive search for a specific cause of KFD.

Nosocomial Kikuchi's disease--a search for herpesvirus sequences in lymph node tissues using PCR.

BACKGROUND: Histiocytic necrotizing lymphadenitis, also known as Kikuchi's disease (KD), is a rare disease. Fever and lymphadenopathies with characteristic pathologic features are present. The etiology of this disease remains undetermined. Since the disorder is self-limiting, different viruses have been implicated as the causative agent. PATIENTS AND METHODS: Seven cases of KD were studied. Three patients acquired the disease nosocomially, three had community-acquired KD and one case was associated with systemic lupus erythematosus. PCR was performed on DNA extracted from lymph node tissues in order to detect herpesvirus-specific DNA sequences: herpes simpLex virus type 1 and 2 (HSV1-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV8). RESULTS: Viral DNA was not detected in any of the lymph node tissues from the seven cases of KD. CONCLUSION: We conclude that these herpesviruses were not involved in the etiology of the three cases of nosocomial KD, nor in the other four cases of KD investigated in this study.

DNA typing of HLA class II genes (HLA-DR, -DQ and -DP) in Japanese patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease).

The pathogenesis of histiocytic necrotizing lymphadenitis (HNL), which was reported first by Kikuchi et al. and Fujimoto et al. in 1972, is as yet unknown. HNL is frequently reported in Asian countries including Japan, however it is rare in Europe and North America. To elucidate whether the human leukocyte antigen (HLA) alleles and haplotypes are associated with HNL, we performed DNA typing of HLA class II genes (HLA-DR, -DQ, and -DP) in 86 patients with HNL and 525 unrelated healthy Japanese controls with polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP). In this study, we found DPA1*01 and DPB1*0202 allele frequencies in HLA class II genes are significantly higher in HNL patients than in normal controls. It is known that the frequency of DPB1*0202 alleles is extremely low or absent in Caucasians (e.g., French 0.4%, Italian 0.8%) and Negroid (e.g., South African 0%, Hottentot 0%), but relatively frequent in Asians (e.g., Korean 9.9%, Japanese 4.5%). Previous reports have said the incidence of HNL is frequent in Asians but rare in other races. In light of this background, HLA class II genes of HNL and the incidence of HNL in Asian countries, including Japan, might have a positive relationship to DPA1*01 and DPB1*0202 allele.