Fulminant Infectious Mononucleosis Research Articles

X-LINKED LYMPHOPROLIFERATIVE DISEASE: DIAGNOSTIC CHALLENGE IN A MIDDLE-AGED MALE

<h3>Introduction</h3> X-Linked Lymphoproliferative Disease Type 1 (XLP1) is a rare disease of males caused by mutation in the gene <i>SH2D1A</i> and is characterized by vulnerability to EBV infection, lymphoma and dysgammaglobulinemia. Fulminant infectious mononucleosis in early childhood is the most common clinical manifestation, but on rare occasions XLP1 does not present until adulthood. <h3>Case Description</h3> We present a 43-year-old male with a history of recurrent sinusitis and bronchitis and leukopenia since childhood. He had EBV infection when he was 18 years old complicated by jaundice and hepatitis that required treatment with corticosteroids. At the age of 42, he developed ITP and was found to have mild splenomegaly. Serum immunoglobulins were mildly abnormal with IgG of 575, IgM of 762 and IgA of 145 mg/dL. Lymphocyte immunophenotyping was within normal limits and serum protein electrophoresis and serum free light chains were normal. Bone marrow biopsy was unremarkable. Invitate PID panel was performed, which revealed a pathogenic variant in SH2D1A gene (c.2T>C). SAP expression by flow cytometry revealed absence in NK cells but present in 17% of CD8+ T cell population suggestive of a somatic reversion in this population. He had mildly decreased NK cell function and positive EBV serology. <h3>Discussion</h3> We present a case of XLP1 diagnosis in adulthood with a history of EBV infection of moderate severity and mild initial immunologic abnormalities. In patients with somatic reversion in CD8+ T cells, milder disease may be more common and genetic testing should be considered early. The management options including bone marrow transplant should be carefully considered.

Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease

AbstractThe purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families—large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV+ and EBV−males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP.

Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell–directed therapy

AbstractX-linked lymphoproliferative disease (XLP) is a congenital immunodeficiency that is characterized by an abnormal immune response to primary Epstein-Barr virus (EBV) infection. After EBV exposure, affected patients often develop fulminant infectious mononucleosis (FIM), a life-threatening condition marked by the uncontrolled expansion and activation of T and B lymphocytes and macrophages. We hypothesized that the rapid elimination of B cells immediately following EBV exposure might reduce the severity of primary EBV infection in patients with XLP. To test this possibility, we administered the anti-CD20 antibody rituximab to 2 patients who presented with acute infection. Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed FIM or lymphoma in more than 2 years of follow-up. These data suggest that the pre-emptive use of B-cell–directed therapy may reduce the morbidity and mortality of primary EBV infection in XLP-affected individuals.

Human immunity against EBV-lessons from the clinic.

The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell–mediated therapy to treat disorders associated with or induced by EBV infection.

Postmortem diagnosis of fulminant infectious mononucleosis

Fulminant infectious mononucleosis (FIM) is a rare but life-threatening complication of Epstein-Barr virus infection that usually affects immunodeficient individuals. It is a hyperinflammatory syndrome caused due to release of massive amount of various cytokines, leading to hemophagocytic lymphohistiocytosis on histopathology, and a plethora of clinical manifestations due to simultaneous involvement of multiple organs of the body. The case of a young male who presented with fever and dyspnea and died within 12 h of presentation to the hospital was taken for autopsy. The postmortem evidence of hemophagocytic lymphohistiocytosis in the spleen, bone marrow, lymph nodes, liver, and lungs and the presence of large, basophilic intranuclear inclusions that stained latent membrane protein-1 positive on immunohistochemistry led to the diagnosis of FIM.

Variable clinical phenotypes of X-linked lymphoproliferative syndrome in China: Report of five cases with three novel mutations and review of the literature

BackgroundX-linked lymphoproliferative disease (XLP) is a rare life-threatening syndrome. Rapid recognition and definitive diagnosis are critical to improve the prognosis and survival of patients with XLP. Nowadays, little is known about patients with XLP in China. MethodsWe report the characterization of five Chinese XLP patients with three novel mutations and review the literature related to this syndrome. Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viraemia were enrolled in this study. The patients’ clinical features were assessed by retrieval of data from medical records. Immunological function included analysis of lymphocyte subsets and the detection of immunoglobulins G, A, M and/or E were evaluated by flow cytometry and nephelometry. Direct sequencing was used to detect SH2D1A/XIAP gene mutations. ResultsTwenty-two male patients with FIM, EBV-associated HLH or persistent EBV viraemia were evaluated among 421 PID patients in our centre. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. The onset age of the 5 patients range from 1month to 4years which was earlier than that in the western world. The diagnosis age was between 16months and 9years with a long diagnosis lag (1–97months). Two of them had positive family history. The clinical phenotypes varied in different patients among which two patients with FHLH and hypogammaglobulinaemia, one with hypogammaglobulinaemia, lymphoma and aplastic anaemia (AA) which is the first case with AA in China, one with hypogammaglobulinaemia only and the other one with FHLH. For immunological function, three exhibited reduced CD4/CD8 ratios. Arg55stop mutations as well as splice mutation in intron 1 were most frequently found and exon 2 was the hottest exon in China. Two patients died at the time of diagnosis for severe infection or hepatic coma. Three were alive and waiting for haematopoietic stem cell transplantation (HSCT). ConclusionFor patients with severe EBV-associated HLH, hypogammaglobulinaemia, lymphoma and aplastic anaemia, possibility of XLP should be considered and if confirmed, HSCT should be performed as soon as possible.

Study of SH2D1A gene mutation in paediatric patients with B-cell lymphoma

BackgroundX-linked lymphoproliferative disease (XLP) is an often fatal inherited immunodeficiency disorder characterised by fulminant infectious mononucleosis, acquired haemophagocytic lymphohistiocytosis, dysgammaglobulinaemia and malignant lymphoma. Given the paucity of data on the genetic stratification of XLP gene mutations in paediatric patients diagnosed with B-cell lymphoma, we sought to determine the existence of such association in the present study. MethodsWe studied 20 male subjects diagnosed with non-Hodgkin B-cell lymphoma. ResultsEleven patients had laboratory evidence of EBV infection by serology and quantitative PCR. The SH2D1A gene analysis was negative in all patients. ConclusionsThis is the first study to analyse the SH2D1A gene mutations in Iranian paediatric patients diagnosed with lymphoma. Although we could not demonstrate such an association in our cohort of patients, larger, multi-centre studies are required to extend and confirm our early findings.

Flow cytometric assays to investigate b and T cell subsets in primary immunodeficiency

The focus of our laboratory has been trying to decipher the development, differentiation and function of B and T cells in humans. We do this by studying these lymphocyte populations in primary immunodeficiencies (PIDs) due to monogenic mutations in critical genes. During the course of our study of PIDs, it has become evident that different cohorts of patients display distinct B and/or T cell phenotypes that are often diagnostic even prior to the discovery of the genetic lesion. For example X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency due to mutations in SH2D1A encoding the intracellular adaptor protein SAP. Clinically, XLP patients present with hypogammaglobulinaemia, fulminant infectious mononucleosis, and/or lymphoma. We have previously found SAP is required for the development of NKT cells, which in humans are defined as CD3 + Va24 + Vb11 + cells, and are absent in XLP patients. Furthermore, consistent with hypogammaglobulinaemia, the B cell compartment from XLP patients was found to have a severe reduction in CD27 + memory B cells and Ig class switched cells. More recently we have developed an intracellular staining method for detecting SAP expression. In normal healthy donors SAP can be detected in T cells, but not B cells, as these cells do not express SAP. In XLP patients, SAP is absent in both the B and T cell compartments. Furthermore, XLP carriers can be readily identified, as due to random X-inactivation, they have T cells that are both SAP + as well as SAP – . Similarly, patients with loss of function mutations in STAT3 and DOCK8 present with a distinct lymphocyte phenotype, which can be readily revealed through flow cytometry-based assays; these will be further discussed.

Clinical and molecular characteristics of Chinese patients with X-linked lymphoproliferative syndrome type 1.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inherited, life-threatening immunodeficiency disorder caused by mutations in SH2D1A gene. It affect approximately two to three males per million. Fewer than 10 cases with definite gene mutations have been reported in Chinese mainland and no rapid diagnosis method has been established. We determined the clinical and molecular characteristics of five patients with XLP1. The SH2D1A gene were amplified by PCR and sequenced, the SAP expression was analyzed by flow cytometry. Two patients had novel SH2D1A mutations and three had mutations that have been previously reported. Three patients presented with fulminant infectious mononucleosis or hemophagocytic lymphohistiocytosis and one presented with lymphoma. Null or decreased SAP expression on PBMCs was noted. The remaining patient presented with unique, recurrent, nonfulminant infectious mononucleosis and bimodal intracellular SAP protein expression. The overall molecular characteristics and clinical phenotypes of Chinese patients with XLP1 matched previous reports. The unique bimodal intracellular SAP protein expression indicated the presence of some residual SAP-positive T cells that are able to respond to persistent Epstein-Barr virus infection and could explain the relatively mild clinical phenotype of this patient.

Clinical features and gene mutation analysis of 4 Chinese children with X-linked lymphoproliferative disease

Objective To summarize clinical, gene mutation and their families of 4 Chinese children with X-linked lymphoproliferative (XLP) disease. Methods The clinical records and 6 genes of immunodeficiency associated with Epstein-Barr(EBV) infection were summarized and the literatures were reviewed. Results The four cases were all boys younger than 3 years old, who had onset with fever. They were all treated with ganciclovir, plasma, intravenous immunoglobulin and methylprednisolone after hospitalization, but 3 cases had the features of fulminant or fatal infectious mononucleosis(FIM), whose progression of disease was getting worse and died of second hemophagocytic lymphohistiocytosis (HLH) in the end. The survival time after onset was about 20 days. One boy had the complications of HLH associated with EBV infection and drug-induced hypersensitivity syndrome, who was improved and discharged from hospital. Two cases had adverse family history in which brothers or cousins died at younger ages. EBV-CAIgM and EBV-DNA of the 4 cases were all positive, with the copy of EBV DNA >108 copies/L. The results of the 6 genes of immunodeficiency associated with EBV infection of the 4 boys showed SH2D1A mutation. Mothers of 3 cases separately had the same SH2D1A mutation as her boy, while 1 mother refused to have the genes detected. Conclusions Patients who had the XLP were all male. Infants and young children under 5 years old usually had the features of FIM, with the complication of EBV associated HLH. Patients with XLP showed SH2D1A mutation. For male patients with FIM, especially those under 5 years, it is important to perform genetic detection early and to receive therapy as early as possible. Key words: X-linked lymphoproliferative; SH2D1A mutation; Fulminant or fetal infectious mononucleosis; Haemophagocytic lymphohistiocytosis

Clinical and Genetic Features of 5 Chinese Patients with X‐linked lymphoproliferative Syndrome

In this study, we report the clinical and genetic features of Chinese patients with X-linked lymphoproliferative syndrome (XLP). Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viremia were enrolled in this study. Direct sequencing was used to detect SH2D1A/XIAP gene mutations. The patients' clinical features were assessed by retrieval of data from medical records. Twenty-one male patients with FIM, EBV-associated HLH or persistent EBV viremia were evaluated. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. All five of these patients had symptoms of HLH and EBV infection. Among the five patients, the youngest one was only 1 month old at onset. One patient exhibited hypogammaglobulinemia. Of four patients evaluated for immunological function, all exhibited reduced CD4/CD8 ratios. Three patients had rapid disease progression and died. One patient received haematopoietic stem cell transplantation and is well. The overall clinical phenotypes of Chinese patients with XLP matched previous reports. For patients with severe EBV-associated HLH, our results indicate the need to examine the possibility of XLP.

Index of Suspicion

An 18-year-old girl presents with nighttime fevers to 39°C for 8 days. She complains also of headache, myalgia, and rash during the fevers. Eighteen days ago, she removed a tick from her neck after attending a festival in the northeastern United States. One week ago, she presented to her pediatrician with a sore throat and rash. She was hyponatremic (sodium, 129 mEq/dL) and was started on doxycycline for presumed Rocky Mountain spotted fever (RMSF). Her condition has not improved. She admits to multiple unprotected sexual encounters and cocaine abuse. The girl appears weak. Her vital signs include temperature of 38.7°C; heart rate, 84 beats per minute; respiratory rate, 20 breaths per minute; and blood pressure, 113/73 mm Hg. A salmon-colored macular rash is present on her trunk and proximal extremities. She also exhibits dermatographia. There are no mucosal lesions. The liver is enlarged to 2.5 cm beyond the rib margin, and she has right upper quadrant tenderness. Her muscles are tender to deep palpation in all four extremities. She is able to bear weight but refuses to ambulate due to bilateral lower extremity myalgia and arthralgia. A CBC demonstrates a normochromic, normocytic anemia, and leukocytosis with a left shift. ESR and CRP are elevated at 109 mm/hour and 19.8 mg/dL, respectively. A mild transaminitis is present. Ultrasonography reveals a mildly enlarged and echogenic liver. Small pleural and pelvic effusions are present on CT scan. A bone marrow biopsy and a glycosylated ferritin fraction are obtained. A clinical diagnosis is made. An 11-year old Hispanic boy who had poststreptococcal reactive arthritis (PSRA) and rheumatic fever (RF) diagnosed at age 6 years has been symptom-free while taking oral penicillin (PCN). Two months ago, he developed lemon-sized, reddish, painful subcutaneous nodules that were warm to touch on both lower extremities and revealed acute …

Fatal EBV Infection and Variable Clinical Manifestations in an XLP-1 Pedigree – Rapid Diagnosis of Primary Immunodeficiencies may Save Lives

Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

B Lymphocyte Memory in X-Linked Lymphoproliferative Disease (XLP)

X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma associated to mutations of the SH2D1A gene, encoding SAP (signaling lymphocytic activation molecule-associated protein). The initial encounter with Epstein Barr virus (EBV) triggers a massive response that leads to a fatal outcome in around 50% of the XLP individuals. Most surviving patients develop hypogammaglobulinemia and eventually B cell lymphoma. B lymphocyte development seems to be normal, but there is a marked reduction of memory B cells (CD27+ B lymphocytes). In addition, Th1 cell mediated immune responses predominate over Th2 responses. Hypogammaglobulinemia and failure to develop a long term humoral immune response can be explained because both the germinal center (GC) reaction and GC formation in secondary lymphoid organs are greatly impaired both in human XLP and in experimental SAP deficiency. Non switched memory B cells (IgM+, IgD+, CD27+ B lymphocytes) persist in XLP patients, suggesting that in spite of the lack of a GC reaction, some subgroups of memory B lymphocytes can play a role in immune homeostasis in these patients. In addition, their persistence in the presence of EBV infection, could perhaps be associated to late occurrence of extranodal B-cell lymphoma, which is another pathological condition associated to the absence of SAP in humans. Keywords: B cell memory, XLP, SAP, humoral response, CD27, long term memory.

Fulminant Infectious Mononucleosis and Recurrent Epstein‐Barr Virus Reactivation in an Adolescent

We describe a unique case of fulminant infectious mononucleosis and recurrent Epstein-Barr virus reactivation presenting in an adolescent. Detailed assays of Epstein-Barr virus-specific T cell immunity revealed defects in the patient's T cell receptor signalling pathway characterized by a lack of interleukin-2 and CD25 expression, which may have contributed to her clinical course. Allogeneic stem cell transplantation reversed the clinical and laboratory phenotype.

Hemophagocytic lymphohistiocytosis in a patient with x-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency affecting approximately 1 to 3 per million live male births. Patients are generally healthy until facing a viral infection such as Epstein-Barr Virus and then may develop fulminant infectious mononucleosis and die. XLP patients are also at increased risk of hemophagocytic lymphohistiocytosis (HLH), which may be triggered by assorted viruses. Here we report a novel case of HLH in a patient with XLP. Significant to his presentation is a paradoxical increase in natural killer (NK) cell activity. We hypothesize that this indicates that Parvovirus B19 activates NK cells via a signaling lymphocytic activation molecule-associated protein (SAP)-independent mechanism. Our case demonstrates an important etiology to consider in the differential diagnosis of XLP patients with nonfocal findings and febrile illnesses.

Follicular Lymphoma in a X‐linked Lymphoproliferative Syndrome Carrier Female

X-linked lymphoproliferative (XLP) syndrome is a rare primary immune-deficiency disorder caused by mutations of the SH2D1A or XIAP genes. Males with the disorder are usually in good health until contracting Epstein-Barr virus (EBV) whereupon the majority of patients die from fulminant infectious mononucleosis, lymphoma or hypogammaglobulinaemia. This report describes a female carrier with an XLP phenotype who was retrospectively identified after her grandson died from the disorder. Subsequent genetic testing identified the patient's mother and affected maternal grandmother as XLP carriers. The family's medical records were significant. The proband had lymphoma at ages 2 and 8 and made a full recovery following treatment. Both the maternal grandmother and uncle died of non-Hodgkin's lymphoma. We were concerned that the XLP carrier mother may be predisposed to lymphoma if the normal X chromosome is skewed towards inactivation. The human androgen receptor assay detected random X chromosome inactivation in the carrier mother. EBV was not detected in the lymphoma tissues of the proband and his grandmother, confirming previous findings that EBV is not always associated with lymphoma in XLP. More significantly, our study highlights the importance of identifying XLP in families with a high incidence of lymphoma.

High Level EBV Persistence in the IgM+ IgD+ CD27+ B Cell Subset in Patients with X-Linked Lymphoproliferative Disease Lacking Isotype-Switched Memory B Cells.

Epstein-Barr virus (EBV) infects >90% of population world wide and, in healthy virus carriers, establishes life long persistence in the immunoglobulin (Ig)Dneg, CD27+ (“class-switched”) memory B cell compartment normally produced by antigen stimulation and transit through germinal centres. Patients with the X-linked lymphoproliferative disease (XLP) cannot make such class-switched memory B cells due to an inherited mutation in the slam-associated protein (SAP) gene involved in the maturation of antibody responses. Interestingly, XLP patients are highly susceptible to severe primary EBV infection and develop a fulminant infectious mononucleosis (IM) which is often fatal and where the symptoms progress to resemble those of a different (non-familial) disease, EBV-associated haemophagocytosis syndrome (EBV-AHS), caused by virus entry into the NK or T cell system. Some XLP patients survive their primary infection, but the nature of EBV carriage in these individuals (lacking conventional memory B cells) remains unresolved. To investigate this further we obtained blood samples from 8 such XLP patients. EBV load in total peripheral blood mononuclear cells (PBMC), determined by quantitative PCR, occupied a broad range but on average was 2 to 3-fold fold higher than that of healthy controls. The virus was concentrated within the B cell (CD19+) compartment, as in healthy carriers, and not within T or NK cells, as typically seen in EBV-AHS. We then confirmed that these XLP patients indeed lacked conventional class-switched memory B cells but did carry a small population of IgM+, IgD+, CD27+ (“non-switched”) memory cells; however their circulating B cell pool was dominated by naïve (IgM+, IgD+, CD27neg) cells and by expanded numbers of immature “transitional” (CD10+ CD27neg) cells. In each of 4 cases studied by cell sorting, EBV was concentrated in this small subset of “non-switched” memory B cells. To see if the high virus load detected in these patients indicated true virus persistence as opposed to recent or recurrent infection, serial samples obtained over a 3 year period from two XLP patients were assayed. Virus load was stable and, in one case with the highest load, screening with markers of virus polymorphism detected the same resident strain over time. Our results in XLP patients make it clear that EBV can persist in the absence of a conventional class-switched memory B cell compartment. Instead, the virus is sequestered in a small population of “non-class-switched memory” cells with Ig gene mutations. The origin of such cells, which are also detectable in the blood of normal donors, is uncertain; however their existence in XLP patients suggests that such cells arise independently of germinal centre activity and hence that EBV may be able to colonise its host without exploiting germinal centre transit.

Simultaneous Manifestation of Fulminant Infectious Mononucleosis With B-Cell Non-Hodgkin's Lymphoma

Simultaneous Manifestation of Fulminant Infectious Mononucleosis With B-Cell Non-Hodgkin's Lymphoma