Severe chronic EBV infection associated with specific EBV immunodeficiency and an EBNA+ T-cell lymphoma containing linear, EBV DNA

A patient with severe chronic Epstein-Barr virus (EBV) infection (CEBVI) of 6 years duration developed an EBV+ T-cell lymphoma. To determine whether the development of the T-cell tumor was linked to EBV, we studied this patient's EBV-specific immune response and her T-cell tumor tissue for evidence of EBV infection. Peripheral blood lymphocytes from this patient were systematically studied for immune function and response to EBV. Tumor tissue was examined for EBV genome and for evidence of EBV replication. This patient failed to develop anti-EBV nuclear antigen (EBNA) antibodies and had decreased mitogen responsiveness. Her T-cells showed a broad suppression of both autologous and allogeneic B-cells, which was coincident with clinical hypoimmunoglobulinemia. A selective cytotoxic T-cell defect toward autologous EBV-infected B lymphoblasts, which could not be corrected by the addition of lymphokine-mediated T-cell help, was also documented. A lymph node biopsy taken 5 years after her clinical presentation revealed lymph node architecture completely effaced by a diffuse CD3+, CD4+, Ia+, CR2+ T-cell lymphoma containing EBNA and linear, replicating EBV DNA. Select CEBVI patients with humoral and combined cellular aberrations in the immune response to EBV may be predisposed to the development of EBV+ T-cell tumors.     

From infection to autoimmunity

We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents. Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards. The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection. T cells and autoantibodies have been shown to be important for the development of autoimmune myocarditis. Many researchers have investigated the role of molecular mimicry in the development of myocarditis after viral infection. This review explores the 'adjuvant' effect of infection on the innate immune response and how this determines the progression to autoimmune disease. We show that NK cells protect against the development of disease, while complement and complement receptors are involved in the development of autoimmune myocarditis induced by inoculation with virus or cardiac myosin, respectively. Our results suggest that the innate immune response to viral and self-antigens may determine whether susceptible strains of mice progress to chronic autoimmune disease. These findings have broad implications for understanding the role of infection in inducing autoimmune disease.     

Immune deficiency and autoimmunity

Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.     

IgA deficiency and autoimmunity

IgA is the most abundant immunoglobulin in the human body, and performs a very specialized role which involves mucosal immunity, development of tolerance and protection against infection. IgA is the key immunoglobulin in the respiratory and gastrointestinal tracts, which provide the most intimate interface between the environment and self. Normal levels of IgA are based on early studies consisting of only small numbers of patients. The international consensus definition of IgA deficiency is a level of 0.07 g/l after the age of four years in the absence of IgG and IgM deficiencies. The epidemiology of IgA deficiency reveals interesting variances between geographical regions – the incidence in Caucasians being much higher than that in Asians. IgA deficiency has also been found to co-exist with autoimmune diseases, allergies and malignancies. The association with autoimmunity is particularly interesting because it suggests a common genetic linkage that could potentially also explain the diversity in geoepidemiology. Both MHC and non-MHC associations have been described and the 8.1 haplotype has been significantly associated with autoimmunity in IgA deficiency patients over controls. Non-MHC genetic associations include IFIH1 and CLEC16A. The mutations leading to IgA deficiency have not been defined, but in some cases of IgA deficiency it has been suggested that the pathogenesis involves a failure in switched memory B cells that can lead to this cohort experiencing an increased incidence of recurrent bacterial infections or autoimmune diseases. Attempts to investigate the role of cytokines that can induce IgA synthesis in cells of patients with IgA deficiency, such as IL21 or the combination of CD40L/anti-CD40, IL-4 and IL10, are underway.     

Primary bone natural killer/T cell lymphoma,nasal type without EBV infection: a case report

Primary bone NK/T cell lymphoma is very rare. We report a case of 52-year-old man of primary bone NK/T cell lymphoma and then progressed to NK leukemia. The patient had low-grade fever for 4-month, and Ultrasonic B revealed a diffuse hepatosplenomegaly without lymphadenopathy. PET scanning showed increased FDG uptake in many bones of the whole body. The diagnosis was established by bone specimen. These neoplastic cells demonstrated a typical immunophenotype of CD56, CD3, CD2 and MPO positive, and CD5, CD20, CD30, PAX-5, CD4 and CD8 negative. Primary bone ENKTL is very rare; it should be made with the combination of clinical feature, PET-CT image, and pathological characteristics, and should be distinguished from other lymphomas or leukemia involved in bone.     

Selective IgA deficiency and autoimmunity

Laboratory and clinical data are presented in fifteen patients under the age of sixteen years with selective IgA deficiency, all of whom had normal serum IgG, IgM, IgD and IgE. Results indicate a high incidence of autoimmune disease, autoimmune phenomenon or unusual antibody formation. Three patients had thyroiditis, one cerebral vasculitis, one pulmonary haemosiderosis, one cystic fibrosis and nine had recurrent upper respiratory tract infections. Ten out of fifteen were positive for one or more `autoantibodies.' Selective IgA deficiency cannot always be considered a benign entity and individuals with this defect warrant complete investigation.     

Virus infection,antiviral immunity,and autoimmunity

As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.     

Immunoglobulin deficiencies and susceptibility to infection among homozygotes and heterozygotes for C2 deficiency

About 25% of C2-deficient homozygotes have increased susceptibility to severe bacterial infections. C2-deficient homozygotes had significantly lower serum levels of IgG2, IgG4, IgD, and Factor B, significantly higher levels of IgA and IgG3 and levels of IgG1 and IgM similar to controls. Type I (28 bp deletion in C2 exon 6 on the [HLA-B18, S042, DR2] haplotype or its fragments) and type II (non-type I) C2-deficient patients with increased susceptibility to bacterial infection had significantly lower mean levels of IgG4 (p < 0.04) and IgA (p < 0.01) than those without infections (who had a higher than normal mean IgA level) but similar mean levels of other immunoglobulins and Factor B. Of 13 C2-deficient homozygotes with infections, 85% had IgG4 deficiency, compared with 64% of 25 without infections. IgD deficiency was equally extraordinarily common among infection-prone (50%) and noninfection-prone (70%) homozygous type I C2-deficient patients. IgD deficiency was also common (35%) among 31 type I C2-deficient heterozygotes (with normal or type II haplotypes), but was not found in 5 type II C2-deficient heterozygotes or 1 homozygote. Thus, C2 deficiency itself is associated with many abnormalities in serum immunoglobulin levels, some of which, such as in IgG4 and IgA, may contribute to increased susceptibility to infection. In contrast, IgD deficiency appears not to contribute to increased infections and appears to be a dominant trait determined by a gene or genes on the extended major histocompatibility complex (MHC) haplotype [HLA-B18, S042, DR2] (but probably not on type II C2-deficient haplotypes) similar to those previously identified on [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3].     

The high frequency of EBV infection in pediatric Hodgkin lymphoma is related to the classical type in Bahia, Brazil

Pediatric Hodgkin lymphoma (HL) occurring in developing regions is different from HL in industrialized countries due to the higher frequency of association with Epstein–Barr virus (EBV) infection. This infection is related to classical HL (cHL) but is virtually absent in nodular lymphocyte predominant HL (nLPHL). We studied the phenotype and the expression of EBV gene products in 90 pediatric cases by immunohistochemistry and in situ hybridization. EBV-positive tumor cells were found exclusively in cHL. The infection occurred with high frequency in all cHL subtypes, but it predominated in the mixed cellularity and lymphocyte depletion subtypes. These results reinforce the hypothesis that EBV plays a major role in the etiology of pediatric cHL in developing areas. Curiously, the frequency of EBV infection in HL was identical to the previously described for Burkitt’s lymphoma in the same pediatric population. As both lymphomas have a postulated precursor cell in the germinal center (GC), the pattern of latently EBV-infected GC cells previously described in Bahia may be related to the development of these lymphomas.     

Parasitic infection and autoimmunity

The studies summarized in this paper indicate that parasitic infections can serve as a trigger factor of autoimmune reactivity by several mechanisms. The relationship between parasites and autoimmunity could be manifested by the presence of autoantibodies or T-cells with autoreactivity. In spite of the evidence that has accumulated, the specific association between infection and autoimmunity is still obscure. The reasons for tissue damage in parasitic diseases are controversial. Some believe it is the result of pathogenic autoantibodies or autoreactive T-cells. Others argue against the causative role of autoimmunity in the formation of tissue lesions. The parasite itself could be the cause of tissue destruction, thus releasing high amounts of self antigens which might stimulate the autoreactivity. There is now little doubt that some degree parasite/host cross-reactivity occurs, and definition of cross-reacting antigens and epitopes is now taking place. It seems likely that a combination of events could result in cross-reactivity including: parasites themselves have cross reactive molecules and altered self antigens by adsorbing of parasite material to surrounding host cells. The mechanisms involved in parasites autoimmunity are complex and numerous, requiring a rigorous experimental approach to rationalize each step and determine its clinical importance. The developed methods in immunochemistry, monoclonal antibodies and hybridoma technology, and recombinant DNA research not only facilitate this kind of approach but also allow optimism for a successful outcome.     

Cryptic infection and autoimmunity

Infection as an environmental factor in autoimmunity has long been recognized. Numerous examples can be found in which pathogens express antigens that cross-react with host antigens or induce local inflammatory responses that can lead to autoimmune responses through a very complex set of circumstances. Borrowing from the relationship between chronic infection with hepatitis C virus and autoimmune hepatitis as an example, we consider the possibility that infection with an unknown virus having specific tissue tropism could lead to a perceived autoimmune process. We raise the question whether such should be considered for Type 1 diabetes.     

Common variable immune deficiency and autoimmunity

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by various degrees of hypogammaglobulinemia. Similar to many immunodeficiency disorders, autoimmunity is common with an association with autoimmune cytopenias, a sarcoidosis-like disorder and inflammatory bowel disease. Recent efforts have characterized selective immunological defects and genetic associations in CVID and demonstrate an increased tendency towards loss of tolerance. The mainstay of treatment of autoimmune disease in such patients is often high dose IVIG and corticosteroids, although other therapies, including TNF-alpha antagonists, have been reported. While the etiology of increased autoimmunity in CVID remains elusive, certain genetic predispositions in combination with repeated antigen exposure and overall immune dysregulation inherent in CVID likely play a significant role.     

HHV-6 and EBV DNA quantitation in lymph nodes of 86 patients with Hodgkin's lymphoma

Human herpesvirus (HHV-6) and Epstein-Barr virus (EBV), are two ubiquitous human herpesviruses which share many common features although they belong to different sub-families. In particular, both viruses are found in lymph nodes of patients suffering from Hodgkin's lymphoma. The aim of this study was to detect and to quantify independently HHV-6 and EBV by a real-time PCR in lymph nodes from 86 patients with Hodgkin's lymphoma. EBV quantitative method was compared with LMP-1 protein detection among the same samples. EBV genome was detected for 61.6% of the patients (53/86) and the highest prevalence of this virus was observed in Hodgkin's lymphoma with mixed-cellularity histopathological type (80%). In contrast to that, HHV-6 genome was detected for 79.1% of the patients (68/86) and was most observed in the nodular-sclerosis group (83.6%). Among the 68 HHV-6 positive samples, 63 belonged to the B subtype. A large number of biopsies (47.7%) were positive for both viruses whereas a little number (7%) was negative for both. EBV quantitation and LMP-1 immunohistochemistry were correlated statistically but this latter technique was less sensitive. Among the nodular-sclerosis patients, HHV-6-/EBV+ patients were significatively older than HHV-6+/EBV- patients. Patients infected dually had higher values of quantitation for each virus than those positive for one virus. Data of the clinical follow-up obtained by diagnosis and during the treatment of 83 patients, were correlated with the virological findings.     

Lyme borreliosis: from infection to autoimmunity

Lyme borreliosis in humans is an inflammatory disease affecting multiple organ systems, including the nervous system, cardiovascular system, joints and muscles. The causative agent, the spirochaete Borrelia burgdorferi, is transmitted to the host by a tick bite. The pathogenesis of the disease in its early stages is associated largely with the presence of viable bacteria at the site of inflammation, whereas in the later stages of disease, autoimmune features seem to contribute significantly. In addition, it has been suggested that chronic persistence of B. burgdorferi in affected tissues is of pathogenic relevance. Long-term exposure of the host immune system to spirochaetes and/or borrelial compounds may induce chronic autoimmune disease. The study of bacterium-host interactions has revealed a variety of proinflammatory and also immunomodulatory-immunosuppressive features caused by the pathogen. Therapeutic strategies using antibiotics are generally successful, but chronic disease may require immunosuppressive treatment. Effective and safe vaccines using recombinant outer surface protein A have been developed, but have not been propagated because of fears that autoimmunity might be induced. Nevertheless, new insights into the modes of transmission of B. burgdorferi to the warm-blooded host have been generated by studying the action of these vaccines.     

CCR1 deficiency increases susceptibility to fatal coronavirus infection of the central nervous system

The role of CC chemokine receptor 1 (CCR1) in host defense and disease development was determined in a model of viral-induced neurologic disease. Intracerebral (IC) infection of mice with mouse hepatitis virus (MHV) results in an acute encephalitis followed by a chronic demyelinating disease similar in pathology to the disease multiple sclerosis (MS). No increase in mortality was observed during the acute phase of disease following MHV infection of mice lacking CCR1 (CCR1-/-) as compared to wild-type (CCR1+/+) mice. However, by 21 d post-infection, 74% of CCR1-/- mice had succumbed to death compared to only 32% mortality of CCR1+/+ mice, indicating that chemokine signaling through CCR1 significantly (p 相似文献   

EB病毒与人疱疹病毒6型感染在药疹发生中的作用

目的 本研究主要就人疱疹病毒6型(HHV-6)与EB病毒(EBV)感染在药疹产生过程中的作用展开分析,以此来为药疹患者的临床治疗提供参考.方法 选择我院2012年12月--2013年12月所收治的62例药疹患者作为观察组,另选148例健康献血人员作为对照组,采用巢式PCR对HHV6 DNA进行检测、采用PCR-Southern对EBV DNA进行检测、采用ELISA法对EBV VCA-IgM进行检测,并对其检测结果进行比较.结果 两组患者的EBV DNA、HHV6 DNA、EBV VCA-IgM阳性率存在明显差异,具有统计学意义(P＜0.05).结论 绝大部分药疹患者存在EBV感染的情况,且EBV感染与HHV6感染之间存在相互激活的作用,在药疹诊断过程中具有较高的临床应用价值,可以将其作为药疹的临床诊断指标之一.