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Viruses have been implicated in the initiation, progression, and exacerbation of several human autoimmune diseases. Evidence also exists that viruses can protect against autoimmune disease. Several proposed mechanisms explain the viral effects. One mechanism is "molecular mimicry" which represents a shared immunologic epitope with a microbe and the host. We consider, using a simple mathematical model, whether and how a viral infection with molecular mimicry can be beneficial or detrimental for autoimmune disease. Furthermore, we consider the possibility of development of a vector therapeutic vaccine that can relieve autoimmune disease symptoms. Our findings demonstrate that vaccine therapy success necessitates (i) appropriate immune response function, (ii) appropriate affinities with self and non-self antigen, and (iii) a replicative vector vaccine. Moreover, the model shows that the viral infection can cause autoimmune relapses.

The incidence of follicular lymphoma differs significantly between white and Japanese individuals. Translocation between the BCL-2 and immunoglobulin heavy chain genes is detected in 85% to 90% of all follicular lymphomas in whites. Recently, BCL-2/J(H) translocation was detected in peripheral blood lymphocytes from more than 50% of healthy white individuals. To clarify the reason for the difference in incidence of follicular lymphoma between whites and Japanese, the frequency of BCL-2/J(H) translocation in peripheral blood lymphocytes of healthy Japanese individuals was compared with that of German individuals. The prevalence of BCL-2/J(H) translocation in Japanese adults appeared to be significantly lower than that in German adults. The present data suggest that the low frequency of BCL-2/J(H) translocation in the Japanese general population may be one of the major reasons for the difference in incidence of follicular lymphoma between whites and Japanese.

It has been reported recently that CD4 is a major component of the receptor for human herpesvirus-7 (HHV-7), which has been newly identified as a T-lymphotropic virus. To investigate further the role of CD4 in HHV-7 infection, we examined the susceptibility to HHV-7 infection of various CD4-negative or weakly positive cell lines into which the cDNA for CD4 was transferred using an adenovirus vector. Out of 13 cell lines transduced with a CD4 gene, one T-lymphoid cell line, one monocytoid cell line, and two myeloid cell lines showed high susceptibility to HHV-7 infection. Taken together with previous studies, these data suggest strongly that CD4 is a major component of the binding receptor for HHV-7.

It has been reported recently that CD4 is a major component of the receptor for human herpesvirus 7 (HHV-7), which has been newly identified as a T-lymphotropic virus. To investigate further the role of CD4 in HHV-7 infection, we examined the susceptibility to HHV-7 infection of various CD4-negative or weakly positive cell lines into which the cDNA for CD4 was transferred using an adenovirus vector (Adex1CACD4). Of 13 cell lines transduced with Adex1CACD4, including T-lymphoid, B-lymphoid, monocytoid, and myeloid cell lines, one T-lymphoid cell line, one monocytoid cell line, and two cell lines established from the blast crisis of chronic myelogenous leukemia showed high susceptibility to HHV-7 infection. Taken together with the results of previous studies, these data suggest strongly that CD4 is a major component of the binding receptor for HHV-7. This study also shows that HHV-7 may be able to infect CD4-positive hematopoietic precursor cells as well as T lymphocytes.

An enzyme linked immunosorbent assay (ELISA) system to study specific anti-herpes simplex virus (HSV) antibody production in vitro by human peripheral blood mononuclear cells (PBMC) has been developed. HSV specific antibody production was detected in culture supernatants of PBMC from HSV seropositive healthy individuals by stimulating with optimal concentrations of HSV antigen without mitogens. To investigate the specificity of the resulting antibody, a limiting dilution analysis was performed as follows. PBMC from HSV-1 seropositive and HSV-2 seronegative individuals were stimulated by wild type HSV-1 (KOS), glycoprotein C deletion mutant of HSV-1 (MP), and wild type HSV-2 (186), and the precursor frequencies of B cells which produce antibodies to HSV-1 (KOS), HSV-1 (MP) and HSV-2 (186) were then estimated. When PBMC from five individuals were stimulated by HSV-1 (KOS), the estimated precursor frequencies of B cells which produced antibodies to HSV-1 (KOS), HSV-1 (MP), and HSV-2 (186) were 1/79,000 to 1/37,000, 1/104,000 to 1/52,000. and 1/78,000 to 1/101,000, respectively. On the other hand, when PBMC were stimulated by HSV-1 (MP) and HSV-2 (186), the precursor frequencies of B cells which produced antibody to HSV-1 (KOS) were the same as those to HSV-1 (MP) and HSV-2 (186), respectively. By using the experimental systems reported here, it became possible to determine clearly the immune status to HSV type-specific and type-common antigens and to each viral glycoprotein.

The levels of rheumatoid factor (RF), antinuclear antibody (ANA), and composition of peripheral lymphocyte subsets in 515 dogs were examined. Of these sample cases, 33 cases were diagnosed as immune-mediated fever that presented with high C-reactive protein (CRP), 31 cases were diagnosed with Hansen's Type 1 disc herniation and the remaining 415 cases were clinically healthy dogs, and served as controls. In the cases diagnosed with immune-mediated fever, 84% of the dogs tested positive to either RF or ANA (RF positive 60.6%; ANA positive 24.2%). By contrast, 16.2% of the healthy dogs were positive for either RF or ANA (RF positive 14.9%; ANA 1.3%). The CD4/CD8 ratio for peripheral lymphocyte was high for all analysed cases diagnosed with immune-mediated fever, and was significantly higher than those of healthy controls. These results indicate that the abnormal levels of lymphocytes may be an effective indicator for immune-mediated disease coupled to immune-mediated fever. [ABSTRACT FROM AUTHOR]

Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in experimental graft-vs-host disease (GVHD) models. Chemokines play an important role in the recruitment of alloreactive donor T cells into target organs during GVHD. In this study, we investigated the effectiveness of targeted delivery of CD4+CD25+ regulatory T cells via a transfected chemokine receptor on reduction of organ damage during acute GVHD. High levels of expression of Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and their receptor CXCR3 were observed in the liver, lung and intestine of GVHD-induced recipient mice. Recipient mice that had undergone transfer of CD4+CD25+Foxp3+ CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver, lung and intestine in comparison with recipient mice that had received CD4+CD25+Foxp3+ T cells (Treg cells) or naturally occurring CD4+CD25+ regulatory T cells. This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in Th1-associated chemokine-expressing organs, resulting in stronger suppressive activity. We succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.Gene Therapy (2008) 15, 171–182; doi:10.1038/sj.gt.3303051; published online 8 November 2007 [ABSTRACT FROM AUTHOR]

Mediation of Epstein-Barr virus (EBV)-specific cytotoxicity in T lymphocyte via the perforin/granzyme pathway has been demonstrated; therefore, a study involving cytolytic molecules was essential for the clarification of hemophagocytic lymphohistiocytosis (HLH) pathogenesis. This investigation, which analysed the frequency of three allelic mutations of granzyme-B (55Q/R, 95P/A and 247Y/H) in patients with EBV-HLH and infectious mononucleosis, identified the high prevalence of the QPY haplotype in EBV-HLH patients in comparison with healthy controls. A > G polymorphism was also detected in intron 5; furthermore, nearly complete linkage disequilibrium was observed among these polymorphisms. The recessive role of the QPY haplotype of granzyme-B might be responsible for the pathogenesis of EBV-HLH. Cytotoxicity and DNA fragmentation of cytotoxic T lymphocytes did not differ among patients characterized by the QPY/QPY, RAH/RAH and QPY/RAH genotypes. This finding suggested that DNA fragmentation in target cells is mediated not only by granzyme-B but also by other molecules, including other granzymes or Fas. [ABSTRACT FROM AUTHOR]

Background: Familial haemophogocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. Objective: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients. Methods: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4 deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. Results: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18 and exons 8 and 19. Two famlies had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. Conclusions: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway. [ABSTRACT FROM AUTHOR]

In vitro cell-mediated immune responses to rotavirus in humans were studied. Peripheral blood mononuclear cells (PBMC) of healthy adults proliferated in response to stimulation with the infectious and u.v.-inactivated Wa strain of human rotavirus, showing a maximum response on day 7 of culture; however, cord blood lymphocytes failed to respond to rotavirus. A cross-reactive proliferative response of PBMC detected by stimulation with the NCDV strain of bovine rotavirus suggests the existence of epitopes common to both human and bovine rotaviruses, which are recognized by human T lymphocytes. The phenotype of the majority of activated lymphocytes was CD3+4+8-, indicating that the cells mainly activated were helper T cells. Culture supernatants of PBMC stimulated with rotavirus contained interleukin-2 (IL-2) and interferon-gamma (IFN-γ). In addition, PBMC stimulated with rotavirus demonstrated significantly enhanced cytotoxic activity against natural killer (NK) sensitive K562 cells as well as an NK-resistant Epstein-Barr virus-immortalized lymphoblastoid cell line (LCL). Treatment of PBMC with anti-CD16 or NKHIA monoclonal antibody, both of which react with most NK cells and lymphokine-activated killer cells and complement markedly reduced the cytotoxic activity against K562 and LCL. These results suggest that stimulation of human PBMC with rotavirus results in the production of lymphokines, such as IL-2 and IFN-γ, by rotavirus-reactive helper T cells and that these lymphokines augment NK activity and generate other forms of non-specific cytotoxic human lymphocyte activity. These cell-mediated immune responses observed in the present in vitro study might play an important role in protection and recovery from rotavirus infection. [ABSTRACT FROM AUTHOR]

T-cell prolymphocytic leukemia (T-PLL) is a postthymic T-cell neoplasm with a characteristic morphology and heterogeneous immunophenotype. Most cases of T-PLL express membrane T-cell receptors (TCRs) of the αβ phenotype. We experienced a 30-year-old man suffering from TCRγδ T-cell leukemia with morphology compatible to T-PLL with a postthymic phenotype. He was admitted with skin eruption and pancytopenia. Peripheral blood and bone marrow were occupied with medium-sized lymphocytes, which had moderately condensed chromatin with a single nucleolus and sparse, nongranular basophilic cytoplasm. The immunophenotype was CD1a–, CD2–, CD3+, CD4–, CD5+, CD7+, CD8–, and terminal deoxynucleotidyl transferase negative. Hepatosplenomegaly was absent. He was diagnosed as having T-PLL and was treated with combination chemotherapy. Six months later the leukemic cell became chemoresistant. Although the patient showed transient improvement in response to pentostatin, he died 13 months after the diagnosis. To our knowledge, this is the first case of T-PLL with a TCRγδ phenotype. [ABSTRACT FROM AUTHOR]