Role of basophils in protective immunity to parasitic infections

Basophils have been recognized as important players for protective immunity against a variety of different endo- and ectoparasites. Although basophils represent a relatively rare and short-lived cell type, they produce large quantities of effector molecules including histamine, cytokines, chemokines, and lipid mediators which promote type 2 immune responses. Basophils can be activated either directly by parasite-derived factors or indirectly by recognition of parasite-derived antigens via IgE bound to its high-affinity receptor FcεRI on the cell surface. Many parasitic infections cause expansion and tissue recruitment of basophils, but the role of basophils for protective immunity remains poorly understood. The development of basophil-deficient mouse models over the past few years makes it possible to study their contributions in various infections. We review here the current knowledge regarding the role of basophils for protective or immunomodulatory functions of basophils mainly during infections of mice with protozoan parasites, helminths, and ectoparasites.     

Primary immunodeficiencies of protective immunity to primary infections

The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations in IL12B or IL12RB1 typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations in IRAK4 or MYD88 suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations in UNC93B1 and TLR3 are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.     

Serological speciation of human T-cell leukaemia virus infections using synthetic peptide antigens

In order to assess the specificity and sensitivity of two peptide-based assays (Synth^TM HTLV-I and HTLV-II enzyme-linked immunoassay [EIA] [UBI] and Select-HTLV^TM EIA [IAF]) in discriminating between antibody to HTLV-I and HTLV-II infection, a panel of 186 well-characterised serum/plasma samples was tested by the two assays. The panel comprised 160 samples that by Western blot were confirmed to contain antibodies to HTLV-I/II and 26 samples that showed reactivity with gag but not env gene products. Both assays were found to be specific in that they did not misclassify any of the 80 specimens from cases of tropical spastic paraparesis or adult T-cell leukaemia/lymphoma, diseases believed to be HTLV-I associated, as anti-HTLV-II positive. Of the 160 specimens confirmed as anti-HTLV-I/II positive by Western blot, 6.2% were negative or untypable in the Synth EIA compared with 13.7% in the Select EIA. Of the 26 Western blot indeterminate samples, 16 were negative by both assays. Five were typed as anti-HTLV-I by both assays and 5 as anti HTLV-II by Select EIA only. The peptide based EIAs offer an economical and, in most cases, reliable means of discriminating between anti-HTLV-I and anti-HTLV-II. However, they should only be applied to sera that have been confirmed by Western blot or other methods as anti-HTLV-I/II positive. Even then they may fail to speciate sera from non-Japanese, non-Afrocaribbean populations. © 1993 Wiley-Liss, Inc.     

The early cellular signatures of protective immunity induced by live viral vaccination

Here, we have used primary vaccination of healthy donors with attenuated live yellow fever virus 17D (YFV-17D) as a model to study the generation of protective immunity. In short intervals after vaccination, we analyzed the induction of YFV-17D specific T- and B-cell immunity, bystander activation, dendritic cell subsets, changes in serum cytokine levels, and YFV-17D-specific antibodies. We show activation of innate immunity and a concomitant decline of numbers of peripheral blood T and B cells. An early peak of antigen-specific T cells at day 2, followed by mobilization of innate immune cells, preceded the development of maximal adaptive immunity against YFV-17D at day 14 after vaccination. Interestingly, potent adaptive immunity as measured by high titers of neutralizing YFV-17D-specific antibodies, correlated with early activation and recruitment of YFV-17D-specific CD4(+) T cells and higher levels of sIL-6R. Thus our data might provide new insights into the interplay of innate and adaptive immunity for the induction of protective immunity.     

Cell-mediated immunity to respiratory virus infections

The mucosal surfaces of the lungs pose tremendous problems for an immune system charged with maintaining a sterile pulmonary environment. Despite these problems, the immune system is effective at controlling most pulmonary infections. Over the past few years significant progress has been made in our understanding of how adaptive (humoral and cellular) immunity is able to control infections in the respiratory tract. Recent advances include the identification of effector memory T-cell populations in the lungs and an appreciation for the role of cytokines in regulating memory T-cell pools.     

Mammary epithelial cells support and transfer productive human T-cell lymphotropic virus infections

OBJECTIVES: To investigate whether luminal and basal human mammary epithelial cells (HMEC) are susceptible to productive infection by human T-cell lymphotropic virus types I and II (HTLV-I and HTLV-II) and whether HTLV infection of breast epithelial cells could contribute to the seeding of milk with HTLV infectivity and support virus transmission from mother to nursing infant. STUDY DESIGN/METHODS: Primary cultures of basal epithelial cells were infected by coculture with mitomycin-C-treated HTLV-producer T-cell lines and HTLV-infected milk epithelial cells, and the transfer of infection was monitored by polymerase chain reaction (PCR) amplification and immunocytochemical staining. RESULTS: Basal mammary epithelial cells were found to be susceptible to HTLV infection and capable of transferring HTLV infection to normal peripheral blood lymphocytes (PBL). CONCLUSIONS: A reservoir for HTLV infectivity could exist in mammary epithelial cells and contribute to the introduction of HTLV infectivity into milk by infecting lymphocytes that traverse the epithelium and by the release of infected epithelial cells, infectious cell fragments, and free virions directly into the milk.     

T-cell imbalances and NK activity in varicella-zoster virus infections

Samples of peripheral blood lymphocytes (PBMC) were serially obtained from 30 patients with herpes zoster (HZ) and 10 patients with chickenpox (CP). Cells were assayed for NK-cell function and for the expression of surface membrane antigens which identify T-cell and NK-cell subsets. During the acute phase of disease (less than 7 days from onset), PBMC from patients with HZ had low proportions of T-helper (CD 4+) cells and a large number of T-suppressor (CD 8+) cells, resulting in a low T-helper/T-suppressor ratio. There was an increased percentage of nonspecific suppressor cells (GD 8+-CD 11+ cells) and increased expression of HLA-DR determinants on both CD 8+ and CD 4+ cells. The NK activity was depressed with no concomitant decrease in NK cells (CD 16+ or Leu 7+ cells). In the early convalescing phase of disease (8-14 days), there was a significant increase in CD 16+ cells and increased expression of HLA-DR on these cells, correlating with increased NK activity. In the late recovery phase (greater than 14 days), NK activity and levels of T-cell subpopulations were normal with the exception of increased CD 4+ cells and, consequently, of the helper/suppressor ratios. In the acute phase of CP (less than 7 days), the T-cell imbalances were similar to those encountered with HZ patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections.

In serum, the enzyme adenosine deaminase (ADA) is known to be divided into two isoenzymes, ADA1 and ADA2, which have different molecular weights and kinetic properties. The present study investigated ADA isoenzyme levels in the sera of patients infected with retroviruses associated with adult T-cell leukemia (ATL), human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), and AIDS, ADA isoenzyme activities were found to be significantly (P < 0.001) higher in the sera of patients with ATL, HAM, and AIDS than in the sera of healthy controls. In the case of the ADA subtypes in the sera of patients with ATL, ADA1 activity was significantly (P < 0.001) elevated in patients with the acute and lymphoma types of ATL compared with that in patients with the chronic and smoldering types of ATL. ADA2 activity was significantly elevated in the sera of patients with the acute, lymphoma, and chronic types of ATL (P < 0.001) compared with that in patients with smoldering ATL and HTLV-1 carriers. In the case of patients with human immunodeficiency virus type 1 (HIV-1) infection, ADA1 and ADA2 activities in the sera of patients with AIDS and HIV-1 antibody-positive individuals were significantly (P < 0.001) higher than those in the sera of HIV-1 antibody-negative individuals. A significant elevation in ADA2 activity was also seen in the sera of AIDS patients (P < 0.01) compared with that in the sera of HIV-1 antibody-positive individuals. These results suggest that the magnitude of elevation of ADA isoenzyme levels in serum correlates well with the clinical conditions of the patients with these diseases. Measurement of the activities of ADA isoenzymes may therefore provide an additional parameter for distinguishing the subtypes of ATL and may prove to be useful as prognostic and therapeutic monitors in diseases associated with HTLV-1 and HIV-1 infections.     

Cellular immunity and memory to respiratory virus infections

Respiratory virus infections, such as those caused by influenza and parainfluenza viruses, are a major cause of morbidity and mortality worldwide. Current vaccines against these pathogensrely on the induction of humoral immune responses that target viral coat proteins. Although this type of immunity provides solid protection against homologous virus strains, it is ineffective against heterologous virus strains that express serologically distinct coat proteins. In contrast, cellular immune responses can target internal an tigens that are shared between heterologous viral strains. This form of immunity, sometimes referred to as heterosubtypic immunity, can mediate a substantial degree of protection. Thus, vaccines that emphasize cellular immune responses would be a valuable complement to available humoral vaccines. However, we only have a rudimentary understanding of which T cell subsets mediate protective immunity, how T cell memory isestablished and maintained, how that memory is recalled in a secondary infection, and why cellular immunity wanes rapidly with time. Here we review the role of CD4⁺ and CD8⁺ T cells in the recall response to influenza and parain fluenza viruses. In particular we focus on the recent observation that substantial numbers of memory T cells are established in the lung tissues and discuss the potential role of these cells in mediating a recall response. A thorough understanding of the cellular immune response to infection in the lungs is essential for future vaccine development.     

The role of RNAi and microRNAs in animal virus replication and antiviral immunity

The closely related microRNA (miRNA) and RNAi pathways have emerged as important regulators of virus–host cell interactions. Although both pathways are relatively well conserved all the way from plants to invertebrates to mammals, there are important differences between these systems. A more complete understanding of these differences will be required to fully appreciate the relationship between these diverse host organisms and the various viruses that infect them. Insights derived from this research will facilitate a better understanding of viral pathogenesis and the host innate immune response to viral infection.     

Development of protective immunity against bacterial and viral infections in tumor-bearing mice coincident with suppression of tumor immunity

This report addresses the question whether Meth A (methylcholanthrene-induced fibrosarcoma) tumor bearing Balb/c mice are able to develop specific antimicrobial immunity. Although specific suppressor T lymphocytes appeared during tumor growth which prevented expression of antitumor immunity, the development of protective immunity to L monocytogenes, S. pneumoniae or ectromelia virus infections was unimpaired. The Meth A tumor produced a soluble immunosuppressive factor which inhibited lymphocyte and macrophage functions in vitro. Tumor growth failed to inhibit the formation of immunoglobulin essential to antipneumococcal immunity, or the development of a specific acquired cellular resistance of primary importance in immunity to listeria and ectromelia virus infections. That tumor growth did not interfere with the development of cell mediated immunity was demonstrated by the effective transfer of antilisteria immunity by immune spleen from tumor-bearing mice.     

T-cell memory and recall responses to respiratory virus infections

Summary: The respiratory tract is characterized by its large surface area and the close association of an extensive vasculature with the external environment. As such, the respiratory tract is a major portal of entry for many pathogens. The immune system is able to effectively control most pulmonary pathogens and establish immunological memory that is capable of mediating an accelerated and enhanced recall response to secondary pathogen challenge. A key component of the recall response in the lung involves the rapid response of antigen‐specific memory CD8⁺ T cells. Recent studies have shown that memory CD8⁺ T cells are extremely heterogeneous in terms of phenotype, function, anatomical distribution, and longevity. However, we have little understanding of how the different subsets of memory cells actually contribute to the recall response, especially with respect to peripheral or mucosal sites, such as the lung. Since immunological memory is the cornerstone of vaccination, it is essential that we understand how different memory CD8⁺ T‐cell subsets are initially generated, maintained over time, and contribute to recall responses. This review focuses on memory T cells that mediate recall responses to influenza and parainfluenza virus infections in the lung.     

Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes,independent of T-cell immunity

Homologous and heterologous parenteral prime–mucosal boost immunizations have shown great promise in combating mucosal infections such as tuberculosis and AIDS. However, their immune mechanisms remain poorly defined. In particular, it is still unclear whether T-cell and innate immunity may be independently affected by these immunization modalities and how it impacts immune protective outcome. Using two virus-based tuberculosis vaccines (adenovirus (Ad) and vesicular stomatitis virus (VSV) vectors), we found that while both homologous (Ad/Ad) and heterologous (Ad/VSV) respiratory mucosal boost immunizations elicited similar T-cell responses in the lung, they led to drastically different immune protective outcomes. Compared with Ad-based boosting, VSV-based boosting resulted in poorly enhanced protection against tuberculosis. Such inferior protection was associated with differentially imprinted innate phagocytes, particularly the CD11c⁺CD11b^+/− cells, in the lung. We identified heightened type 1 interferon (IFN) responses to be the triggering mechanism. Thus, increased IFN-β severely blunted interleukin-12 responses in infected phagocytes, which in turn impaired their nitric oxide production and antimycobacterial activities. Our study reveals that vaccine vectors may differentially imprint innate cells at the mucosal site of immunization, which can impact immune-protective outcome, independent of T-cell immunity, and it is of importance to determine both T-cell and innate cell immunity in vaccine studies.     

Transfer of protective immunity in murine histoplasmosis by a CD4+ T-cell clone.

We have reported that a murine Histoplasma capsulatum-reactive CD4+ T-cell line and clones thereof did not adoptively transfer protection against H. capsulatum infection in normal or cyclophosphamide-treated C57BL/6 mice. One explanation for the results was that the T cells failed to traffic to lymphoid organs in these animals. In this study, we have sought to determine whether one of these clones, 2.3H3, could mediate protection in nude (C57BL/10) or irradiated (5 Gy) heterozygous nude (nu/+) C57BL/6 mice. Mice were inoculated intravenously with 10(7) resting 2.3H3 cells or with an equal number of cells of the ovalbumin-reactive clone 1S6; 2 h later, the mice were challenged intranasally with 5 x 10(6) yeast cells. By day 5 of infection, lungs, livers, and spleens of nude and irradiated nu/+ mice given 2.3H3 contained significantly fewer (P < 0.05) CFU than the same organs from mice inoculated with 1S6. This effect was specific for H. capsulatum, since 2.3H3 did not reduce the number of Coccidioides immitis CFU in lungs, livers, and spleens of irradiated nu/+ mice. By day 10, the amounts of H. capsulatum CFU in lungs, livers, or spleens of nude and irradiated nu/+ mice inoculated with 2.3H3 were smaller than those in 1S6-inoculated mice, but these differences did not reach statistical significance (P > 0.05). The mortality rate of mice inoculated with 2.3H3 and that of mice inoculated with 1S6 were similar. Histopathological examination of tissues from 2.3H3- and 1S6-inoculated mice demonstrated the presence of granulomatous inflammation in organs from both groups. Tissues from 2.3H3-treated mice contained fewer yeasts per high-power field than tissues from 1S6-treated mice. Thus, irradiated or nude mice are permissive for the expression of protective immunity by a CD4+ T-cell clone. Although the protective capacity of T cells in these animals is transient, these animals will be useful for differentiating protective from nonprotective T-cell clones.