ABSTRACT One’s history of infections can affect the immune response to unrelated pathogens and inﬂuence disease outcome through the process of heterologous im- munity. This can occur after acute viral infections, such as infections with lympho- cytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study heterologousimmunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV ⫹ MCMV), they had more severe im- munopathology, enhanced viral burden in multiple organs, and suppression of MCMV-speciﬁc T cell memory inﬂation. MCMV infection initially reduced the num- bers of LCMV-speciﬁc memory T cells, but continued MCMV persistence did not fur- ther erode memory T cells speciﬁc to LCMV. When MCMV infection was given ﬁrst (MCMV ⫹ LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly deﬁned putative MCMV epitope sequence, M57 727–734 , and the
induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral chal- lenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host’s TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homolo- gous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonal- ity, including extremes in clonal dominance, may be a consequence of heterologousimmunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes.
Despite the evidence that cross-species immunity can be highly protective, it remains controversial whether this form of immunity plays a role in protection from malaria. Malaria is a parasitic disease caused by ﬁve species of Plasmodium with overlapping endemicity in many geographic areas. Population-based data from several regions where multiple species of Plasmodium coexist, such as South Asia, Southeast Asia and parts of Oceania, are consistent with heterologousimmunity against Plasmo- dium falciparum following prior infection with Plasmodium vivax (9–13). However, the mechanism of heterologousimmunity to malaria is not deﬁned. In humans, T cells induced by vaccination with P. falciparum respond in vitro to Plasmodium knowlesi- infected red blood cells, suggesting a role for the cellular arm of the immune system (14). In other studies, there is clearly heterologous cross-reactivity between antibodies as sera from patients infected with P. vivax cross-reacted with antigens from P. falciparum (15–19). These antibodies may cross-react with orthologous proteins in- volved in the same biological pathways in each species, such as PfMSP5/PvMSP5 (20), PfCLAG9/PvCLAG9 (21), PfAMA-1/PvAMA-1 (22), PfCSP/PvCSP and PfMSP-1/PvMSP-1 (23), and between Pfs48/45 and Pvs48/45 (24). However, functional activity of these cross-reactive antibodies was not reported.
An important question is how histories of exposures to pathogen-specific vaccines have influenced the outcome of in- fections with other pathogens. Two human diseases that have affected millions are tuberculosis and smallpox, and millions of individuals have also been vaccinated against those diseases. Vaccination against M. tuberculosis uses a closely related but less virulent strain of Mycobacterium bovis, referred to as ba- cillus Calmette-Guerin (BCG) (33). Several early reports indi- cated that a recent exposure of mice to BCG or to M. tuber- culosis rendered them more resistant to infection to a variety of bacteria and to ectromelia virus (16, 40, 44), the mouse form of smallpox, and to VV (3, 56), which is used for vaccination of humans against smallpox. An unspecified IFN was suggested to be involved in the protection against ectromelia virus (40, 44). Given the importance of these vaccines and pathogens, we have examined the mechanism of this protection, using mod- ern immunological approaches. We show here evidence for a CD4 T-cell-mediated heterologousimmunity between a myco- bacterium (BCG) and a virus, VV.
mycin, did not significantly inhibit memory cell func- tion in our model. In contrast, the combination of T cell costimulation blockade and the immunosuppressive agent DSG synergized to inhibit the function of memo- ry T cells in both allograft and viral models. The putative mechanism of action of DSG is to inhibit translocation of NF-κB, a transcription factor involved in many cellu- lar processes, including T cell activation (41). Interest- ingly, NF- κ B plays a critical role in determining the bal- ance between pro- and antiapoptotic factors, which in turn determine the fate of the cell (42, 43). The experi- ments in which we cotransfer LCMV-specific and allo- specific memory cells indicate that the combination of DSG and costimulation blockade can induce inactiva- tion of antigen-specific memory cells, since only those cells encountering their cognate ligands during the peri- od of drug administration were affected. Protective immunity was preserved, since viral memory cells not specific for the tolerogen (donor marrow) remained fully competent and capable of responding to a subsequent viral rechallenge. Inhibition of NF- κ B at a key step in memory T cell activation may result in a decrease in essential cellular survival signals and tip the balance toward cell death, permitting the deletion of antigen- specific memory cells.
The types of crossreactive T-cell response that are listed above would indicate that hosts that have never experienced a particular pathogen might, nevertheless, have memory T-cell pools that are specific for it by virtue of crossreactivity. The discovery of the epitope that is crossreactive between HCV and influenza virus was, in fact, made when individuals that were sero- negative for HCV were found to generate a putative ‘HCV-specific’ T-cell response 94 . Such a phenomenon could relate to recent findings of HIV-specific T cells in HIV-seronegative individuals who show no signs of harbouring HIV 98 . Several HIV-exposed persistently seronegative individuals have low-level HIV-specific T-cell responses to epitopes that are different from those that are recognized by HIV-infected seropositive individuals in the same community. Could the T-cell responses in the HIV-resistant subjects be the result of memory T cells that are crossreactive with other pathogens, and could those crossreactive responses confer a state of immunity? Of interest is the very recent observation that HIV-infected patients that are co-infected with the GBV-C flavivirus tend not to progress to AIDS 99,100 . Could this be an important example of heterologousimmunity?
Because the sIgA system is not fully mature until 4 years of age, it has been postulated that the barrier is in itself not fully mature until this time. sIgA derived from breast milk provides passive immunity against pathogens and may provide some form of barrier function in the newborn. IgE is not a well-recognized antibody in the GI tract. It is heavily glycosylated like IgA but can easily be degraded in the stomach and upper small intestine by proteases. Clearly in food allergy, IgE must be present in the GI tract. The studies described above by Berin et al 24 support the
20. What is a "state" for immunity purposes? s.14: Section 14 of the SIA deals with the meaning of "state" and largely reflects common law and customary international law. A distinction is made between the state, the head of state, its constituent/federal parts, and entities which may carry on the activities of the state but are not part of the state itself. Whether a territory is a state or not is settled by a certificate from The Secretary of State for Foreign and Commonwealth Affairs (s.21 SIA). A constituent territory of a federal state is only immune if an Order in Council so states (See Pocket Kings Ltd v Safenames Ltd  EWHC 2529 (Ch);  Ch. 438 about the US state of
Abstract: Sleep has been reported in several studies as an important function of the organism, as well as its deprivation as harmful to the production of defense cells, which affects our immunity. It is also demonstrated in the literature that sleep is fundamental for the metabolism of free radicals and for the body to be able to restore cardiorespiratory functions. The weakened immune system implies an increase in the chances of contracting infectious diseases, in addition to having difficulty recovering from relatively simple illnesses such as colds and flu. This study discusses sleep and its implications for organismic immunity. The results highlighted the need to perform sleep hygiene, defined as the change from dysfunctional patterns to a new organization of habits and activities that allow better sleep induction and quality.
Not only does T-helper and cytototoxic cell activation at the single cell level change with ageing, but the frequency and behaviour of regulatory T cells is attracting increased attention once more, also in the context of ageing. The maintenance of immunity has to be balanced with appro- priate controls to prevent non-specific inflammation and immunopathology, which it is thought are major prob- lems in ageing. Arne Akbar (University College, Lon- don), studying the susceptibility to apoptosis, telomere length, turnover and clonal composition of the regulatory population, reported that CD4+CD25+ T-regulatory cells (T-regs) are generated continuously, most likely by differ- entiation of CD4+ T-cells in the presence of regulatory cues . These concepts on the mechanisms and dynamic contributing to peripheral tolerance by CD4+CD25+ T-regs, have important implications for the design of therapeutic strategies involving generation and use of CD4CD25+ T-regs in autoimmune and inflamma- tory diseases. Clearly, their manipulation in ageing will also be of great potential benefit.
Although assessment of anti-DNA remains clinically valu- able, recent data suggest that the current conceptualization of anti-DNA needs revision. These data provide a new perspec- tive on lupus serology and show clearly that production of anti-DNA occurs in hosts with normal immunity as well as those with aberrant immunity. The salient feature of the pro- duction of normal anti-DNA, however, is its specificity for bacterial DNA. Furthermore, as shown in studies with both mice and humans, antibody induction is just one facet of bac- terial DNA’s far-reaching immunological properties. This re- view considers current information on antibody responses to DNA, focusing on their role in SLE as well as normal host defense.
lavage fluid collected from Ad5-HA/CA09-vaccinated pigs would cross-react with MN08 antigen. However, this was not the case. MN08-specific antibody was detected only in the lung lavage fluid of pigs in the Ad5-HA/MN08 group (Fig. 4C and D). The detec- tion of MN08-specific antibody in the BALF of Ad5-HA/MN08- vaccinated pigs was associated with a decrease in virus titers in the BALF at the same time point (5 dpi) (Table 3), as well as a decrease in lung IAV antigen scores compared to those of Ad5-empty/ MN08-challenged controls (Fig. 3C). Detection of cross-reactive antibody to MN08 in conjunction with a decrease in IAV in the lungs of Ad5-HA-vaccinated pigs (Table 3) suggests an involve- ment of antibody in the clearance of virus. We speculate that mu- cosal antibody participated in the clearance of heterologous virus and that its production was a consequence of MN08 virus chal- lenge and subsequent reactivation of Ad5-HA-primed CMI. This does not exclude the contribution of CTL involvement to clear- ance of virally infected cells from the respiratory tract, and further work is warranted to investigate the mechanism of more rapid viral clearance. Regardless of the mechanism, the clearance of het- erologous virus reduced the duration and amount of viral shed- ding, a situation that would likely result in a reduction of trans- mission within and between swine herds. A vaccine that reduces heterologous viral transmission and disease would significantly lessen the economic impact experienced during an outbreak of a novel IAV strain in a herd.
Saccharomyces cerevisiae has been reported as a safe (Generally Recognized as Safe, GRAS) and robust host cell to produce heterologous carotenoids, including lyco- pene , β-carotene  and astaxanthin . Thus, in our study, crocetin was successfully synthesized in S. cerevisiae through incorporating heterologous CrtZ and CCD in an existing β-carotene producing strain SyBE_Sc0014CY06 (with β-carotene titer of 220 mg/L) (Table 1). A higher crocetin titer was achieved by adjust- ing the culture temperature from 30 to 20 °C. The pro- duction of crocetin was further enhanced by 2.8-fold via screening of CrtZ/CCD combination and ALD sources. Moreover, the crocetin titer was reached to 1219 μg/L by increasing the copy numbers of ccd and ald. Finally, the highest reported crocetin titer as 6278 μg/L was archived in 5-L bioreactors. This study sets a good example of fine- tuning multiple enzymes systematically for heterologous biosynthesis of desired pharmaceuticals and chemicals.
In contrast to RV, VSV appears to use a nonspecific way of incorporating the VSV G protein (33) or heterologous trans- membrane proteins (18, 20, 34) into the envelope. For exam- ple, substitution of the CD4 transmembrane and cytoplasmic domains for those from VSV G did not increase the level of CD4 incorporation into the VSV particle (34, 35); conversely, CD4 and CXCR4 proteins were efficiently incorporated into RV only when the autologous RV G tail was present (27). Moreover, it has been shown that 9 amino acids of the normal VSV G tail were sufficient to drive nearly normal budding efficiency but that the G protein with only 1 cytoplasmic amino FIG. 7. Successful replacement of both the IHNV M and G genes by their VHSV counterparts. After four passages, viral genomic RNA extracted from supernatants of cells infected with either wild-type IHNV or rIHNV-M-Gvhsv was amplified by RT-PCR with specific M or G primers derived from IHNV or VHSV sequences. PCR products were analyzed on a 1% agarose gel with (⫹) or without (⫺) restriction enzyme digestion. A control without reverse transcriptase (⫺RT) was added to ensure that no contaminating plasmids were present in the rIHNV-M- Gvhsv-infected cell supernatant. The sizes of the fragments (in nucleotides) are given on the left for the IHNV M and G genes and on the right for the VHSV M and G genes.
Jones’s key submission was ‘that the proscription of torture […] precludes the grant of immunity’. 97 Naturally, Lord Bingham considered the ECtHR’s decision in Al-Adsani. This decision would ordinarily be followed unless its reasoning was unclear or unsound, which His Lordship found was not the case 98 . His Lordship then analysed the text of art 14 of the Convention Against Torture, which Jones relied on. Lord Bingham here noted an interpretative declaration attached by the US to its acceptance of the Convention Against Torture, which stated that art 14 only provided a right of action ‘for torture committed in territory under the jurisdiction of that State Party.’ 99 Lord Bingham declined to treat the declaration as a reservation, but considered that in the ‘20 years [which] have passed … there is no reason to think that the United States would now subscribe to a rule of international law conferring a universal tort jurisdiction which would entitle foreign states to entertain claims against US officials based on torture allegedly inflicted by the officials outside the state of the forum.’ 100 Whatever the accuracy of this statement at the time it was written, this supposition is clearly now false. The final result of the Samantar litigation proved that at least some US courts consider it acceptable under the FSIA to exercise a universal civil jurisdiction in a claim against a former foreign official who had committed torture (although there is a circuit split). 101 If the US has allowed an alien to deploy universal civil jurisdiction to successfully bring a torture claim against a former Somali official, it would be unable to defend in principle a hypothetical exercise of universal tort jurisdiction against a US official based on torture inflicted outside the forum. Despite the limiting of the ATCA’s scope in Sosa and Kiobel, the chain