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Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus‐2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen‐specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope–specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV‐19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV‐19 elicits a good CD8+ T‐cell response in older bodies, but that typical age‐associated features are evident on these vaccine reactive T cells. [ABSTRACT FROM AUTHOR]

The lack of progress in development of vaccines to stimulate local protection in the urinary tract is attributable in part to the lack of information regarding mechanisms of local immunity and to the difficulty in antigen administration at this site. Experiments reported in this paper indicate that the urinary tract in rats forms part of an effector network linking mucosal organs (the common mucosal immune system). Concomitant immunization of the intestine and urinary tract with ovalbumin resulted in the appearance at both sites of antiovalbumin-containing cells (ACC) of IgA specificity. The gut origin of ACC in the urinary tract was confirmed by demonstrating in similarly immunized rats abrogation of the urinary tract response by chronic drainage of the thoracic lymphatic duct during the post-challenge period and by demonstrating the appearance of radio labelled ACC in the urinary tract after injection of labelled autologous thoracic duct lymphocytes collected during the post-challenge period. These experiments indicate a role for oral immunization in enhancing the local antibody response in the urinary tract against invading pathogens. [ABSTRACT FROM AUTHOR]

Afterward, N SB 52-59 sb -specific T cells were fluorescence-activated cell sorting-based isolated from the spleen and transferred to new hosts bearing the CD45.2 genetic marker, to facilitate discrimination between transferred antigen-specific T cells and I de novo i -generated host antigen-specific T cells. Keywords: adaptive immunity; immune memory; memory T-cell; T-cell EN adaptive immunity immune memory memory T-cell T-cell 374 376 3 05/03/23 20230501 NES 230501 T-cell memory is considered long-lasting, but new evidence recently published in I Nature i by Soerens I et al i . shows that, under certain conditions, mouse memory T-cell immunity can span several mouse lifetimes. Age is just a number: long-lasting T-cell immunity can span several lifetimes. [Extracted from the article]

Dendritic cells (DCs) are essential for initiating immune responses. Depending on the environment, the type of DC and the way in which they interact with T cells, these immune responses can be beneficial or detrimental. DCs can be exploited as cellular vectors for vaccines against infection and cancer. The development and maintenance of DCs is dependent on the FMS‐like tyrosine kinase 3 (Flt3)/Flt3 ligand (Flt3L) signaling cascade. Flt3 is also one of the most commonly mutated genes in acute myeloid leukemia and as such represents an attractive drug target. In this review, Flt3 is discussed with a particular focus on DCs. We detail the lifecycle of Flt3, from transcription to degradation, and interrogate recent studies as to how this pathway can be manipulated for immunotherapy, vaccination and treatment of autoimmune disease. [ABSTRACT FROM AUTHOR]

The immune system is usually viewed as an effector mechanism reacting to environmental antigenic challenge with defensive responses designed to eliminate 'foreign' substances and return to standby or surveillance mode. However, there is now substantial evidence to suggest that immunity is not effector-biased but is also a sensory organ and forms part of an integrated homeostatic network. Evidence that communication pathways exist between the immune and central nervous sytems which support bi-directional information flow, and that the output of the immune system influences other physiological adjustments to environmental change, is discussed in this paper, The proposition that an endocrine-immune gradient determines the homeostatic response to combined microbial and other ambient stressors is established and the potential for management of this gradient is explored. [ABSTRACT FROM AUTHOR]

Co-selection is a term used to denote the mutual positive selection of individual members from within two diverse populations, such that selection of members within one population is dependent on interaction with (recognition of) one or more member(s) within the other population. Coselection is a recurring theme of the idiotypic network model that my colleagues and I have developed. This paper discusses the role that co-selection plays in basic symmetrical network theory and in a network model that resolves the I-J paradox. It proposes that co-selection of helper T cells and HIV variants plays a role in the pathogenesis of AIDS. The AIDS model involves a role for the T cell receptor in the infection of T cells. Finally, a way in which a co-selection process may potentially be used in the prevention and therapy of harmful forms of immunity is described. [ABSTRACT FROM AUTHOR]

This paper presents an overview of the evolution of defence reactions in multicellular animal life. The co-evolution of hosts and pathogens provides the context to describe the major features of defence reactions and the countermeasures they evoke in their targets. Three major types of solutions to the riddle of self-non-self discrimination are discussed briefly: non-clonal recognition mediated by lectins, the preferential accumulation of C3 in microbial surfaces and vertebrate clonal immunity. Vertebrate immunity is described as a specialized type of inflammation against infectious agents that evolved in response to countermeasures successfully used by intracellular pathogens against non-specific defences. [ABSTRACT FROM AUTHOR]

The article focuses on the clonal selection theory of acquired immunity proposed by Macfarlane Burnet, a virologist and Director of the Walter and Eliza Hall Institute (WEHI). It talks about Burnet being awarded the Nobel Prize for his work in Virology. It discusses events that led to enunciation of the clonal selection theory and the evidences which supported the theory. It discusses the hybridoma technology is offered. It appreciates Burnet's contribution in the immunological research.

Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine‐induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine‐induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B‐cell antibody and "trained" innate cells as alternative mediators of protective immunity is explored. [ABSTRACT FROM AUTHOR]

The β-1, 3 (d)-glucan (β-glucan) present in the cell wall of Candida albicans induces epigenetic changes in human monocytes resulting in primed macrophages exhibiting increased cytokine responsiveness to reinfection. This phenomenon is referred to as trained immunity or innate immune memory. However, whether β-glucan can reprogramme murine monocytes in vitro or induce lasting effects in vivo has yet to be elucidated. Thus, purified murine spleen-derived monocytes were primed with β-glucan in vitro and assessed for markers of differentiation and survival. Important macrophage cell markers during monocyte-to-macrophage differentiation were downregulated and survival enhanced due to partial inhibition of apoptosis. Increased survival and not the β-glucan training effect explained the elevated production of tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) induced by subsequent lipopolysaccharide (LPS) challenge. In vivo, 4 days after systemic administration of β-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFα, IL-6 and IL-10, an effect shown to be short lived as enhanced cytokine production was lost by day 20. Here, we have characterised murine macrophages derived from β-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of β-glucan in vivo declines within a 3-week period. [ABSTRACT FROM AUTHOR]

The article presents an analysis regarding the integration of self-tolerance to a single mechanism that sets T helper cells as the pivotal element between T- and B-cell tolerance and immunity. It argues that the integration was an oversimplification due to various tolerization occurring before and after a cell matures in the developed animal. It states that there may be tolerization mechanisms for cytotoxic T cells that do not apply for B cells.

The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body's first line of defense against infection. Although signaling pathways and transcription factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary cell lineage as well as context-specific gene expression in diverse innate immune cell types. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental triggers also induce changes in histone modifications that can either promote tolerance or 'train' innate immune cells for a more robust antigen-independent secondary response. Here we review the important contribution of epigenetic factors to the initiation, maintenance and training of innate immune responses. In addition, we explore how pathogens have hijacked these mechanisms for their benefit and the potential of small molecules targeting chromatin machinery as a way to boost or subdue the innate immune response in disease. [ABSTRACT FROM AUTHOR]

The December 2020 issue contains a Special Feature on Infection and Immunity, featuring selected presentations from the 10th Lorne Infection and Immunity Conference. They discuss how these immune responses are initiated, and for example, the molecules characterizing dendritic cells on exposure to allergens and the mediators they produce to signal CD4 T cells to become effector T helper 2 cells. Saunders and McConville2 complement this theme with a review of host-pathogen interactions in leishmaniasis, a parasitic infection that causes cutaneous and visceral diseases in humans. [Extracted from the article]

The emergence of the novel reassortant A(H1N1)-2009 influenza virus highlighted the threat to the global population posed by an influenza pandemic. Pre-existing CD8+ T-cell immunity targeting conserved epitopes provides immune protection against newly emerging strains of influenza virus, when minimal antibody immunity exists. However, the occurrence of mutations within T-cell antigenic peptides that enable the virus to evade T-cell recognition constitutes a substantial issue for virus control and vaccine design. Recent evidence suggests that it might be feasible to elicit CD8+ T-cell memory pools to common virus mutants by pre-emptive vaccination. However, there is a need for a greater understanding of CD8+ T-cell immunity towards commonly emerging mutants. The present analysis focuses on novel and immunodominant, although of low pMHC-I avidity, CD8+ T-cell responses directed at the mutant influenza DbNP366 epitope, DbNPM6A, following different routes of infection. We used a C57BL/6J model of influenza to dissect the effectiveness of the natural intranasal (i.n.) versus intraperitoneal (i.p.) priming for generating functional CD8+ T cells towards the DbNPM6A epitope. In contrast to comparable CD8+ T-cell responses directed at the wild-type epitopes, DbNP366 and DbPA224, we found that the priming route greatly affected the numbers, cytokine profiles and TCR repertoire of the responding CD8+ T cells directed at the DbNPM6A viral mutant. As the magnitude, polyfunctionality, and T-cell repertoire diversity are potential determinants of the protective efficacy of CD8+ T-cell responses, our data have implications for the development of vaccines to combat virus mutants. [ABSTRACT FROM AUTHOR]

Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating 'seasonal' influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal 'seasoned' vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most 'seasoned' vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas. [ABSTRACT FROM AUTHOR]

Effector memory T cells (TEM) have an important role in immunity against infection. However, little is known about the factors regulating TEM maintenance and proliferation. In this study, we investigated the role of direct interactions between CD4+ and CD8+ T cells (TC) for human TEM expansion. Proliferation of separated or mixed CD4+ and CD8+TEM populations was analyzed after polyclonal stimulation in vitro. Compared to each isolated subset mixed TEM populations showed increased proliferation and expansion of both CD4+ and CD8+TEM subpopulations. Combined activation of CD4+ and CD8+ memory T cells (Tmem) induced an increased expression of CD40L and CD40 on both populations. Subsequently, CD40/CD40L caused a bi-directional stimulation of CD40+CD4+TEM by CD40L+CD8+TEM and of CD40+CD8+TEM by CD40L+CD4+TEM. Blocking of CD40L on activated CD8+TEM selectively inhibited proliferation of CD4+TEM, while blocking of CD40L on CD4+TEM abrogated proliferation of CD8+TEM. Taken together, we demonstrate for the first time that the expression of CD40L is exploited on the one hand by CD8+TEM to increase the proliferation of activated CD4+TEM and on the other hand by CD4+TEM to support the expansion of activated CD8+TEM. Thus, efficient TEM expansion requires bi-directional interactions between CD4+ and CD8+TEM cells. [ABSTRACT FROM AUTHOR]

The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward beta-amyloid, whereas minimizing the risks of a cell-mediated adverse reaction. We describe here two novel anti-beta-amyloid vaccines that consist of 'virus like particles' formed by a domain of the bacterial protein E2 that is able to self-assemble into a 60-mer peptide. Peptides 1-11 and 2-6 of beta-amyloid were displayed as N terminal fusions on the surface of the E2 particles. E2-based vaccines induced a fast-rising, robust and persistent antibody response to beta-amyloid in all vaccinated mice. The immune memory induced by a single administration of vaccine (1-11) E2 can be rapidly mobilized by a single booster injection, leading to a very high serum concentration of anti-beta-amyloid antibodies (above 1 mg ml−1). E2 vaccination polarizes the immune response toward the production of the anti-inflammatory cytokine interleukin-4 and does not induce a T cell response to beta-amyloid. Thus, E2-based vaccines are promising candidates for the development of immunotherapy protocols for AD. [ABSTRACT FROM AUTHOR]

Live virus vaccines provide a unique opportunity to study human CD8+ T-cell memory in the context of a controlled, primary acute viral infection. Yellow fever virus-17D and Dryvax are two such live-virus vaccines that are highly efficacious, used worldwide and provide long-term immunity against yellow fever and smallpox respectively. In this review, we describe the properties of virus-specific memory CD8+ T cells generated in smallpox and yellow fever vaccinees. We address fundamental questions regarding magnitude, functional quality and longevity of the CD8+ T-cell response, which are otherwise challenging to address in humans. These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8+ T-cell response that can be used to evaluate novel candidate vaccines. [ABSTRACT FROM AUTHOR]

Host-mediated recognition of mannose-rich glycans on the surface of pathogens represents an ancient mechanism of innate immune defence. In this study, we demonstrate that the virus strains that differ in the degree of N-linked glycosylation on the globular head of their hemagglutinin glycoprotein also differed in their (i) sensitivity to neutralization by a mannose-specific lectin in mouse lung fluids and (ii) ability to infect (and, therefore, to be destroyed) by airway macrophages. Virus strain BJx109 (H3N2), but not PR8 (H1N1), was sensitive to neutralization by mouse lung fluids and infected airway macrophages efficiently in vitro and these antiviral activities were blocked by mannan, a complex polymer of mannose residues. Although intranasal (i.n.) infection of mice with PR8 led to severe disease and mortality, mice infected with an equivalent dose of BJx109 displayed no signs of disease. However, i.n. treatment of BJx109-infected mice with mannan led to viral pneumonia, severe disease and death characterized by excessive virus replication, pulmonary inflammation, vascular leak and lung edema. Thus, when mannose-specific innate defences were inhibited in vivo, virus strain BJx109 induced severe viral pneumonia similar to that of PR8. Together, these findings highlight the importance of N-linked glycans as a target for recognition and destruction of influenza viruses by the innate immune system. Moreover, soluble and cell-associated lectins coordinate to modulate disease severity following influenza virus infection of mice. [ABSTRACT FROM AUTHOR]

Langerhans cells (LC) are unique members of the dendritic cell (DC) family residing in the epidermis of skin and mucosa. Specific autocrine and environmental factors shape the biology of LC, such as TGF-β1, IL-10, vitamin D3, UV light or neuropeptides, which are required for LC development but also influence their capacity to induce immunity or tolerance. Both, immunogenic and tolerogenic functions require antigen transport from the skin to the draining lymph nodes, but the LC maturation grade directs the differential outcome. In this review, we recapitulate early indications for LC tolerogenicity and oppose them to more recent findings with gene-targeted mice, which dramatically challenged some of the early results. The newly discovered Langerin+ dermal DC subset (DDC) seems to be responsible also for many tolerogenic effects that were initially attributed to steady state migratory LC. Transfer of antigens from LC to other DC subsets as well as transport of HIV are discussed as part of the complex interactions between LC and other cells or as mechanisms of immune evasion. Finally, the first clinical trials on allergy therapies targeting skin DC in the steady state are mentioned as they may open the door to curative tolerogenic therapies. [ABSTRACT FROM AUTHOR]

The skin, and in particular the epidermis, is a physical barrier that protects the body from external threats and is critically involved in immune reactivity. Professional antigen-presenting cells, such as epidermal Langerhans cells and dermal dendritic cells, are gaining prominence as principal players orchestrating the decision between immunity and tolerance. A focus of research interest in recent years has been the investigation of these cells in mammalian prenatal skin. In this review, we will compare the recent progress in dissecting the phenotype and functional role of antigen-presenting cells in the developing human and mouse skin before birth and perinatally, and will discuss how this knowledge improves our understanding of the level of immunocompetence of the skin in utero. [ABSTRACT FROM AUTHOR]

Changes in plasma lipoprotein profiles, particularly low levels of high-density lipoprotein (HDL) cholesterol, are associated with several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis, implying the potential link between HDL and immunity. Accumulating evidence suggests that HDL possesses anti-inflammatory effects and has an important function in host defense as part of the innate immune system. In addition, HDL inhibits the ability of antigen-presenting cells (APCs) to stimulate T cells. It is subsequently discovered that HDL or HDL-associated platelet-activating factor-acetylhydrolase can restore the emigratory process of monocyte-derived dendritic cells and thus result in resolution of inflammatory reactions in atherosclerotic plaques. Lipid rafts in plasma membrane are the key structure responsible for the immunomodulation effects of HDL, the remarkable ability of HDL to regulate innate and adaptive immune responses extends our understanding of its atheroprotective role, and provides new therapeutic approaches to atherosclerosis and other inflammatory conditions. [ABSTRACT FROM AUTHOR]

The author reflects on the working life of virologist Macfarlane Burnet. He considers most of Burnet's work to be aimed at understanding infectious processes. An overview of Burnet's involvement with the chick embryo as a tool for dissecting virus pathogenesis and immunity is offered. He narrates Burnet's influence on his life. He believes that Burnet left enough documentation for the enthusiastic scholars. He appreciates Brunet's intellectuality that led to clonal selection theory.

Live attenuated Salmonella are attractive vaccine candidates for mucosal application because they induce both mucosal immune responses and systematic immune responses. After breaking the epithelium barrier, Salmonella typhimurium is found within dendritic cells (DC) in the Peyer’s patches. Although there are abundant data on the interaction of S. typhimurium with murine epithelial cells, macrophages and DC, little is known about its interaction with human DC. Live attenuated S. typhimurium have recently been shown to efficiently infect human DC in vitro and induce production of cytokines. In this study, we have analysed the morphological consequences of infection of human DC by the attenuated S. typhimurium mutant strains designated PhoPc, AroA and SipB and the wild-type strains of the American Type Culture Collection (Manassas, VA, USA), ATCC 14028 and ATCC C53, by electron microscopy at 30 min, 3 h and 24 h after exposure. Our results show that genetic background of the strains profoundly influence DC morphology following infection. The changes included (i) membrane ruffling; (ii) formation of tight or spacious phagosomes; (iii) apoptosis; and (iv) spherical, pedunculated membrane-bound microvesicles that project from the plasma membrane. Despite the fact that membrane ruffling was much more pronounced with the two virulent strains, all mutants were taken up by the DC. The microvesicles were induced by all the attenuated strains, including SipB, which did not induce apoptosis in the host cell. These results suggest that Salmonella is internalized by human DC, inducing morphological changes in the DC that could explain immunogenicity of the attenuated strains. [ABSTRACT FROM AUTHOR]

Numerous studies have aimed to overcome the barrier to xenotransplantation posedby xenoreactive antibodies and the antigens they recognize. Whetherthis work will eventually lead to the widespread clinical applicationof xenotransplantation remains unknown. However, the benefits ofthis research are already substantial, with research leading todramatic new developments in fields other than xenotransplantation.Our understanding of natural immunity, particularly the nature andfunction of natural antibodies, has taken quantum leaps forward,with far-reaching implications. Our improved understanding of theimmune response to xenografts has proven invaluable in the characterizationof the human immune reaction to commonly used biological therapeuticsof xenogeneic origin. Our understanding of cell surface carbohydratesand our ability to modify these carbohydrates in living animalshas advanced substantially, with implications for diseases suchas cancer and autoimmunity. With this in mind, it is argued thatcontinued work in xenotransplantation is of great value, not onlybecause of the great potential benefits of xenotransplantation,but also because of the more certain benefits that arise from settingour sights on a difficult challenge. [ABSTRACT FROM AUTHOR]

There has been a recent resurgence of interest into new and improved vaccine adjuvants. This interest has been stimulated by the need for new vaccines to combat problematic pathogens such as SARS and HIV, and to counter potential bioterrorist attacks. A major bottleneck in vaccine development is the low immunogenicity of purified subunit or recombinant proteins, creating the need for safe human adjuvants with high potency. A major problem in the search for the ideal adjuvant is that adjuvants that promote cell-mediated (Th1) immunity (e.g. Freund's complete adjuvant) generally have unacceptable local or systemic toxicity that precludes their use in human vaccines. There is a need for a safe, non-toxic adjuvant that is able to stimulate both cell-mediated and humoral immunity. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against hepatitis B, malaria and other pathogens. If such trials are successful, then it is possible that inulin-derived adjuvants will one day replace alum as the adjuvant of choice in most human prophylactic vaccines. [ABSTRACT FROM AUTHOR]

Summary Heavy exertion has acute and chronic influences on systemic immunity. In the resting state, the immune systems of athletes and non-athletes are more similar than disparate with the exception of NK cell activity, which tends to be elevated in athletes. Many components of the immune system exhibit adverse change after prolonged, heavy exertion. These immune changes occur in several compartments of the immune system and body (e.g. the skin, upper respiratory tract mucosal tissue, lung, blood and muscle). Although still open to interpretation, most exercise immunologists believe that during this ‘open window’ of impaired immunity (which may last between 3 and 72 h, depending on the immune measure) viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. The infection risk may be amplified when other factors related to immune function are present, including exposure to novel pathogens during travel, lack of sleep, severe mental stress, malnutrition or weight loss. [ABSTRACT FROM AUTHOR]

Summary Overtraining is a process of excessive exercise training in high-performance athletes that may lead to overtraining syndrome. Overtraining syndrome is a neuroendocrine disorder characterized by poor performance in competition, inability to maintain training loads, persistent fatigue, reduced catecholamine excretion, frequent illness, disturbed sleep and alterations in mood state. Although high-performance athletes are generally not clinically immune deficient, there is evidence that several immune parameters are suppressed during prolonged periods of intense exercise training. These include decreases in neutrophil function, serum and salivary immunoglobulin concentrations and natural killer cell number and possibly cytotoxic activity in peripheral blood. Moreover, the incidence of symptoms of upper respiratory tract infection increases during periods of endurance training. However, all of these changes appear to result from prolonged periods of intense exercise training, rather than from the effects of overtraining syndrome itself. At present, there is no single objective marker to identify overtraining syndrome. It is best identified by a combination of markers, such as decreases in urinary norepinephrine output, maximal heart rate and blood lactate levels, impaired sport performance and work output at 110% of individual anaerobic threshold, and daily self-analysis by the athlete (e.g. high fatigue and stress ratings). The mechanisms underlying overtraining syndrome have not been clearly identified, but are likely to involve autonomic dysfunction and possibly increased cytokine production resulting from the physical stress of intense daily training with inadequate recovery. [ABSTRACT FROM AUTHOR]

Summary The present review examines the effects of exercise on mucosal immunity in recreational and elite athletes and the role of mucosal immunity in respiratory illness. Habitual exercise at an intense level can cause suppression of mucosal immune parameters, while moderate exercise may have positive effects. Saliva is the most commonly used secretion for measurement of secretory antibodies in the assessment of mucosal immune status. Salivary IgA and IgM concentrations decline immediately after a bout of intense exercise, but usually recover within 24 h. Training at an intense level over many years can result in a chronic suppression of salivary immunoglobulin levels. The degree of immune suppression and the recovery rates after exercise are associated with the intensity of exercise and the duration or volume of the training. Low levels of salivary IgM and IgA, particularly the IgA1 subclass, are associated with an increased risk of respiratory illness in athletes. Monitoring mucosal immune parameters during critical periods of training provides an assessment of the upper respiratory tract illness risk status of an individual athlete. The mechanisms underlying the mucosal immune suppression are unknown. [ABSTRACT FROM AUTHOR]

The antibody response of mice and adult humans to immunization with subunit vaccines derived from a pair of antigenically distinct influenza A H1N1 viruses isolated in eggs was investigated. Although the haemagglutinin molecule of each virus differed by only three amino acid residues, highly specific antibody responses were elicited in mice as determined by haemagglutination inhibition and radioimmunoprecipitation assays. Results from competitive radioimmunoassays using monoclonal antibodies of known specificity and a study of the reactivity of mouse antisera with H1N1 field strains indicated that the marked differences in the antibody responses to the two vaccines was due to an amino acid substitution in the distal tip of the haemagglutinin molecule. In contrast, crossreactive antibody responses were elicited in humans presumably due to exposure to viruses related to the candidate vaccine prior to vaccination. Although immunogenic differences are apparent in this pair of antigenically distinct viruses in naive laboratory animals, these differences are not apparent following vaccination of humans that had prior exposure to related viruses. [ABSTRACT FROM AUTHOR]

In previous studies we have demonstrated that the male urinary tract forms part of the common mucosal immune system, and that the gut contributes to local defences at this site.' The question arises as to the extent to which the reproductive tract also forms part of the common mucosal immune system. Rats were immunized by a variety of routes designed to stimulate a local response in the intestine and/or the reproductive tract. Rats immunized only by the intratesticular (i.t.) route yielded no antibody-containing (ACC) response in any of the tissues examined. Intestinal immunization using intraperitoneal priming followed by intraduodenal challenge (i.p./i.d.) yielded a substantial IgA-specific ACC response in the jejunum, but no ACC were detectable in any of the reproductive tract tissues. However, when intestinal and testicular immunizations were combined, large numbers of IgA-specific antibodies were detected in all tissues examined. Chronic drainage of the thoracic lymphatic duct throughout the post-challenge period abrogated the ACC response in all tissues of the reproductive tract, indicating that the ACC appearing at these sites after immunization were of gut origin. The IgA-specific anti-OVA antibody detectable in serum, saliva and testis homogenate reflected the ACC counts in histological sections. The studies reported here confirm that the male reproductive tract does form part of a common mucosal immune system and that gut-associated lymphoid tissues may contribute cellular precursors for ACC, particularly those of IgA specificity, appearing in the tract after local challenge. The implications of these findings to infectious disease involving the urogenital tract are obvious and investigation of oral vaccines to control sexually transmitted disease as well as acquired urinary tract infections deserves further attention. There are further implications, however, for the understanding and management of male infertility. [ABSTRACT FROM AUTHOR]

Highlights developments in immunology in Australia. Observation that Australia's involvement in academic immunology grew out of a scientific climate in which the search for new vaccines and the local production of known vaccines commanded a high priority; Introduction of myxomatosis virus to combat the rabbit plague; Discovery of the cellular basis of immunity and tolerance.

Polyreactive immunoglobulin (Ig) secreted by CD5-bearing B cells has the capacity to bind a broad range of self and foreign antigens. Flow cytometric analysis was used to detect low-affinity binding of mouse Ig molecules Io the surface of CD5-bearing B cells from patients with chronic lymphocytic leukaemia (CLL). Mouse Ig isotypes G. A. and M. and IgG subclasses C1, C2a, and G3 bound to the B cell surface via a mechanism not involving the antigen-binding site of the mouse Ig molecule. Fab and F(ab')2 fragments of mouse Ig associated with the CLL cells in a similar manner to intact Ig, indicating that Fe receptor interactions were not involved. Dissociation of the mouse Ig from the B cell surface by three washing steps distinguished this lower-affinity binding from high-affinity binding which occurs through the antigen-binding site of a mouse monoclonal antibody (MoAb) when it recognizes a specific ceil surface epitope. Blocking studies suggest that the low-affinity binding occurred via surface IgM and surface IgD (sIgM/sIgD) on the CD5-bearing B cells. The results are consistent with the expression of polyreactive Ig on the surface of CD5-bearing B cells in CLL. [ABSTRACT FROM AUTHOR]

The immunoregulatory effect of non-transferrin-bound iron (Fe3+) on the proliferative and cytotoxic responses of normal human T lymphocytes was studied using a sensitive limit-dilution technique capable of detecting the responses of individual lymphocytes. Iron, present in the form of ferric citrate at concentrations from 0.03 to 1.0 mmol/L, significantly reduced the cloning frequency of peripheral blood T lymphocytes. The effect of iron appeared, however, to be targeted to individual clones in that some clones that did grow in the presence of iron achieved a normal rate of proliferation. Thus, iron was not non-specifically toxic. At these same concentrations ferric citrate also produced significant reductions in the cloning frequency of CD4+ CD8-precursor T lymphocytes. Reductions in the response of T lymphocyte precursors capable of cytotoxic activity occurred in the presence of ferric citrate from 0.1 to 1.0 mmol/L. These data support the hypothesis that non-transferrin-bound iron has an immunoregulatory role in cell-mediated immunity. [ABSTRACT FROM AUTHOR]

Genetic susceptibility to infection with M. leprae was studied in 10 multiple case families of Australian Aborigines. Of the 87 members available for study, 24 had proven stable clinical leprosy which had been or was still being treated with diamino diphenyl sulphone. Evidence of contact with M. Ieprae in the remaining 63 members as assessed by ELISA to M. Ieprae sonicate and phenolic glycolipid (PGL) or by indirect immunofluorescence antibody assay was found in 78%, 64% and 71%, respectively. By contrast, in vitro assays of I cell function (LMAT and LTT) were less reliable indicators of exposure. Evidence was sought for possible linkages between human leucocyte antigen (HLA) or non-HLA genes and four marker phenotypes including clinical leprosy, clinical subtype of leprosy and lymphocyte transformation or leucocyte migration inhibition factor (LIF) production in response to M. leprae antigen. No associations were found with any particular HLA or non-HLA gene, On the other hand, sequential analysis of the data from the 10 families was strongly suggestive of a linkage between HLA haplotype and lion-responsiveness to M. Ieprae as manifest by lack of LIF production but not lymphocyte transformation. The model which best fits the data is for a gene on chromosome 6 in close linkage with the HLA haplotype, with two alleles, autosomal recessive inheritance and penetrance of 90%. On this basis, it can be suggested that disease type (lepromatous leprosy) rather than disease susceptibility may be controlled by genes within or closely linked to the major histocompatibility gene complex. [ABSTRACT FROM AUTHOR]

The binding patterns of 28 monoclonal antibodies (MAB) recognizing antigens belonging to Cluster of Differentiation One (CD-1) were analyzed in order to investigate heterogeneity within this cluster. Competitive binding assays using radiolabelled MAR provided detailed information on CD-1 antigenic heterogeneity, and demonstrated that at least six epitopic regions are recognised as CD-1 MAB. Further studies, based on single cell suspension immunofluorescence assays (using thymocytes and subclones on the cell line Molt-4), suggested that the majority of MAB studied could be serologically separated into three groups. In view of the most recent information suggesting that CD-1 MAB recognize at least three different early T-cell differentiation molecules, our results indicate that there are three or more distinct epitopes on the %#x2018;gp49’ (HTA-1/CD-1a) molecule, two on the ‘gp45’ (HTA-3/CD-1b) molecule and one on ‘gp43’ (HTA-2/CD-1c). [ABSTRACT FROM AUTHOR]

Macrophages were pulsed with Listeria monocytogenes antigens by intraperitoneal injection prior to harvesting and thoroughly washing the cells. The pulsed macrophages were injected into the feet of Listeria-immune or naive mice to elicit a delayed hypersensitivity reaction. Where soluble Listeria antigen was used, presentation by donor macrophages to host T cells required identity within the I region of the H-2 complex. However, presentation of alcohol-killed Listeria organisms or of a living, temperature-sensitive mutant of Listeria was apparently not H-2 restricted. When T cells enriched in vitro for Listeria reactivity were injected into the feet of naive mice, they reacted in an H-2 restricted manner to antigen presented to them either by the pulsed macrophages or host cells apparently acquiring antigen from the original pulsed macrophages. [ABSTRACT FROM AUTHOR]

A crude soluble extract (AWH) obtained from homogenized adult Nematospiroides dubious worms was fractionate into normal (NMtgAg) and immune (IMlgAg) antigens by sequential passage through Sepharose 4B, and CNBr-activaled Sepharose 4B to which immunoglobulins from normal (NMIg) and N. dt(U5-infected mouse serum (IMIg) had been coupled. Sodium do decyl sulphate polyacrylamide gel electrophoresis (SDS-PAGF) under reducing conditions showed that MNtgAgand IMtgAg contained several proteins with molecular weights (MW) between 20,000 and 200,0(X). IMtgAg contained 2 poly peptides, MW 24,000 and 55,(XX), which reacted strongly in western blob analysis against Mig; the larger molecule related lo a cuticular component of the worm. Protective high MW AWH G-200 filtrates shared 5 poly peptides with IMlgAg (MW 85,000-200.000) together with several smaller molecules (MW 30,000-< 10,000). The MW 55,O(X) and 24.0(X) components concentrated in JMlgAg were restricted to non-protective low MW AWH gel fires. BCM mice vaccinated with IMtgAg were protected against N. dubious. Worm numbers, size and feignedly were reduced to an extent commensurate with that obtained in mice vaccinated wish AWH. Mice vaccinated wish NMIgAg showed partial resistance. The role of surface and dominant parasite immunogen's in immunity is discussed. [ABSTRACT FROM AUTHOR]

Recombinant viral vectors offer a potential means of vaccinating against diseases for which there are no current safe vaccines. One of the criteria on which a viral vaccine vector would be selected is that it either circulates in the human or livestock population without producing overt disease (e.g. adenovirus) or has a history as a safe vaccine (e.g. vaccinia virus). However, this selection criterion also means that the target population is likely to have circulating antibodies that are specific to the vaccine vector. Since a percentage of the world's population has been vaccinated during the World Health Organization's Smallpox Eradication Campaign, such antibody titres, which are likely to lower vaccine efficacy, have been raised as an objection to the use of recombinant vaccinia viruses as vaccines. We have tested the effect of vaccinia-specific immunity on the protective efficacy of a recombinant virus, VV-PR8-HA6 (I) which expresses the haemagglutinin of the influenza virus A/PR/8/34. [ABSTRACT FROM AUTHOR]

A review is presented of the article "Shigella IpaB and IpaD displayed on L. lactis bacterium-like particles induce protective immunity in adult and infant mice" by S.J. Heine and colleagues.

The article discusses the study regarding the transcriptional repressor Bach2 which regulates regulatory T cells development programs of conventional CD4 T cells. It mentions that Bach2 is a factor that strikes multiple levels in controlling the immune hoeostasis. It focuses on the deleterious effects of tolerance breakdown and inflammatory T-cell expansion in Bach2 mice.

The author reflects on the progress made in the understanding of human immune regulation with extensive studies on hormonal and cellular immunity. He argues to look at the experimental design and how people have used the artificial model antigens, recombinant viruses and inappropriate cancer cells to modify the outcome of studies based on animal models. He raises the question of the objective metrics that characterize a healthy human immune system.

The article focuses on the nonobese diabetic (NOD) inbred mouse model proposed by Anna Lonyai, which has a genetic predisposition for the spontaneous development of T-cell-dependent autoimmune diabetes. It is mentioned that NOD mice are susceptible to multiple other autoimmune disorders. A role for additional target organ-intrinsic polymorphisms in directing autoimmunity towards specific organs has not been excluded despite the abundance of data for immune tolerance defects in NOD mice.