Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, β-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the...

Exercise and the Immune System: Regulation, Integration, and Adaptation

As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, self-limiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

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Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19.

Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and comprised of of IgG, IgA and IgE. Here we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva and broncho-alveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal-homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably one month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against re-infection, and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.

IgA dominates the early neutralizing antibody response to SARS-CoV-2.

Introduction: To determine time trends in myopia over a 20-year period in Taiwan, we conducted 5 nationwide surveys pertaining to the ocular refraction of schoolchildren in 1983, 1986, 1990, 1995 and 2000. Materials and Methods: The sampling technique used herein involved the assessment of stratified systematic clusters, with the unweighted myopic rate being repre- sented using data derived from different sectors of the population, such as metropolitan, city, town, and aboriginal. The mean values for the spherical equivalent of the cycloplegic refractive status and the dimension of corneal radii as determined by the autorefractometer were used for the calculation. Results: In our review of 5 nationwide myopia surveys, we found that the mean prevalence of myopia among 7 year olds increased from 5.8% in 1983 to 21% in 2000. At the age of 12, the prevalence of myopia was 36.7% in 1983 increasing to 61% in 2000, corresponding figures for 15-year-olds being 64.2% and 81%, respectively. The prevalence of myopia increased from 74% in 1983 to 84% in 2000 for children aged between 16 and 18 years, and, in addition, the prevalence of high myopia (over -6.0 D) increased from 10.9% in 1983 to 21% of 18-year-old students of Taiwan in 2000. The mean refractive status at the age of 12 deteriorated from -0.48 D in 1983 to -1.45 D in 2000, and from -1.49 D to -2.89 D for children aged 15, whilst for individuals aged 18, it deteriorated from -2.55 D in 1983 to -3.64 D in 2000. The mean ocular refraction began to progress to a myopic condition at the age of 11 in 1983, this becoming an age of 8 years in 2000. There appeared to be significant difference in both the prevalence and the degree of myopia between study participants residing in cities and villages. Conclusions: We conclude that the cause of the relative increasing severity of myopia among the schoolchildren was due to the onset of myopia at a very young, and progressively-decreasing, age over the study period. Thus, to reduce the prevalence and severity of myopia, we should pay more attention to the eye care of pre-schoolchildren. Ann Acad Med Singapore 2004;33:27-33

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Prevalence of myopia in Taiwanese schoolchildren: 1983 to 2000.

Immunological memory is a hallmark of the immune system. Evolution can teach us which effector arms of immunological memory are biologically relevant against which virus. Antibodies appear to be the critical protective mechanism against cytopathic viruses. Since these viruses cause cell damage and disease directly, particularly in the absence of an immune response, mothers protect their offspring during a critical immunoincompetent period (a consequence of MHC- restricted T cell recognition) by passive transfer of neutralizing antibodies. In contrast, CTL appear to be the crucial effector mechanism against noncytopathic viruses. Since MHC polymorphism has made vertical transmission of T cell memory impossible, immunoincompetent offspring are not, and need not be, protected against such noncytopathic viruses. During the primary response and again during secondary infection, the most important function of CTL is to eliminate noncytopathic viruses, which may otherwise cause lethal immunopathology. Increased precursor frequencies of B and T cells appear to remain in the host independent of antigen persistence. However, in order to protect against cytopathic viruses, memory B cells have to produce antibody to maintain protective elevated levels of antibody; B cell differentiation into plasma cells is driven by persisting antigen. Similarly, to protect against infection with a noncytopathic virus, CTL have to recirculate through peripheral organs. Activation and capacity to emigrate into solid tissues as well as cytolytic effector function are also dependent upon, and driven by, persisting antigen. Because no convincing evidence is available yet of the existence of identifiable B or T cells with specialized memory characteristics, the phenotype of immunological memory correlates best with antigen-driven activation of low frequency effector T cells and plasma cells.

On immunological memory.

Mice previously infected with an aerosol of A/Rec 31 influenza virus were strongly protected against an aerosol challenge with A/Vic influenza as judged by lung virus titers recovered 2 days after the challenge infection. Such complete homotypic immunity was not achieved by priming with live Rec 31 virus injected i.v. or UV-inactivated Rec 31 virus administered s.c. together with Al(OH)3 and saponin. The reason for the superior protective effect of the natural infection was investigated. The protection induced by respiratory infection with Rec 31 virus was specific for influenza A viruses. It was not correlated with specific serum hemagglutination inhibition antibody titer or cross-reactive cytotoxic T (Tc) cell reactivity. Moreover, the transfer of splenic and lymphoid T cell populations with strong secondary Tc activity did not significantly reduce lung virus titers in recipient mice 3 days after infection. The protection however occurred in parallel with the presence of cross-reactive IgA antibody in the lung washings. It thus appears that local secretory IgA plays a causal role in the prevention of cross-infection by influenza A virus. Serum antibody and Tc cells, on the other hand, may be crucial for recovery from such infection. All mice primed with live Rec 31 virus, administered i.v. or by aerosol and expressing equally high levels of Tc reactivity, survived a lethal challenge with A/PR8 virus. The same challenge, however, killed half of the mice immunized s.c. with inactivated Rec 31 virus which induced only a low level of Tc reactivity.

Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity.

Mice infected with an aerosol of influenza virus or immunized with purified UV- inactivated whole virus or viral subunits developed delayed-type hypersensitivity (DTH) to influenza virus. The level of DTH was greatly enhanced when mice were injected intraperitoneally 2 days prior to immunization with 200 mg/kg of cyclophosphamide. The reaction peaked at 24 h after elicitation, had the classical DTH histology, and was transferable by immune cells but not by immune serum. DTH induced in cyclophosphamide-pretreated mice persisted for at least 40 days after sensitization. DTH induced by deoxycholate-treated subviral particles (DC particles) or the matrix protein of the influenza virus was type-specific, i.e. DTH induced by DC particles or matrix protein of type A virus cross-reacted only with type A virus and not with type B virus. DTH induced by purified hemagglutinin (HA) subunits, on the other hand, showed subtype specificty. Thus, DTH induced by HA of X 31 virus (H3) did not cross-react with PR 8 virus (H 0). However, DTH induced by HA of one subtype cross-reacted significantly with the variants of the same subtype. Thus, it appears that the effector T cells of DTH do not discriminate between the antigenic variants of influenza virus that are distinguishable by serology. DTH induced by purified, UV- inactivated whole virus showed extensive cross-reactivity. This nonspecific reaction was shown to be due to host-derived material, the lipid bilayer. - The theoretical and practical implications of these findings are discussed.

Colin M. Brand

Papers

Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity.

Induction and characterization of delayed-type hypersensitivity to influenza virus in mice.