Evolution, the Immune System, and the Health Consequences of Socioeconomic Inequality

Healthy development and function of essentially all physiological systems and organs, including the brain, require exposure to the microbiota of our mothers and of the natural environment, especially in early life. We also know that some infections, if we survive them, modulate the immune system in relevant ways. If we study the evolution of the immune and metabolic systems, we can understand how these requirements developed and the nature of the organisms that we need to encounter. We can then begin to identify the mechanisms of the beneficial effects of these exposures. Against this evolutionary background, we can analyze the ways in which the modern urban lifestyle, particularly for individuals experiencing low socioeconomic status (SES), results in deficient or distorted microbial exposures and microbiomes. Thus, an evolutionary approach facilitates the identification of practical solutions to the growing scandal of health disparities linked to inequality

The old friends hypothesis: evolution, immunoregulation and essential microbial inputs

In wealthy urbanised societies there have been striking increases in chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel diseases. There has also been an increase in the prevalence of individuals with systemically raised levels of inflammatory biomarkers correlating with increased risk of metabolic, cardiovascular and psychiatric problems. These changing disease patterns indicate a broad failure of the mechanisms that should stop the immune system from attacking harmless allergens, components of self or gut contents, and that should terminate inappropriate inflammation. The Old Friends Hypothesis postulates that this broad failure of immunoregulation is due to inadequate exposures to the microorganisms that drive development of the immune system, and drive the expansion of components such as regulatory T cells (Treg) that mediate immunoregulatory mechanisms. An evolutionary approach helps us to identify the organisms on which we are in a state of evolved dependence for this function (Old Friends). The bottom line is that most of the organisms that drive the regulatory arm of the immune system come from our mothers and family and from the natural environment (including animals) and many of these organisms are symbiotic components of a healthy microbiota. Lifestyle changes that are interrupting our exposure to these organisms can now be identified, and many are closely associated with low socioeconomic status (SES) in wealthy countries. These insights will facilitate the development of education, diets and urban planning that can correct the immunoregulatory deficit, while simultaneously reducing other contributory factors such as epithelial damage

Loss of NK Stimulatory Capacity by Plasmacytoid and Monocyte-Derived DC but Not Myeloid DC in HIV-1 Infected Patients

Dendritic cells (DC) are potent inducers of natural killer (NK) cells. There are two distinct populations in blood, myeloid (mDC) and plasmacytoid (pDC) but they can also be generated In vitro from monocytes (mdDC). Although it is established that blood DC are lost in HIV-1 infection, the full impact of HIV-1 infection on DC-NK cell interactions remains elusive. We thus investigated the ability of pDC, mDC, and mdDC from viremic and anti-retroviral therapy-treated aviremic HIV-1+ patients to stimulate various NK cell functions. Stimulated pDC and mdDC from HIV-1+ patients showed reduced secretion of IFN-α and IL-12p70 respectively and their capacity to stimulate expression of CD25 and CD69, and IFN-γ secretion in NK cells was also reduced. pDC activation of NK cell degranulation in response to a tumour cell line was severely reduced in HIV-1+ patients but the ability of mDC to activate NK cells was not affected by HIV-1 infection, with the exception of HLA-DR induction. No differences were observed between viremic and aviremic patients indicating that anti-retroviral therapy had minimal effect on restoration on pDC and mdDC-mediated activation of NK cells. Results from this study provide further insight into HIV-1 mediated suppression of innate immune functions

Cellular Immune Responses to Nine Mycobacterium tuberculosis Vaccine Candidates following Intranasal Vaccination

BACKGROUND: The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. METHODS AND PRINCIPAL FINDINGS: In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. CONCLUSION AND SIGNIFICANCE: Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis

Neurocranium versus Face: A Morphometric Approach with Classical Anthropometric Variables for Characterizing Patterns of Cranial Integration in Extant Hominoids and Extinct Hominins

The relative importance of the two main cranial complexes, the neurocranium and the splanchnocranium, has been examined in the five species of extant hominoids and in a huge sample of extinct hominins using six standard craniometric variables that measure the length, width and height of each cranial module. Factor analysis and two-block partial least squares were used for establishing the major patterns of developmental and evolutionary integration between both cranial modules. The results obtained show that all extant hominoids (including the anatomically modern humans) share a conserved pattern of developmental integration, a result that agrees with previous studies. The pattern of evolutionary integration between both cranial modules in australopiths runs in parallel to developmental integration. In contrast, the pattern of evolutionary and developmental integration of the species of the genus Homo is the opposite, which is probably the consequence of distinctive selective regimes for both hominin groups.JAPC, JMJA and PP received fundings from Ministerio de Ciencia e Innovación, Gobierno de España (http://www.idi.mineco.gob.es), project CGL2011-30334, and Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, España (http://www.juntadeandalucia.es/organismo​s/economiainnovacioncienciayempleo.html), project P11-HUM-7248 and Research Groups RNM-146 and HUM-607

The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis

Background: NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB). Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-alpha synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB).Methods: We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti-tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells.Results: No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro.Conclusion: There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations

Evolution and the critical role of the microbiota in the reduced mental and physical health associated with low socioeconomic status (SES)

The evolution of the gut-microbiota-brain axis in animals reveals that microbial inputs influence metabolism, the regulation of inflammation and the development of organs, including the brain. Inflammatory, neurodegenerative and psychiatric disorders are more prevalent in people of low socioeconomic status (SES). Many aspects of low SES reduce exposure to the microbial inputs on which we are in a state of evolved dependence, whereas the lifestyle of wealthy citizens maintains these exposures. This partially explains the health deficit of low SES, so focussing on our evolutionary history and on environmental and lifestyle factors that distort microbial exposures might help to mitigate that deficit. But the human microbiota is complex and we have poor understanding of its functions at the microbial and mechanistic levels, and in the brain. Perhaps its composition is more flexible than the microbiota of animals that have restricted habitats and less diverse diets? These uncertainties are discussed in relation to the encouraging but frustrating results of attempts to treat psychiatric disorders by modulating the microbiota