Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders

Abstract

In the rich, developed parts of the world there has been a steady and simultaneous increase in at least three groups of disease: (1) allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohn's disease and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and multiple sclerosis). Because the medical world is so compartmentalised it was some time before the connection between these increases was noticed and understood. There is now evidence that the simultaneous increase in these diseases of immunodysregulation is at least partly attributable to malfunction of regulatory T cells (Treg). This paper provides an overview of relevant work in each of these fields of medicine (though with emphasis on the allergic disorders), and concludes that the increasing failure of Treg is a consequence of diminished exposure to certain micro-organisms that are "old friends", because of their continuous presence throughout mammalian evolution. These organisms, which include saprophytic mycobacteria, helminths and lactobacilli, are recognised by the innate immune system as harmless, and as adjuvants for Treg induction. Polymorphisms of components of the innate immune system such as TLR2 and NOD2 appear to define subsets of the population that will develop immunoregulatory disorders when living in the modern environment. A further role of the "old friends" and of the Treg that they induce might be to maintain the levels of regulatory IL-10 secreting macrophages and antigen-presenting cells, which are depleted in asthma and Crohn's disease. These concepts are leading to novel therapies based on harmless organisms or their components. Phase I/II clinical trials have yielded some statistically significant results, and phase II trials are in progress.

Early environments and the ecology of inflammation

“…Might our understanding of how inflammation is regulated and how inflammation provides protection against some diseases but contributes to others be advanced by a comparative, developmental perspective that foregrounds ecological factors as drivers of functional variation? Our findings from the Philippines point to early environmental factors as critical determinants of the dynamics of inflammation in adulthood, and circumstantial evidence for the importance of early microbial environments in shaping inflammatory phenotypes also comes from rising rates of allergic and autoimmune diseases over the past three decades, particularly among lowerincome nations, where rates of these diseases tend to increase after economic development (40,42). One might also interpret the divergent patterns of association between body fat and CRP discussed above in this light.…”

“…Frequent but transient encounters with microbes in the local environment may be important in this process, and/or local environments may influence the structures of resident microbial communities in the human gut and on mucosal and skin surfaces that have lasting effects on immune development (22,67). The cellular mechanisms underlying these processes are not clear, but they likely involve regulatory T cells and the balance of pro-and antiinflammatory cytokine production and related intracellular signaling pathways (40,65). Epigenetic modifications to genes involved in these processes represent a viable molecular mechanism through which microbial exposures in infancy may have a durable impact on inflammatory phenotypes (68,69), particularly because prior research has documented substantial between-individual variation in the methylation status of genes involved in inflammation (70).…”

“…In particular, saprophytic mycobacteria, lactobacilli, and many helminthes common in rotting vegetable matter, soil, and untreated water represent disappearing classes of microorganisms that have been part of the human and mammalian environment for millennia and are generally treated as harmless by their hosts (40). Of course, there is substantial heterogeneity in nutritional and microbial environments within contemporary industrialized nations, much of it structured by socioeconomic and geographic factors.…”

Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood

“…Recent research has underscored the importance of plasticity and ecological responsiveness in the development and function of the immune system, and microbial exposures in infancy may comprise a critical set of inputs that promote the development of regulatory T cells and effective anti-inflammatory regulatory networks (Yazdanbakhsh et al 2002;Rook et al 2004;McDade 2005). We speculate that a lack of such inputs may lead to a pro-inflammatory immunophenotype that is more likely to produce CRP in response to inflammatory stimuli, or less likely to downregulate CRP production following activation.…”

Primary prevention of allergy: avoiding risk or providing protection?

“…In contrast, a higher degree of overall diversity in the fecal microbiota at 1 week of age might be an important factor for the prevention of the development of atopic eczema [104]. Finally, longitudinal studies have shown that mildpathogenic intracellular bacteria (including non-typhoid Salmonellae and saprophytic Mycobacteria) might protect from the inception of atopic sensitization and respiratory allergies [105,106].…”