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Probiotics and autoimmunity: An evolutionary perspective
Medical Hypotheses (2008) 70, 657–660
http://intl.elsevierhealth.com/journals/mehy
Probiotics and autoimmunity: An evolutionary perspective ´mez, R. Flores-Mejı´a, E.B. Canche-Pool, R. Cortez-Go ´lez-Gonza ´lez, M.E. Gonza ´lez-Serrano, M.C. Lara-Rodrı´guez, E. Gonza ´nchez, Y. Ledesma-Soto, M.D. Mendoza-Aguilar, D.E. Meza-Sa * ´nchez, M.R. Thompson-Bonilla, ´nchez-Garcı´a , A. Silva-Sa F.J. Sa M.G. Trujillo-Vizuet, I. Wong-Baeza ´gicas, Instituto Polite ´cnico Nacional, Departamento de Inmunologı´a, Escuela Nacional de Ciencias Biolo ´s, Me ´xico D.F. 11340, Mexico Carpio y Plan de Ayala, Col. Sto. Toma Received 5 July 2007; accepted 5 July 2007
Summary Probiotics are microorganisms that have demonstrated beneficial effects on human health. Probiotics are usually isolated from the commensal microflora that inhabits the skin and mucosas. We propose that probiotics represent the species of microorganisms that have established a symbiotic relationship with humans for the longest time. Cultural practices of ancient human societies used to favor that symbiosis and the transmission of probiotics from generation to generation. New practices, introduced as a result of industrialization, such as childbirth by surgical delivery, ingestion of pasteurized and synthetic compounds-supplemented food, cleaner homes, indiscriminate use of antibiotics and so on, have led in recent years to the replacement of probiotics by other microorganisms that are not as well adapted to the microenvironments of the human body. These newly settled microorganisms lack many of the beneficial effects of probiotics. Our hypothesis is that the sudden change (from an evolutive perspective) in human intestinal microflora may importantly contribute to the rise in the incidence of autoimmune diseases, observed in the last half a century. c 2007 Elsevier Ltd. All rights reserved.
Background The survival of an organism is largely dependent on the equilibrium that it is capable to establish with its environment and, when this equilibrium is lost, * Corresponding author. Tel.: +52 55 55729 6300x62370; fax: +52 55 55396 3503. E-mail address: [email protected] (F.J. Sa ´nchez-Garcı´a).
the organism in question is in disadvantage and could even face extinction. Humans interact with a good deal of commensal microorganisms that live in their skin and mucosas, particularly in the gastrointestinal tract. It is estimated that up to 1012 bacteria/ml, belonging to 400–1000 different species colonize the human colon. This complex interaction between human epithelial cells and commensal microorganisms usually takes place without any sign of harm or
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.07.008
658 pathological condition for the host. In fact, this normal microflora is beneficial for the host, since it helps to avoid the colonization of the gut by pathogenic microorganisms (by nutrient competition, production of anti-microbial factors such as bacteriocines and lactic acid), favors the appropriate development of intestinal mucosas, metabolizes and eliminates potentially carcinogenic molecules taken up in the diet, synthesizes vitamins (biotin and folate) and, breaks down un-digested residues [1]. Probiotics are microorganisms that have a clear beneficial effect for a host i.e. that establish a true symbiotic relationship. Right from birth, humans are in contact with probiotics and the newborn immune system allows commensal microorganisms to colonize the intestine without a potentially harmful inflammatory response in the host [2]. In this regard, there is evidence on the presence of probiotics such as Lactobacillus gasseri, L. fermentum, L. salivarius and prebiotics (such as oligosaccharides, which help to support intestinal microflora) in the maternal milk so, in this way, this nutritive milieu would besides contribute to the prevention of newborn’s infections [3]. The ingestion of probiotics has been associated with a diminution in the severity of autoimmune, particularly intestinal inflammatory, diseases as well as allergic disorders [4]. More than a century ago, Paul Ehrlich stated that the immune system does not respond against the own organism (against the ‘‘self’’, in more current terminology). However, he also observed that sometimes an ‘‘auto-toxic horror’’ or immune response against the self takes place, giving rise to the concept of autoimmunity. It is worth noting that the first autoimmune disease identified as such, was in 1904 by Donath and Landsteiner, who described the cold-induced haemoglobinuria that was attributed to the presence of an autohaemolysin in the blood. Since then, an array of autoimmune diseases as well as different mechanisms that contribute to their onset have been described [5]. It is quite likely that the intestinal microflora has been changing along the human evolution, due in part to changes in diet, and that this co-evolution has provided mutual benefits. On this line, it is also likely that our recent ancestors kept an intestinal microflora that is no longer present in the human intestinal ecosystem. This may be related to the increase in the susceptibility to autoimmune diseases, that are worsened by additional genetic, environmental, and molecular (mimetism between self antigens and pathogenic microorganisms) factors [6–8].
Canche-Pool et al. In the ‘‘postmodern’’ times we are living, the human diet is very different from that we had in times long gone by. Food used to be more natural, in sharp contrast with the current mass produced, industrially processed, and long held in store food of nowadays. These changes directly affect the intestinal flora, by limiting their diversity and worst, by avoiding the human contact with those microorganisms through pasteurization, ultra-pasteurization, and so on. In addition, we have modified the environment we live in. Currently, in urban zones, children are born by cesarean delivery, are no longer in direct contact with soil or mud and, their aliments and belongings (toys, for instance) are sterilized or disinfected so that, new born children are not colonized by the microorganisms present in the birth canal and young children are not exposed to soil microorganisms that should form part of their normal microflora. Several studies have demonstrated that animals born by cesarean delivery and under sterilized environments, are not colonized by a normal intestinal microflora and show an unusually high immune response against any microorganism, pathogenic or not [9,10]. The daily contact with normal microflora helps to develop self-tolerance, recognize and eliminate pathogens, and maintain the equilibrium with non-pathogenic bacteria. Animals from this experimental model lack all this and tend to develop autoimmune disorders. In this regard, it has been shown that the presence of intestinal microflora (probiotics) provides a tolerogenic environment to the host [9]. Humanity is currently living under a so-called ‘‘stress syndrome’’, on drug prescription (antibiotics, that lower the incidence of deaths by infection but, disrupt the intestinal ecosystem), and contaminated food (agrochemicals and pathogenic bacteria such as Salmonella). All this, along with changes in diet and even the aging process, may have a drastic impact on the intestinal ecosystem, leading to the lost of beneficial bacteria, thus reducing the opportunity for the host intestinal epithelial cells-commensal bacteria normal interaction to take place and for human autoimmune disease-free living.
The hypothesis Human primates co-evolved with environmental bacteria and in due course established a symbiotic relationship, i.e. bacteria colonize the intestine with no harm to any part. Intestinal microflora, among other benefits to the host, helped to avoid autoimmunity, by inducing self-tolerance. Civiliza-
Probiotics and autoimmunity: An evolutionary perspective tion, and the consequent changes in lifestyle and diet have been modifying the intestinal ecosystem up to a point where probiotic-induced self-tolerance has been severely impaired, increasing the risks of developing autoimmune diseases. Some evidences in favor of the hypothesis: (1) The incidence of autoimmune diseases, such as multiple sclerosis, is higher in people that lived in highly sanitized places during infancy [11]. (2) There is epidemiological evidence that the incidence of autoimmune diseases over the last three decades, mainly in industrialized countries, has raised. In Sweden and Germany, for instance, the prevalence of autoimmune and allergic diseases doubled in the 1970s and 1980s, along with a diminution in infectious diseases, attributed to the use of antibiotics and vaccines and to improvements in general hygiene conditions [12]. (3) Necrotizing enterocolitis is a gastrointestinal disease that affects premature, low weight newborns. This disease is characterized by an inflammatory response that destroys intestinal epithelia in response to the colonization of microorganisms considered as being part of normal microflora. Newborns feed on maternal milk or those that receive probiotics (Lactobacillus or Bifidobacteria) have a lower incidence of this pathological condition [4]. (4) Probiotics of the Lactobacillus genus inhibit the secretion of tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, by murine macrophages [13]. If our hypothesis is correct, a comparison of the ability of probiotics and other commensal microorganisms to elicit the production of proinflammatory cytokines would reveal that the later induce the production of a larger amount of pro-inflammatory cytokines. (5) Probiotics are able to modulate the immune system. It has been shown that they can be recognized via TLR2 by antigen presenting cells in Peyer patches and to stimulate the production of cytokines such as TNF-alpha and interleukin (IL)-8 [14,15]. Several strains of Lactobacillus can inhibit the proliferation of CD4+ lymphocytes without affecting the expression of FOXP3 or the production of interferon (IFN)-alpha, IL-4, IL-5 and IL-10 both in healthy individuals and in intestinal inflammatory disease patients [16]. Some probiotics are able to diminish the concentration of serum IgE in patients with allergic rhinitis, by increasing Th1-type cytokine production [17].
659
(6) Probiotics compete with non-commensal bacteria and eliminate them by secreting antimicrobial products, increase the production of antibodies and macrophage activity and contribute to the appropriate host nutrition by producing some vitamins and by breaking down un-digested molecules [1]. These characteristics argue in favor of a symbiotic relationship between humans and probiotics. So, if our hypothesis is correct, a phylogenetic analysis should reveal that the microbial species that are probiotic in humans are also probiotic in other primates.
Conclusion Recent changes in lifestyle and diet (new types of foods, maternal milk substitution for other products, etc.) as a direct consequence of industrialization had, quite likely, a profound impact on the human intestinal ecosystem. Microorganisms that took a very long time of evolution to adapt to the human intestinal microenvironment and to establish a symbiotic relationship with intestinal epithelial cells may have been replaced (over the last century or so) by other non-probiotic microorganisms and even, by pathogens. Microorganisms from this new ecosystem may induce a constant activation of the immune system. Although clinical manifestations may not always be apparent, perhaps persistent inflammation favors the development of autoimmune and allergic diseases. This hypothesis would explain, at least in part, why probiotics administration lowers the incidence and severity of both autoimmune and allergic diseases.
Acknowledgments All authors, except F.J.S.G., are recipients of Consejo Nacional de Ciencia y Tecnologı´a (CONACYT) studentships. F.J.S.G. is a COFAA/EDI/SNI fellow. This work resulted from academic discussion in one of the courses of the Immunology postgraduate program (ENCB-IPN) to which we all are indebted.
References [1] O’Hara A, Shanahan F. The gut flora as a forgotten organ. EMBO Rep 2007;7:688–93. [2] Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007;7: 379–90. [3] Dı´az-Argu ¨elles Ramı´rez-Corrı´a V. Lactancia materna: evaluacio ´n nutricional en el recie ´n nacido. Rev Cubana Pediatr 2005;77:36–41.
660
Canche-Pool et al.
[4] Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev 2003;16:658–72. [5] Mackay IR. Roots of and routes to autoimmunity. In: Gallagher RB, Gilder J, Nossal GJV, Salvatore G, editors. Immunology: the making of a modern science. USA: Academic Press Inc.; 1995. [6] Dutta SK, Banerjee N. Autoimmunity. In: Gupta PS, editor. Clinical immunology. USA: Oxford University Press; 2003. [7] Gregersen PK, Behrens TW. Genetic of autoimmune diseases disorders of immune homeostasis. Nat Rev Genet 2006;7:917–28. [8] Samarkos M, Vaiopoulos G. The role of infections in the pathogenesis of autoimmune diseases. Curr Drug Targets Inflamm Allergy 2005;4:99–103. [9] Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005;2:416–22. [10] Christen U, von Herrath MG. Infections and autoimmunity good or bad? J Immunol 2005;174:7481–6. [11] Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M. Epidemiological study of multiple sclerosis in
[12] [13]
[14]
[15]
[16]
[17]
Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 1966;29:60–8. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. New Engl J Med 2002;347:911–20. Chan-Remillard SKW, Ozimek L. Inhibition of TNF by lactic acid bacteria in mouse macrophages. DRTC Dairy Day 2006;5:45–6. Matsuzaki T, Takagi A, Ikemura H, Matsuguchi T, Yokokura T. Intestinal microflora: probiotics and autoimmunity. J Nutr 2007;137(Suppl. 2):798S–802S. Vizoso Pinto MG, Schuster T, Briviba K, Watzl B, Holzapfel WH, Franz CM. Adhesive and chemokine stimulatory properties of potentially probiotic Lactobacillus strains. J Food Prot 2007;70:125–34. Peluso I, Fina D, Caruso R, Stolfi C, Caprioli F, Fantini MC, et al. Lactobacillus paracasei subsp. paracasei B21060 suppresses human T-cell proliferation. Infect Immun 2007;75:1730–7. Morita H, He F, Kawase M, Kubota A, Hiramatsu M, Kurisaki J, et al. Preliminary human study for possible alteration of serum immunoglobulin E production in perennial allergic rhinitis with fermented milk prepared with Lactobacillus gasseri TMC0356. Microbiol Immunol 2006;50:701–6.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
Probiotics and autoimmunity: An evolutionary perspective ´mez, R. Flores-Mejı´a, E.B. Canche-Pool, R. Cortez-Go ´lez-Gonza ´lez, M.E. Gonza ´lez-Serrano, M.C. Lara-Rodrı´guez, E. Gonza ´nchez, Y. Ledesma-Soto, M.D. Mendoza-Aguilar, D.E. Meza-Sa * ´nchez, M.R. Thompson-Bonilla, ´nchez-Garcı´a , A. Silva-Sa F.J. Sa M.G. Trujillo-Vizuet, I. Wong-Baeza ´gicas, Instituto Polite ´cnico Nacional, Departamento de Inmunologı´a, Escuela Nacional de Ciencias Biolo ´s, Me ´xico D.F. 11340, Mexico Carpio y Plan de Ayala, Col. Sto. Toma Received 5 July 2007; accepted 5 July 2007
Summary Probiotics are microorganisms that have demonstrated beneficial effects on human health. Probiotics are usually isolated from the commensal microflora that inhabits the skin and mucosas. We propose that probiotics represent the species of microorganisms that have established a symbiotic relationship with humans for the longest time. Cultural practices of ancient human societies used to favor that symbiosis and the transmission of probiotics from generation to generation. New practices, introduced as a result of industrialization, such as childbirth by surgical delivery, ingestion of pasteurized and synthetic compounds-supplemented food, cleaner homes, indiscriminate use of antibiotics and so on, have led in recent years to the replacement of probiotics by other microorganisms that are not as well adapted to the microenvironments of the human body. These newly settled microorganisms lack many of the beneficial effects of probiotics. Our hypothesis is that the sudden change (from an evolutive perspective) in human intestinal microflora may importantly contribute to the rise in the incidence of autoimmune diseases, observed in the last half a century. c 2007 Elsevier Ltd. All rights reserved.
Background The survival of an organism is largely dependent on the equilibrium that it is capable to establish with its environment and, when this equilibrium is lost, * Corresponding author. Tel.: +52 55 55729 6300x62370; fax: +52 55 55396 3503. E-mail address: [email protected] (F.J. Sa ´nchez-Garcı´a).
the organism in question is in disadvantage and could even face extinction. Humans interact with a good deal of commensal microorganisms that live in their skin and mucosas, particularly in the gastrointestinal tract. It is estimated that up to 1012 bacteria/ml, belonging to 400–1000 different species colonize the human colon. This complex interaction between human epithelial cells and commensal microorganisms usually takes place without any sign of harm or
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.07.008
658 pathological condition for the host. In fact, this normal microflora is beneficial for the host, since it helps to avoid the colonization of the gut by pathogenic microorganisms (by nutrient competition, production of anti-microbial factors such as bacteriocines and lactic acid), favors the appropriate development of intestinal mucosas, metabolizes and eliminates potentially carcinogenic molecules taken up in the diet, synthesizes vitamins (biotin and folate) and, breaks down un-digested residues [1]. Probiotics are microorganisms that have a clear beneficial effect for a host i.e. that establish a true symbiotic relationship. Right from birth, humans are in contact with probiotics and the newborn immune system allows commensal microorganisms to colonize the intestine without a potentially harmful inflammatory response in the host [2]. In this regard, there is evidence on the presence of probiotics such as Lactobacillus gasseri, L. fermentum, L. salivarius and prebiotics (such as oligosaccharides, which help to support intestinal microflora) in the maternal milk so, in this way, this nutritive milieu would besides contribute to the prevention of newborn’s infections [3]. The ingestion of probiotics has been associated with a diminution in the severity of autoimmune, particularly intestinal inflammatory, diseases as well as allergic disorders [4]. More than a century ago, Paul Ehrlich stated that the immune system does not respond against the own organism (against the ‘‘self’’, in more current terminology). However, he also observed that sometimes an ‘‘auto-toxic horror’’ or immune response against the self takes place, giving rise to the concept of autoimmunity. It is worth noting that the first autoimmune disease identified as such, was in 1904 by Donath and Landsteiner, who described the cold-induced haemoglobinuria that was attributed to the presence of an autohaemolysin in the blood. Since then, an array of autoimmune diseases as well as different mechanisms that contribute to their onset have been described [5]. It is quite likely that the intestinal microflora has been changing along the human evolution, due in part to changes in diet, and that this co-evolution has provided mutual benefits. On this line, it is also likely that our recent ancestors kept an intestinal microflora that is no longer present in the human intestinal ecosystem. This may be related to the increase in the susceptibility to autoimmune diseases, that are worsened by additional genetic, environmental, and molecular (mimetism between self antigens and pathogenic microorganisms) factors [6–8].
Canche-Pool et al. In the ‘‘postmodern’’ times we are living, the human diet is very different from that we had in times long gone by. Food used to be more natural, in sharp contrast with the current mass produced, industrially processed, and long held in store food of nowadays. These changes directly affect the intestinal flora, by limiting their diversity and worst, by avoiding the human contact with those microorganisms through pasteurization, ultra-pasteurization, and so on. In addition, we have modified the environment we live in. Currently, in urban zones, children are born by cesarean delivery, are no longer in direct contact with soil or mud and, their aliments and belongings (toys, for instance) are sterilized or disinfected so that, new born children are not colonized by the microorganisms present in the birth canal and young children are not exposed to soil microorganisms that should form part of their normal microflora. Several studies have demonstrated that animals born by cesarean delivery and under sterilized environments, are not colonized by a normal intestinal microflora and show an unusually high immune response against any microorganism, pathogenic or not [9,10]. The daily contact with normal microflora helps to develop self-tolerance, recognize and eliminate pathogens, and maintain the equilibrium with non-pathogenic bacteria. Animals from this experimental model lack all this and tend to develop autoimmune disorders. In this regard, it has been shown that the presence of intestinal microflora (probiotics) provides a tolerogenic environment to the host [9]. Humanity is currently living under a so-called ‘‘stress syndrome’’, on drug prescription (antibiotics, that lower the incidence of deaths by infection but, disrupt the intestinal ecosystem), and contaminated food (agrochemicals and pathogenic bacteria such as Salmonella). All this, along with changes in diet and even the aging process, may have a drastic impact on the intestinal ecosystem, leading to the lost of beneficial bacteria, thus reducing the opportunity for the host intestinal epithelial cells-commensal bacteria normal interaction to take place and for human autoimmune disease-free living.
The hypothesis Human primates co-evolved with environmental bacteria and in due course established a symbiotic relationship, i.e. bacteria colonize the intestine with no harm to any part. Intestinal microflora, among other benefits to the host, helped to avoid autoimmunity, by inducing self-tolerance. Civiliza-
Probiotics and autoimmunity: An evolutionary perspective tion, and the consequent changes in lifestyle and diet have been modifying the intestinal ecosystem up to a point where probiotic-induced self-tolerance has been severely impaired, increasing the risks of developing autoimmune diseases. Some evidences in favor of the hypothesis: (1) The incidence of autoimmune diseases, such as multiple sclerosis, is higher in people that lived in highly sanitized places during infancy [11]. (2) There is epidemiological evidence that the incidence of autoimmune diseases over the last three decades, mainly in industrialized countries, has raised. In Sweden and Germany, for instance, the prevalence of autoimmune and allergic diseases doubled in the 1970s and 1980s, along with a diminution in infectious diseases, attributed to the use of antibiotics and vaccines and to improvements in general hygiene conditions [12]. (3) Necrotizing enterocolitis is a gastrointestinal disease that affects premature, low weight newborns. This disease is characterized by an inflammatory response that destroys intestinal epithelia in response to the colonization of microorganisms considered as being part of normal microflora. Newborns feed on maternal milk or those that receive probiotics (Lactobacillus or Bifidobacteria) have a lower incidence of this pathological condition [4]. (4) Probiotics of the Lactobacillus genus inhibit the secretion of tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, by murine macrophages [13]. If our hypothesis is correct, a comparison of the ability of probiotics and other commensal microorganisms to elicit the production of proinflammatory cytokines would reveal that the later induce the production of a larger amount of pro-inflammatory cytokines. (5) Probiotics are able to modulate the immune system. It has been shown that they can be recognized via TLR2 by antigen presenting cells in Peyer patches and to stimulate the production of cytokines such as TNF-alpha and interleukin (IL)-8 [14,15]. Several strains of Lactobacillus can inhibit the proliferation of CD4+ lymphocytes without affecting the expression of FOXP3 or the production of interferon (IFN)-alpha, IL-4, IL-5 and IL-10 both in healthy individuals and in intestinal inflammatory disease patients [16]. Some probiotics are able to diminish the concentration of serum IgE in patients with allergic rhinitis, by increasing Th1-type cytokine production [17].
659
(6) Probiotics compete with non-commensal bacteria and eliminate them by secreting antimicrobial products, increase the production of antibodies and macrophage activity and contribute to the appropriate host nutrition by producing some vitamins and by breaking down un-digested molecules [1]. These characteristics argue in favor of a symbiotic relationship between humans and probiotics. So, if our hypothesis is correct, a phylogenetic analysis should reveal that the microbial species that are probiotic in humans are also probiotic in other primates.
Conclusion Recent changes in lifestyle and diet (new types of foods, maternal milk substitution for other products, etc.) as a direct consequence of industrialization had, quite likely, a profound impact on the human intestinal ecosystem. Microorganisms that took a very long time of evolution to adapt to the human intestinal microenvironment and to establish a symbiotic relationship with intestinal epithelial cells may have been replaced (over the last century or so) by other non-probiotic microorganisms and even, by pathogens. Microorganisms from this new ecosystem may induce a constant activation of the immune system. Although clinical manifestations may not always be apparent, perhaps persistent inflammation favors the development of autoimmune and allergic diseases. This hypothesis would explain, at least in part, why probiotics administration lowers the incidence and severity of both autoimmune and allergic diseases.
Acknowledgments All authors, except F.J.S.G., are recipients of Consejo Nacional de Ciencia y Tecnologı´a (CONACYT) studentships. F.J.S.G. is a COFAA/EDI/SNI fellow. This work resulted from academic discussion in one of the courses of the Immunology postgraduate program (ENCB-IPN) to which we all are indebted.
References [1] O’Hara A, Shanahan F. The gut flora as a forgotten organ. EMBO Rep 2007;7:688–93. [2] Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007;7: 379–90. [3] Dı´az-Argu ¨elles Ramı´rez-Corrı´a V. Lactancia materna: evaluacio ´n nutricional en el recie ´n nacido. Rev Cubana Pediatr 2005;77:36–41.
660
Canche-Pool et al.
[4] Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev 2003;16:658–72. [5] Mackay IR. Roots of and routes to autoimmunity. In: Gallagher RB, Gilder J, Nossal GJV, Salvatore G, editors. Immunology: the making of a modern science. USA: Academic Press Inc.; 1995. [6] Dutta SK, Banerjee N. Autoimmunity. In: Gupta PS, editor. Clinical immunology. USA: Oxford University Press; 2003. [7] Gregersen PK, Behrens TW. Genetic of autoimmune diseases disorders of immune homeostasis. Nat Rev Genet 2006;7:917–28. [8] Samarkos M, Vaiopoulos G. The role of infections in the pathogenesis of autoimmune diseases. Curr Drug Targets Inflamm Allergy 2005;4:99–103. [9] Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005;2:416–22. [10] Christen U, von Herrath MG. Infections and autoimmunity good or bad? J Immunol 2005;174:7481–6. [11] Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M. Epidemiological study of multiple sclerosis in
[12] [13]
[14]
[15]
[16]
[17]
Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 1966;29:60–8. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. New Engl J Med 2002;347:911–20. Chan-Remillard SKW, Ozimek L. Inhibition of TNF by lactic acid bacteria in mouse macrophages. DRTC Dairy Day 2006;5:45–6. Matsuzaki T, Takagi A, Ikemura H, Matsuguchi T, Yokokura T. Intestinal microflora: probiotics and autoimmunity. J Nutr 2007;137(Suppl. 2):798S–802S. Vizoso Pinto MG, Schuster T, Briviba K, Watzl B, Holzapfel WH, Franz CM. Adhesive and chemokine stimulatory properties of potentially probiotic Lactobacillus strains. J Food Prot 2007;70:125–34. Peluso I, Fina D, Caruso R, Stolfi C, Caprioli F, Fantini MC, et al. Lactobacillus paracasei subsp. paracasei B21060 suppresses human T-cell proliferation. Infect Immun 2007;75:1730–7. Morita H, He F, Kawase M, Kubota A, Hiramatsu M, Kurisaki J, et al. Preliminary human study for possible alteration of serum immunoglobulin E production in perennial allergic rhinitis with fermented milk prepared with Lactobacillus gasseri TMC0356. Microbiol Immunol 2006;50:701–6.
Available online at www.sciencedirect.com