Sidny
Senior Member
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http://www.discoverymedicine.com/Am...t-pathogens-autoantibodies-molecular-mimicry/
The Concept of the “Autoantibody”
In the early 1900s, antibody production was identified in a range of acute infectious diseases such as diphtheria, tuberculosis, and polio. It was quickly apparent that the human immune system produces antibodies to target pathogen-associated proteins. This knowledge improved diagnostics for acute infection and has formed the basis of vaccine development.
However, antibodies were additionally detected in patients with a range of chronic inflammatory conditions including Grave’s disease, Hashimoto’s thyroiditis, RA, and MS. These antibodies might have been tied to the presence of chronic human pathogens, but at the time, culture-based laboratory techniques could detect only a handful of the microbes now understood to persist in Homo sapiens. The human body was consequently regarded as largely sterile.
Re-evaluating the “Autoantibody”
It follows that patients with autoimmune disease harbor thousands, if not more, pathogens and/or pathobionts whose presence might be tied to “autoantibody” production. This strongly suggests that “autoantibodies” may be normal antibodies created in response to microbiome pathogens.
Indeed, “autoantibodies” are regularly detected in non-autoimmune patients suffering from infection. Berlin et al. (2007) analyzed sera from patients with a range of bacterial, viral, parasitic, and rickettsial infections. Elevated titers of “autoantibodies” including anti-annex in-V, prothrombin, antinuclear antibodies (ANA), anti-Saccharomyces cerevisiae (ASCA), and antiphospholipid antibodies (Anti-PL) were identified in a high percentage study subjects. Indeed, ~39% of subjects harbored elevated titers of at least two of these “autoantibodies.”
Patients in the study by Berlin et al. (2007) presented with acute disease. However, most of the pathogens in the study also survived in persistent forms. For example, anti-annexin-V “autoantibodies” were detected in 80% of patients with hepatitis A, a virus tied to chronic liver cirrhosis. “Autoantibody” production was also associated with H. pylori, S. aureus, Enterobacter, S. pneumonia, Stomatococcus, E.coli, and Klebsiella pneumonia. These pathogens are repeatedly detected in genome-based analyses of human microbiome communities.
It is much more likely that such “autoantibodies” are created in response to these and other chronic, persistent microbiome pathogens as opposed to transient pathogens postulated to “trigger” autoreactive B cells (the hit and run model). Indeed, a growing number of studies demonstrate that acute human pathogens persist in the human microbiome. For example, EBV causes acute mononucleosis, but can additionally persist inside long-lasting human lymphoblastic B cells (Yenamandra et al., 2009). Ebola virus RNA has been detected in men’s semen for up to two years after “recovery” (Fischer et al., 2017). Brodin et al. (2015) found that the lifelong need to control persistent CMV infection caused 10% of T cells in CMV+ individuals to be directed against the virus.
This fits with data obtained by Kriegel/Vieira et al. (2018), who recently tied “autoantibody” production to yet another persistent member of the human microbiome. The team identified pathobiont E. gallinarum in the mesenteric veins, mesenteric lymph nodes, liver, and spleens of mice made genetically prone to autoimmunity. In these mice, E. gallinarum initiated the production of “autoantibodies,” activated T cells, and inflammation. This “autoantibody” production stopped when E. gallinarum’s growth was suppressed with the antibiotic vancomycin.
Discussion
The discovery of the human microbiome has forever changed our understanding of human biology. Humans are superorganisms colonized by trillions of persistent microbes. This human microbiome extends to nearly every human body site, including tissue and blood. Thousands of newly discovered pathogens and/or pathobionts have been detected in these microbiome ecosystems. Even then, the genomes of most bacteria, viruses, and bacteriophages in the human microbiome have yet to be fully characterized. For example, it is estimated that only 2% of viruses on Earth have been sequenced (Anthony et al., 2013).
This increases the likelihood that “autoantibodies” are created in response to chronic microbiome pathogens. Under such conditions, molecular mimicry or structural homology between pathogen and host proteins can result in “collateral damage” towards human tissue. Indeed, a growing body of research has documented “autoantibody” production in response to a range of pathogens/pathobionts. These pathogens are not “triggers” but persist as members of complex microbiome communities.
This opens up new possibilities in “autoimmune” disease research. The concept of the “autoantibody” should be retired in favor of a paradigm that seeks to foster microbiome health, diversity, and balance. Research teams should seek to better characterize and identify microbiome pathogens capable of driving antibody production. The survival mechanisms and activity of such pathogens should also be investigated.
Additionally, there is no need to segregate “autoimmune” diseases from other chronic inflammatory conditions tied to the human microbiome. The “autoimmune” disease research community should collaborate with these related research communities to better identify common trends associated with microbiome dysbiosis.
The situation also calls for a paradigm shift in “autoimmune” disease treatment. The immunosuppressive medications currently prescribed for these conditions palliate symptoms but allow pathogens in the microbiome to spread with greater ease. Indeed, these medications can drive the very microbiome dysbiosis now connected to most “autoimmune” conditions. This helps explain the poor long-term outcomes associated with their use.
In contrast, treatments that support the immune system in “autoimmune” disease would target microbiome pathogens at the root of the disease process. While such treatments induce temporary immunopathology, patients may eventually reach a state of stable remission. Indeed, the cancer community has introduced T cell immunotherapies with great success, despite the fact that patients administered these immunostimulative treatments must endure an immunopathology “cytokine-storm.”
Paradigm shifts often take decades to implement. We cannot afford the luxury of such a timeline. The incidence and prevalence of nearly every chronic inflammatory condition are on the rise, to a point where we are facing a global epidemic of chronic disease. RAND Health estimates that 60% of Americans adults are taking a drug for at least one chronic diagnosis and 12% suffer five or more comorbidities (Buttorff, 2017). We must revise the study and treatment of these diseases to account for the human microbiome. Otherwise, this trend may further accelerate at a significant cost to patients and society as a whole.
The Concept of the “Autoantibody”
In the early 1900s, antibody production was identified in a range of acute infectious diseases such as diphtheria, tuberculosis, and polio. It was quickly apparent that the human immune system produces antibodies to target pathogen-associated proteins. This knowledge improved diagnostics for acute infection and has formed the basis of vaccine development.
However, antibodies were additionally detected in patients with a range of chronic inflammatory conditions including Grave’s disease, Hashimoto’s thyroiditis, RA, and MS. These antibodies might have been tied to the presence of chronic human pathogens, but at the time, culture-based laboratory techniques could detect only a handful of the microbes now understood to persist in Homo sapiens. The human body was consequently regarded as largely sterile.
Re-evaluating the “Autoantibody”
It follows that patients with autoimmune disease harbor thousands, if not more, pathogens and/or pathobionts whose presence might be tied to “autoantibody” production. This strongly suggests that “autoantibodies” may be normal antibodies created in response to microbiome pathogens.
Indeed, “autoantibodies” are regularly detected in non-autoimmune patients suffering from infection. Berlin et al. (2007) analyzed sera from patients with a range of bacterial, viral, parasitic, and rickettsial infections. Elevated titers of “autoantibodies” including anti-annex in-V, prothrombin, antinuclear antibodies (ANA), anti-Saccharomyces cerevisiae (ASCA), and antiphospholipid antibodies (Anti-PL) were identified in a high percentage study subjects. Indeed, ~39% of subjects harbored elevated titers of at least two of these “autoantibodies.”
Patients in the study by Berlin et al. (2007) presented with acute disease. However, most of the pathogens in the study also survived in persistent forms. For example, anti-annexin-V “autoantibodies” were detected in 80% of patients with hepatitis A, a virus tied to chronic liver cirrhosis. “Autoantibody” production was also associated with H. pylori, S. aureus, Enterobacter, S. pneumonia, Stomatococcus, E.coli, and Klebsiella pneumonia. These pathogens are repeatedly detected in genome-based analyses of human microbiome communities.
It is much more likely that such “autoantibodies” are created in response to these and other chronic, persistent microbiome pathogens as opposed to transient pathogens postulated to “trigger” autoreactive B cells (the hit and run model). Indeed, a growing number of studies demonstrate that acute human pathogens persist in the human microbiome. For example, EBV causes acute mononucleosis, but can additionally persist inside long-lasting human lymphoblastic B cells (Yenamandra et al., 2009). Ebola virus RNA has been detected in men’s semen for up to two years after “recovery” (Fischer et al., 2017). Brodin et al. (2015) found that the lifelong need to control persistent CMV infection caused 10% of T cells in CMV+ individuals to be directed against the virus.
This fits with data obtained by Kriegel/Vieira et al. (2018), who recently tied “autoantibody” production to yet another persistent member of the human microbiome. The team identified pathobiont E. gallinarum in the mesenteric veins, mesenteric lymph nodes, liver, and spleens of mice made genetically prone to autoimmunity. In these mice, E. gallinarum initiated the production of “autoantibodies,” activated T cells, and inflammation. This “autoantibody” production stopped when E. gallinarum’s growth was suppressed with the antibiotic vancomycin.
Discussion
The discovery of the human microbiome has forever changed our understanding of human biology. Humans are superorganisms colonized by trillions of persistent microbes. This human microbiome extends to nearly every human body site, including tissue and blood. Thousands of newly discovered pathogens and/or pathobionts have been detected in these microbiome ecosystems. Even then, the genomes of most bacteria, viruses, and bacteriophages in the human microbiome have yet to be fully characterized. For example, it is estimated that only 2% of viruses on Earth have been sequenced (Anthony et al., 2013).
This increases the likelihood that “autoantibodies” are created in response to chronic microbiome pathogens. Under such conditions, molecular mimicry or structural homology between pathogen and host proteins can result in “collateral damage” towards human tissue. Indeed, a growing body of research has documented “autoantibody” production in response to a range of pathogens/pathobionts. These pathogens are not “triggers” but persist as members of complex microbiome communities.
This opens up new possibilities in “autoimmune” disease research. The concept of the “autoantibody” should be retired in favor of a paradigm that seeks to foster microbiome health, diversity, and balance. Research teams should seek to better characterize and identify microbiome pathogens capable of driving antibody production. The survival mechanisms and activity of such pathogens should also be investigated.
Additionally, there is no need to segregate “autoimmune” diseases from other chronic inflammatory conditions tied to the human microbiome. The “autoimmune” disease research community should collaborate with these related research communities to better identify common trends associated with microbiome dysbiosis.
The situation also calls for a paradigm shift in “autoimmune” disease treatment. The immunosuppressive medications currently prescribed for these conditions palliate symptoms but allow pathogens in the microbiome to spread with greater ease. Indeed, these medications can drive the very microbiome dysbiosis now connected to most “autoimmune” conditions. This helps explain the poor long-term outcomes associated with their use.
In contrast, treatments that support the immune system in “autoimmune” disease would target microbiome pathogens at the root of the disease process. While such treatments induce temporary immunopathology, patients may eventually reach a state of stable remission. Indeed, the cancer community has introduced T cell immunotherapies with great success, despite the fact that patients administered these immunostimulative treatments must endure an immunopathology “cytokine-storm.”
Paradigm shifts often take decades to implement. We cannot afford the luxury of such a timeline. The incidence and prevalence of nearly every chronic inflammatory condition are on the rise, to a point where we are facing a global epidemic of chronic disease. RAND Health estimates that 60% of Americans adults are taking a drug for at least one chronic diagnosis and 12% suffer five or more comorbidities (Buttorff, 2017). We must revise the study and treatment of these diseases to account for the human microbiome. Otherwise, this trend may further accelerate at a significant cost to patients and society as a whole.
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