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 Conversely, the Marshall Pathogenesis explains that so-called "autoantibodies" are merely antibodies generated in response to pathogenic bacterial cells that have been destroyed as a result of an active immune response – in essence, collateral damage. Conversely, the Marshall Pathogenesis explains that so-called "autoantibodies" are merely antibodies generated in response to pathogenic bacterial cells that have been destroyed as a result of an active immune response – in essence, collateral damage.
  
-At least [[http://en.wikipedia.org/wiki/Autoimmune_disease|forty different chronic diseases]] are suspected or accepted as being caused by an autoimmune response. According to Yehuda Shoenfeld, when it comes to autoimmune disease, "Everything is infectious until proven otherwise."+At least [[https://en.wikipedia.org/wiki/Autoimmune_disease|forty different chronic diseases]] are suspected or accepted as being caused by an autoimmune response. According to Yehuda Shoenfeld, when it comes to autoimmune disease, "Everything is infectious until proven otherwise."
  
  
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 ===== Autoimmune patients show signs of being immunocompromised ===== ===== Autoimmune patients show signs of being immunocompromised =====
  
-  * **sarcoidosis** – Barna, Kanchwala, //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.(({{pubmed>long:22759465}})) ((Kanchwala, A., B. Barna, et al. (2009). [[http://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Deficiencies of cathelicidin and vitamin D accompany disease severity in sarcoidosis]].)) This was true even despite "healthy" levels of 1,25-D. Wiken //et al.// showed that there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome (a type of acute sarcoidosis).(({{pubmed>long:20813038}})) Note that TLR2 (which the Marshall Pathogenesis theorizes is downregulated in autoimmune disease states) is expressed by the VDR.  +  * **sarcoidosis** – Barna, Kanchwala, //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.(({{pmid>long:22759465}})) ((Kanchwala, A., B. Barna, et al. (2009). [[https://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Deficiencies of cathelicidin and vitamin D accompany disease severity in sarcoidosis]].)) This was true even despite "healthy" levels of 1,25-D. Wiken //et al.// showed that there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome (a type of acute sarcoidosis).(({{pmid>long:20813038}})) Note that TLR2 (which the Marshall Pathogenesis theorizes is downregulated in autoimmune disease states) is expressed by the VDR.  
-  * **Crohn's disease** – Chamaillard concluded in 2011 that "clinical studies have linked the defective expression of both α- and β-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease (CD), respectively."(({{pubmed>long:21350705}})) Wang //et al.// have demonstrated in Crohn's patients a decline in expression of key antimicrobial peptides including cathelicidin and Beta-defensin-2.(({{pubmed>long:19948723}})) Consistent with the Marshall Pathogenesis, the Wang group points to the Vitamin D Receptor as being important in Crohn's patients.+  * **Crohn's disease** – Chamaillard concluded in 2011 that "clinical studies have linked the defective expression of both α- and β-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease (CD), respectively."(({{pmid>long:21350705}})) Wang //et al.// have demonstrated in Crohn's patients a decline in expression of key antimicrobial peptides including cathelicidin and Beta-defensin-2.(({{pmid>long:19948723}})) Consistent with the Marshall Pathogenesis, the Wang group points to the Vitamin D Receptor as being important in Crohn's patients.
  
-Conversely, skin diseases like psoriasis(({{pubmed>long:19919305}})) and cutaneous lupus(({{pubmed>long:21353331}})) have higher expression of AMPs. This immune response protects the skin of the symptomatic host from further bacterial colonization.+Conversely, skin diseases like psoriasis(({{pmid>long:19919305}})) and cutaneous lupus(({{pmid>long:21353331}})) have higher expression of AMPs. This immune response protects the skin of the symptomatic host from further bacterial colonization.
 ===== "Autoantibodies" are produced in response to microbial DNA  ===== ===== "Autoantibodies" are produced in response to microbial DNA  =====
  
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 A litany of research implies a re-evaluation of the "autoantibody." Recently researchers have shown that certain autoantibodies are created in response to several well-studied pathogens and in a variety of states.  A litany of research implies a re-evaluation of the "autoantibody." Recently researchers have shown that certain autoantibodies are created in response to several well-studied pathogens and in a variety of states. 
  
-  * **lupus** – "Lupus specific autoantibodies" such as RO, La or dsDNA are often generated in response to Epstein-Barr Virus.(({{pubmed>long:17917546}})) Similarly, anti-EBNA-1 antibodies are able to bind lupus-specific autoantigens such as Sm or Ro.Harley.(({{pubmed>long:17917546}})) +  * **lupus** – "Lupus specific autoantibodies" such as RO, La or dsDNA are often generated in response to Epstein-Barr Virus.(({{pmid>long:17917546}})) Similarly, anti-EBNA-1 antibodies are able to bind lupus-specific autoantigens such as Sm or Ro.Harley.(({{pmid>long:17917546}})) 
-  * **rheumatoid arthritis** – Casali and Slaughter found that in humans, EBV is a polyclonal B cell activator, and in vitro transformation with EBV results in production of rheumatoid factor (RF).(({{pubmed>long:3105056}})) (({{pubmed>long:214511}})) Possnett et al. argues that high titers of RF are associated with severe rheumatoid arthritis but also appear in a number of other diseases including viral, bacterial, and parasitic infections.(({{pubmed>long:9198668}})) Maturation of RF can be initiated by chronic infections.(({{pubmed>long:8898963}})) For example, patients with subacute bacterial endocarditis, which is frequently tied to the presence of Streptococcus, also often present with high levels of RF.(({{pubmed>long:1299798}})) Williams //et al.// showed that once the offending infectious agent is removed with antibiotic therapy, the RF disappears.(({{pubmed>long:14007218}}))  +  * **rheumatoid arthritis** – Casali and Slaughter found that in humans, EBV is a polyclonal B cell activator, and in vitro transformation with EBV results in production of rheumatoid factor (RF).(({{pmid>long:3105056}})) (({{pmid>long:214511}})) Possnett et al. argues that high titers of RF are associated with severe rheumatoid arthritis but also appear in a number of other diseases including viral, bacterial, and parasitic infections.(({{pmid>long:9198668}})) Maturation of RF can be initiated by chronic infections.(({{pmid>long:8898963}})) For example, patients with subacute bacterial endocarditis, which is frequently tied to the presence of Streptococcus, also often present with high levels of RF.(({{pmid>long:1299798}})) Williams //et al.// showed that once the offending infectious agent is removed with antibiotic therapy, the RF disappears.(({{pmid>long:14007218}}))  
-  * **idiopathic thrombocytopenic purpura (ITP)** – is mediated by what are considered to be anti-platelet autoantibodies. However, Asahi et al. found that eradication of H. pylori is effective in increasing platelet count in nearly half of ITP patients infected with the bacterium.(({{pubmed>long:16963398}})) Barzilai and team also found that Hepatitis B shares amino acid sequences with different autoantigens, further suggesting that so-called autoantibodies may actually be created in response to pathogens.(({{pubmed>long:17917546}})) +  * **idiopathic thrombocytopenic purpura (ITP)** – is mediated by what are considered to be anti-platelet autoantibodies. However, Asahi et al. found that eradication of H. pylori is effective in increasing platelet count in nearly half of ITP patients infected with the bacterium.(({{pmid>long:16963398}})) Barzilai and team also found that Hepatitis B shares amino acid sequences with different autoantigens, further suggesting that so-called autoantibodies may actually be created in response to pathogens.(({{pmid>long:17917546}})) 
   * **Crohn's disease** – Crohn's disease is classified as an autoimmune condition based largely on the presence of perinuclear anti-nuclear cytoplasmic antibodies (pANCA) in patients with the disease. Yet recently two major species of proteins immunoreactive to pANCA were detected in bacteria from anaerobic libraries, implicating colonic bacteria as a possible trigger for the disease-associated immune response.     * **Crohn's disease** – Crohn's disease is classified as an autoimmune condition based largely on the presence of perinuclear anti-nuclear cytoplasmic antibodies (pANCA) in patients with the disease. Yet recently two major species of proteins immunoreactive to pANCA were detected in bacteria from anaerobic libraries, implicating colonic bacteria as a possible trigger for the disease-associated immune response.  
  
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 ==== Patients without autoimmune disease have autoantibodies during infection ====  ==== Patients without autoimmune disease have autoantibodies during infection ==== 
  
-Autoantibodies have been detected in patients without autoimmune disease during periods of infection. Berlin et al. collected sera from 88 patients with acute infections (41 bacterial, 23 viral, 17 parasitic, and 7 rikettsial.(({{pubmed>long:17894023}})) Elevated titers of autoantibodies including annexin-V, prothrombin, ASCA, ANA, or antiphospholipid antibodies were detected in approximately half of the subjects, with 34 individuals harboring elevated titers of at least two "autoantibodies."   +Autoantibodies have been detected in patients without autoimmune disease during periods of infection. Berlin et al. collected sera from 88 patients with acute infections (41 bacterial, 23 viral, 17 parasitic, and 7 rikettsial.(({{pmid>long:17894023}})) Elevated titers of autoantibodies including annexin-V, prothrombin, ASCA, ANA, or antiphospholipid antibodies were detected in approximately half of the subjects, with 34 individuals harboring elevated titers of at least two "autoantibodies."   
      
  
-An increasing number of studies also show that what are currently perceived as autoantibodies can often be detected in so called healthy individuals years before the full presentation of an autoimmune disease state. A 2006 study found that 20% of healthy Chinese subjects had one of three autoantibodies.(({{pubmed>long:16878294}})) Many researchers now espouse that early detection of these antibodies can help predict whether or not such a "healthy" person will develop an autoimmune disease. For example, in an eight-year prospective study, Swaak //et al.// examined the diagnostic significance of anti-double-stranded deoxyribonucleic acid (anti-dsDNA) determination in a group of 441 patients without systemic lupus erythematosus whose sera were found to contain antibodies to dsDNA on routine screening.(({{pubmed>long:3872637}})) Within one year, 69% (304) of these patients fulfilled the preliminary American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE). Eighty-two of the remaining 137 patients were followed up for several years. At the end of the study, 52% of these patients had also developed systemic lupus erythematosus. The team concluded that about 85% of patients without systemic lupus erythematosus with anti-dsDNA in the circulation would develop SLE within a few years.  +An increasing number of studies also show that what are currently perceived as autoantibodies can often be detected in so called healthy individuals years before the full presentation of an autoimmune disease state. A 2006 study found that 20% of healthy Chinese subjects had one of three autoantibodies.(({{pmid>long:16878294}})) Many researchers now espouse that early detection of these antibodies can help predict whether or not such a "healthy" person will develop an autoimmune disease. For example, in an eight-year prospective study, Swaak //et al.// examined the diagnostic significance of anti-double-stranded deoxyribonucleic acid (anti-dsDNA) determination in a group of 441 patients without systemic lupus erythematosus whose sera were found to contain antibodies to dsDNA on routine screening.(({{pmid>long:3872637}})) Within one year, 69% (304) of these patients fulfilled the preliminary American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE). Eighty-two of the remaining 137 patients were followed up for several years. At the end of the study, 52% of these patients had also developed systemic lupus erythematosus. The team concluded that about 85% of patients without systemic lupus erythematosus with anti-dsDNA in the circulation would develop SLE within a few years.  
  
 Another recent study of blood from 441 healthy Portuguese blood-donors found autoantibodies for rheumatoid factor, anti cyclic citrunillated peptides, anti-mitochondria, anti-Sacharomyces cerevisiae, ANA, anti-TTG, and anti-Beta2- glycoprotein.((Tavares-Ratado, P., A. Geraldes, //et al.// 2009. Prevalence of Circulating Autoantibodies in Portugese Blood Donors. 4th Asian Congress on Autoimmunity, Singapore.)) More than 30% of the blood contained one or more of the antibodies, 4% exhibited two antibodies, and nearly 1% had three or more antibodies present. It is clear that sub-clinical autoimmune disease is much more common than previously thought. Another recent study of blood from 441 healthy Portuguese blood-donors found autoantibodies for rheumatoid factor, anti cyclic citrunillated peptides, anti-mitochondria, anti-Sacharomyces cerevisiae, ANA, anti-TTG, and anti-Beta2- glycoprotein.((Tavares-Ratado, P., A. Geraldes, //et al.// 2009. Prevalence of Circulating Autoantibodies in Portugese Blood Donors. 4th Asian Congress on Autoimmunity, Singapore.)) More than 30% of the blood contained one or more of the antibodies, 4% exhibited two antibodies, and nearly 1% had three or more antibodies present. It is clear that sub-clinical autoimmune disease is much more common than previously thought.
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 The concept of autoimmune disease has progressed to the point that now even researchers who previously dismissed the possibility of infection are accepting the possibility that “autoimmune” disease could be triggered by infection. This is some progress, but it’s not enough. Especially since the concept of autoimmunity encourages doctors to prescribe immunosuppressive steroids to patients. But if persistent infection is involved these steroids may exacerbate the fire by allowing pathogens to spread. The concept of autoimmune disease has progressed to the point that now even researchers who previously dismissed the possibility of infection are accepting the possibility that “autoimmune” disease could be triggered by infection. This is some progress, but it’s not enough. Especially since the concept of autoimmunity encourages doctors to prescribe immunosuppressive steroids to patients. But if persistent infection is involved these steroids may exacerbate the fire by allowing pathogens to spread.
  
-//**Paul Ewald**, [[http://bacteriality.com/2008/02/11/ewald/|Bacteriality.com]]// </blockquote>+//**Paul Ewald**, [[https://bacteriality.com/2008/02/11/ewald/|Bacteriality.com]]// </blockquote>
  
 To think that autoimmune disease is caused by an interaction between the environment and human genetics, as a number of commentators have, is only marginally more plausible. Evolutionary theory is clear that any kind of consistent reproductive disadvantage is consistently and ultimately weeded out of the population. To think that autoimmune disease is caused by an interaction between the environment and human genetics, as a number of commentators have, is only marginally more plausible. Evolutionary theory is clear that any kind of consistent reproductive disadvantage is consistently and ultimately weeded out of the population.
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 ===== Conventional therapies for autoimmunity ===== ===== Conventional therapies for autoimmunity =====
  
-According to many doctors and researchers, the best way to treat an overreactive immune response is to suppress it. To that end, many patients with autoimmune diseases are given regular doses of medications that profoundly modulate a body's immune response including corticosteroids, anti-TNF drugs, and others. One provocative study concluded that reduced levels of vitamin D, a known immunosuppressant, was associated with autoimmune response in tuberculosis patients.(({{pubmed>long:22419776}}))+According to many doctors and researchers, the best way to treat an overreactive immune response is to suppress it. To that end, many patients with autoimmune diseases are given regular doses of medications that profoundly modulate a body's immune response including corticosteroids, anti-TNF drugs, and others. One provocative study concluded that reduced levels of vitamin D, a known immunosuppressant, was associated with autoimmune response in tuberculosis patients.(({{pmid>long:22419776}}))
  
 In some cases, patients may experience temporary symptom relief lasting months or even years. Yet, immunomodulatory drugs have a number of liabilities. In some cases, patients may experience temporary symptom relief lasting months or even years. Yet, immunomodulatory drugs have a number of liabilities.
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 It is quite plausible that "autoimmunity" is also caused by bacterial-induced alteration of human genes. All a bacterium would need to do in order to generate an apparent "autoimmune" reaction would be to interfere with the genes necessary for the production of proteins against which autoantibodies are produced. It is quite plausible that "autoimmunity" is also caused by bacterial-induced alteration of human genes. All a bacterium would need to do in order to generate an apparent "autoimmune" reaction would be to interfere with the genes necessary for the production of proteins against which autoantibodies are produced.
  
-According to one analysis, 463 human genes are changed during an infection with //Mycobacterium tuberculosis//.(({{pubmed>long:12890386}})) These mutated genes function in various cellular processes including intracellular signalling, cytoskeletal rearrangement, apoptosis, transcriptional regulation, cell surface receptors, cell-mediated immunity and cellular metabolic pathways.+According to one analysis, 463 human genes are changed during an infection with //Mycobacterium tuberculosis//.(({{pmid>long:12890386}})) These mutated genes function in various cellular processes including intracellular signalling, cytoskeletal rearrangement, apoptosis, transcriptional regulation, cell surface receptors, cell-mediated immunity and cellular metabolic pathways.
  
 There's no reason to think that other bacteria can do just as much damage – or that any pathogenic bacteria, for that matter, can interfere with production of autoantibodies. There's no reason to think that other bacteria can do just as much damage – or that any pathogenic bacteria, for that matter, can interfere with production of autoantibodies.
  
 +{{tag>Alternate_models}}
 +
 +<nodisp>
 ===== Notes and comments ===== ===== Notes and comments =====
  
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 <blockquote>J Exp Med. 1996 Aug 1;184(2):771-5. <blockquote>J Exp Med. 1996 Aug 1;184(2):771-5.
-IL-12 unmasks latent autoimmune disease in resistant mice.(({{pubmed>long:8786337}}))+IL-12 unmasks latent autoimmune disease in resistant mice.(({{pmid>long:8786337}}))
  
 Segal BM, Shevach EM. Segal BM, Shevach EM.
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 Meyer Children's Hospital, Haifa and the B. Rappaport Faculty of Medicine, Technion, Haifa, 36019, Israel. etzioni@rambam.health.gov.il Meyer Children's Hospital, Haifa and the B. Rappaport Faculty of Medicine, Technion, Haifa, 36019, Israel. etzioni@rambam.health.gov.il
 Abstract Abstract
-Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.(({{pubmed>long:14550878}}))+Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.(({{pmid>long:14550878}}))
  
  
 Amy - autoantibodies to cancer  Amy - autoantibodies to cancer
  
-http://www.reuters.com/article/idUSTRE68R4YU20100928+https://www.reuters.com/article/idUSTRE68R4YU20100928
  
 ..trevor.. ..trevor..
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 <blockquote> <blockquote>
 Scientists of the University of Greifswald and Bonn found out, that autoantibodies are the reason for severe neurological reactions on EHEC. Why some people develop these autoantibodies, and others don't is not yet clear. Scientists of the University of Greifswald and Bonn found out, that autoantibodies are the reason for severe neurological reactions on EHEC. Why some people develop these autoantibodies, and others don't is not yet clear.
-German: http://www3.uni-bonn.de/Pressemitteilungen/154-2011 +German: https://www3.uni-bonn.de/Pressemitteilungen/154-2011 
-English short notice: http://www.ndm1bacteria.com/ehec-producing-auto-antibodies+English short notice: https://www.ndm1bacteria.com/ehec-producing-auto-antibodies
 </blockquote> </blockquote>
  
  
 <blockquote>Nat Immunol. 2010 Jan;11(1):28-35. Epub 2009 Dec 17. <blockquote>Nat Immunol. 2010 Jan;11(1):28-35. Epub 2009 Dec 17.
-Influence of microbial environment on autoimmunity.(({{pubmed>long:20016507}}))+Influence of microbial environment on autoimmunity.(({{pmid>long:20016507}}))
  
 Chervonsky AV. Chervonsky AV.
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 <blockquote> <blockquote>
-Infections and autoimmune diseases(({{pubmed>long:16278064}}))+Infections and autoimmune diseases(({{pmid>long:16278064}}))
              
  
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 PMID: 21333492 PMID: 21333492
-URL  - http://www.ncbi.nlm.nih.gov/pubmed/21333492?dopt=Citation+URL  - https://www.ncbi.nlm.nih.gov/pubmed/21333492?dopt=Citation
  
  
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 > >
 > PMID: 21149241 > PMID: 21149241
-> URL  -http://www.ncbi.nlm.nih.gov/pubmed/21149241?dopt=Citation+> URL  -https://www.ncbi.nlm.nih.gov/pubmed/21149241?dopt=Citation
 > >
 > >
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 </blockquote> </blockquote>
  
-<blockquote>http://www.businessweek.com/lifestyle/content/healthday/651995.html+<blockquote>https://www.businessweek.com/lifestyle/content/healthday/651995.html
  
 Nat Med. 2011 Apr 17. [Epub ahead of print]B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011 Apr 17. [Epub ahead of print]B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.
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    * update autoimmunity article to discuss concepts mentioned in Amy's speech in China    * update autoimmunity article to discuss concepts mentioned in Amy's speech in China
  
-===== References =====+===== References =====</nodisp> 
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