Autoimmune diseases are thought to arise from an overactive immune response of the body against substances and tissues normally present in the body. The autoimmune disease theory has yet to present a satisfactory reason, evolutionary or otherwise, why an immune system would attack human tissue.
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 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.”
A number of theories attempt to explain why antibodies are present in certain diseases, why the body might attack itself:
The last of these theories was first proposed by the 1960 Nobel laureate in medicine, Frank M. Burnett, some fifty years ago. The variety and age of these theories suggests how wide open the field is and has been.
The complex interactions between the innate and adaptive immune systems are largely indeterminate – they have evolved over eons, and many of the interactions make no sense when looked at individually. It is a huge mistake to think the immune system as something designed to protect the human body. It evolved over eons as a group of functions which was helpful in survival, and it was not pre-designed so that all immune functions work sensibly and deterministically.
Trevor Marshall, PhD
Autoimmune diseases are characterized largely by the presence of autoantibodies. While autoantibodies were reported over a century ago, many scientists at the time were unwilling to accept the possibility that the immune system attacks its own cells. Ehrlich argued that autoimmunity was not possible and proposed the theory of horror autotoxicus to describe the body's innate aversion to immunological self-destruction by the production of autoantibodies.
Now that humans are understood to be the product of multiple genomes, increasing evidence supports Ehrlich's view. When an innate immune system is forced to respond to a chronic microbiota, the resulting cascade of chemokines and cytokines will also stimulate an adaptive response. Antibodies are notoriously polyspecific, and the likelihood that antibodies generated to target metagenomic fragments will also target human proteins (target “self”) is finite.
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.
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.18 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.19 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.20 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.21 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.
This gradual presentation of an increasing number of so-called “autoantibodies” in the years before a patient meets the official criteria for an autoimmune diagnosis supports the model of successive infection described earlier – pathogenic components of the microbiota gradually accumulate over the course of a lifetime until bacterial, viral and phage load reaches a level at which a diagnosis can be made. It also supports the contention that individuals perceived as “healthy” may still harbor and accumulate pathogenic microbes that will eventually lead to an inflammatory diagnosis, or a process associated with “aging.” Indeed, it is possible that any antibodies that damage “self” do so as an unintended polyspecific consequence of their activity against the metagenomic pathogens.
Beyond the evidence showing that autoimmune patients are immunosuppressed, there are a number of other reasons why the autoimmune explanation of disease is problematic:
The interesting thing was that sarcoidosis there are usually no antibodies. There is usually a very low sedimentation rate indicating that there's no real obvious pathogens, the immune system is not feeling anything. And that's one of the reasons it's such an idiopathic and has been such a puzzling disease.
Yet, when you look at the malaise suffered by the patients, the malaise is a straight line. There is no peaking of the malaise that was coincident with the peaking of the antibodies. In fact, the antibodies just seem to be bystanders, if you like, of the main disease process.
Trevor Marshall, PhD, 2006 Bio21 presentation
A number of evolutionary biologists have taken exception to the theory of autoimmunity based on what they know about how species change over time. According to evolutionary theory, there is no way that genes that determine a person will get an autoimmune disease will stay in a population for long. The forces of reproductive fitness are simply too strong.
One thing that we clearly know causes inflammation is the presence of an infection. So, as soon as I hear the word inflammation I think, “What infectious agents are at play?”
That brings us to the concept of autoimmune disease – the idea that the immune system just “goes crazy.” I think the fact that the concept of autoimmunity was developed in the first place is largely related to the fact that our brains have not evolved to think scientifically. People who have studied disease from their own point of view have recognized that the immune system is extremely important. But as we’ve learned more about the immune system, we’ve realized that it is an extremely complicated system - as complicated as the brain. Just like we can’t look at one type of neuron and infer information about the entire brain, we can’t try to understand the characteristics of only some immune cells and think we understand immune function.
So, over the years, as researchers have been daunted by the complexity of the immune system, it has seemed logical that such a complex entity has the potential to go wrong. Because they are limited by the power of their brains, they tend to simplify the issue and view the immune system in the same way they would view a truck that could break down. There are two problems with this type of thinking. For starters, we can’t trust our intuition that something complex is likely to malfunction. The fact is, the immune system functions just fine in a large proportion of the population. The only logical way to explain the immune activation seen in patients with “autoimmune disease” is to suggest that there is some sort of agent pushing the immune system off balance. This argument is only strengthened by the fact that the same evolutionary forces that would cause a serious disease to be weeded from the population would also cause those people whose immune systems are prone to self-destruction to be eliminated from the population.
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, Baceriality.com
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.
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.22
In some cases, patients may experience temporary symptom relief lasting months or even years. Yet, immunomodulatory drugs have a number of liabilities.
Also, if autoimmunity were causing disease, wouldn't disrupting molecular mechanisms put a stop to autoimmune disease? Shouldn't corticosteroids and anti-TNF drugs cure a patient of autoimmune disease?
Auto-antibodies, antibodies directed at the self, do exist and have been documented – but growing evidence suggests they don't cause autoimmune illnesses.
How then does one account for why these proteins are observed in patients with “autoimmune disease”? Is there a true target?
According to Trevor Marshall, autoantibodies are “incidental roadkill.” Intraphagocytic pathogens do damage via the innate immune system functions which they directly compromise, and auto-antibodies are a byproduct of the cytokine and chemokine cascade which ensues.
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.23 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.
This was supposedly an Ewald quote but I (Paul) couldn't find the source:
During Th1 infection, I am sure that science will eventually be able to find the true targets of these, and that they will be pathogen-related, not self-related.
J Exp Med. 1996 Aug 1;184(2):771-5. IL-12 unmasks latent autoimmune disease in resistant mice.24
Segal BM, Shevach EM. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland 20892, USA. Abstract Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases. PMID: 8786337
INTERLEUKIN-12IL-12 plays an essential role in the interaction and integration of innate and acquired immunity. Endogenous IL-12 is produced primarily by macrophages, dendritic cells, and B lymphocytes and regulates activation, IFN-γ production, and cytotoxicity of T cells and NK cells. Although initial studies suggested a critical role for IL-12 in defense against infection by a variety of intracellular pathogens, recent evidence has been contradictory. Nonetheless, IL-12 has been studied for possible treatment benefit in several infectious diseases. Case reports suggest that use of adjunctive recombinant IL-12 may be beneficial in selected cases of antimicrobial-refractory mycobacterial disease in humans. Despite early promising results, immunomodulatory therapy with recombinant human IL-12 for treatment of chronic HBV and HCV infections has not proved to be clinically effective, and in HCV-infected patients it may be associated with serious toxicity, including fulminant liver failure.[125,126] Phase I trials of IL-12 therapy in HIV-infected subjects have not shown positive treatment effects. – Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Copyright © 2009 Churchill Livingstone, An Imprint of Elsevier
122.. Holland SM: Interferon gamma, IL-12, IL-12R and STAT-1 immunodeficiency diseases: Disorders of the interface of innate and adaptive immunity. Immunol Res 2007; 38:342-346. 123.. Fieschi C, Dupuis S, Catherinot E, et al: Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: Medical and immunological implications. J Exp Med 2003; 197:527-535. 124.. Greinert U, Ernst M, Schlaak M, et al: Interleukin-12 as successful adjuvant in tuberculosis treatment. Eur Respir J 2001; 17:1049-1051. 125.. Rigopoulou EI, Suri D, Chokshi S, et al: Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity. Hepatology 2005; 42:1028-1036. 126.. Pockros PJ, Patel K, O’Brien C, et al: A multicenter study of recombinant human interleukin 12 for the treatment of chronic hepatitis C virus infection in patients nonresponsive to previous therapy. Hepatology 2003; 37:1368-1374. 127.. Jacobson MA, Spritzler J, Landay A, et al: A phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection. AIDS 2002; 16:1147-1154.
“Autoantibodies may be present many years before the diagnosis of diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, and Type 1 diabetes mellitus. Combined with genetic information or family history, the presence of autoantibodies may be highly predictive of the later onset of an autoimmune disorder [3,4].”
3. Arbuckle, MR, McClain, MT, Rubertone, MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349:1526. (14561795) 4. Rose, NR. Predictors of autoimmune disease: autoantibodies and beyond. Autoimmunity 2008; 41:419.(18781467)
Autoimmun Rev. 2003 Oct;2(6):364-9. Immune deficiency and autoimmunity. Etzioni A. Meyer Children's Hospital, Haifa and the B. Rappaport Faculty of Medicine, Technion, Haifa, 36019, Israel. email@example.com 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.25
Amy - autoantibodies to cancer
Vitamin D and autoimmunity
Autoimmun Rev. 2007 Nov;7(1):59-64. Epub 2007 Aug 14. Vitamin D in rheumatoid arthritis. Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B.
Research Laboratory and Academic Clinical Unit of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6 - 16132 Genova, Italy. firstname.lastname@example.org
Abstract The discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that activated dendritic cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties. VDR, a member of the nuclear hormone receptor superfamily, was identified in mononuclear cells, dendritic cells, antigen-presenting cells, and activated T-B lymphocytes. In synthesis, the most evident effects of the D-hormone on the immune system seem to be in the downregulation of the Th1-driven autoimmunity.Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre vitamin D by the ultra violet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain to the latitute-related prevalence of autoimmune diseases such as rheumatoid arthritis (RA), by considering the potential immunosuppressive roles of vitamin D. 25(OH)D3 plasma levels have been found inversely correlated at least with the RA disease activity showing a circannual rhythm (more severe in winter). Recently, greater intake of vitamin D was associated with a lower risk of RA, as well as a significant clinical improvement was strongly correlated with the immunomodulating potential in vitamin D-treated RA patients.
PMID: 17967727 [PubMed - indexed for MEDLINE]
Interestingly, D-hormone administration has been shown to effectively inhibit autoimmunity even when animals were vitamin D sufficient.
In animal models, administration of vitamin D has been shown to effectively inhibit signs of autoimmunity even when animals were vitamin D “sufficient.”(17967727)
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 English short notice: http://www.ndm1bacteria.com/ehec-producing-auto-antibodies
Nat Immunol. 2010 Jan;11(1):28-35. Epub 2009 Dec 17. Influence of microbial environment on autoimmunity.26
Chervonsky AV. Department of Pathology, University of Chicago, Chicago, Illinois, USA. email@example.com Abstract During protective immune responses, the adaptive arm of the immune system requires activation by signals provided by innate immunity and driven by microbial stimuli. Whether the same rules apply to autoimmune diseases involving clonal self-reactive T and B lymphocytes–a process referred to here as 'adaptive autoimmunity'–is not quite clear. Nevertheless, in these diseases, the innate-adaptive connection is likely to be influenced by the microbial environment. This review integrates the results of experiments analyzing autoimmunity in sterile versus nonsterile conditions and experiments testing the role of innate immune receptor signaling in autoimmunity. It proposes that autoimmune diseases can be divided into two groups, the pathogenesis of which either follows the rules of innate-adaptive connection or does not. PMID: 20016507
Infections and autoimmune diseases27
Author(s): Bach JF Source: JOURNAL OF AUTOIMMUNITY Volume: 25 Pages: 74-80 Supplement: Suppl. S Published: 2005 Times Cited: 68 References: 42 Citation Map Abstract: The high percentage of disease-discordant pairs of monozygotic twins demonstrates the central role of environmental factors in the etiology of autoimmune diseases. Efforts were first focussed on the search for triggering factors. The study of animal models has clearly shown that infections may trigger autoimmune diseases, as in the case of Coxsackie 134 virus in type I diabetes and the encephalomyocarditis virus in autoimmune myositis, two models in which viruses are thought to act by increasing immunogenicity of autoantigens secondary to local inflammation. The induction of a Guillain-Barre syndrome in rabbits after immunization with a peptide derived from Campylobacter jejuni is explained by mimicry between C. jejuni antigens and peripheral nerve axonal antigens. Other models involve chemical modification of autoantigens, as in the case of iodine-induced autoimmune thyroiditis. These mechanisms have so far only limited clinical counterparts (rheumatic fever, Guillain-Barre syndrome and drug-induced lupus or myasthenia gravis) but one may assume that unknown viruses may be at the origin of a number of chronic autoimmune diseases, such as type I diabetes and multiple sclerosis) as illustrated by the convergent data incriminating IFN-alpha. in the pathophysiology of type I diabetes and systemic lupus erythematosus. Perhaps the difficulties met in identifying the etiologic viruses are due to the long lag time between the initial causal infection and onset of clinical disease. More surprisingly, infections may also protect from autoimmune diseases. Western countries are being confronted with a disturbing increase in the incidence of most immune disorders, including autoimmune and allergic diseases, inflammatory bowel diseases, and some lymphocyte malignancies. Converging epidemiological evidence indicates that this increase is linked to improvement of the socio-economic level of these countries, posing the question of the causal relationship and more precisely the nature of the link. Epidemiological and clinical data support the hygiene hypothesis according to which the decrease of infections observed over the last three decades is the main cause of the incessant increase in immune disorders. The hypothesis does not exclude an etiological role for specific pathogens in a given immune disorder as might notably be the case in inflammatory bowel diseases. Even in this setting, infections could still have a non-specific protective role. Independently of the need for confirmation by epidemiological prospective studies, the hygiene hypothesis still poses numerous questions concerning the nature of protective infectious agents, the timing of their involvement with regard to the natural history of immune diseases and, most importantly, the mechanisms of protection. Four orders of mechanisms are being explored. Antigenic competition is the first hypothesis (immune responses against pathogens compete with autoimmune and allergic responses). This is probably an important mechanism but its modalities are still elusive in spite of considerable experimental data. Its discussion in the context of homeostatic regulation of lymphocyte pools has shed new light on this hypothesis with possible competition for self MHC peptide recognition and interleukin-7. Another hypothesis deals with immunoregulation. Infectious agents stimulate a large variety of regulatory cells (Th2, CD25 +, Tr1, NKT, …) whose effects extend to other specificities than those which triggered their differentiation (bystander suppression). Infectious agents may also intervene throughcomponents which are not recognized as antigens but bind to specific receptors on cells of the immune system. Major attention has recently been drawn to Toll receptors (expressed on macrophages and possibly on regulatory T cells) and TIM proteins present on Th cells, which may express the function of the virus receptor (as in the case of the Hepatitis A virus and Tim-1). Experimental data will be presented to support each of these hypotheses. In any event, the final proof of principle will be derived from therapeutic trials where the immune disorders in question will be prevented or better cured by products derived from protective infectious agents. Numerous experimental data are already available in several models. Preliminary results have also been reported in atopic dermatitis using bacterial extracts and probiotics. © 2005 Elsevier Ltd. All rights reserved. Document Type: Proceedings Paper Language: English Author Keywords: diabetes; infections; autoimmune diseases; hygiene; mimicry KeyWords Plus: GUILLAIN-BARRE-SYNDROME; MOLECULAR MIMICRY; INTERLEUKIN-10-DEFICIENT MICE; SPONTANEOUS COLITIS; CNS AUTOIMMUNITY; VIRUS-INFECTION; COXSACKIE-VIRUS; POPULATION; ANTIBODIES; CHILDHOOD Reprint Address: Bach, JF (reprint author), Hop Necker Enfants Malad, Immunol Lab, 162 Rue Sevres, F-75743 Paris 15, France Addresses: 1. Hop Necker Enfants Malad, Immunol Lab, F-75743 Paris 15, France E-mail Addresses: firstname.lastname@example.org Publisher: ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD, 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND IDS Number: 999EO ISSN: 0896-8411 DOI: 10.1016/j.jaut.2005.09.024
I am starting to hone in on how antibodies are produced and selected. My thinking, at the molecular level, is generally different from those still thinking at the cellular or tissue levels. It is an interesting study - reminds me of the way that 1,25-D is produced in the kidneys and circulated to the rest of the body. Similarly it is the Lymphoid tissue where all the neat antibody selection occurs. Or so it is said… ..Trevor.. ps: I guess that is why they cut the lymph nodes out of cancer patients - to strengthen their immune systems… … Medicine is so haphazard in its thinking…
Acta Reumatol Port. 2008 Apr-Jun;33(2):137-54. B cells from the bench to the clinical practice. Moura R, Agua-Doce A, Weinmann P, Graça L, Fonseca JE. Unidade de Investigção em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa. Abstract B cells develop in bone marrow and undergo antigen-induced activation and terminal differentiation in germinal centres of secondary lymphoid organs. Each B cell is a clone which means that an individual B cell has a unique genetic code and produces only one type of antibody when stimulated by antigen being able to multiply itself and originate several B cells with the same antigen specificity (clonal selection theory). However their important role in adaptive immune responses is supported by the remarkable capacity of recognizing an unlimited array of antigens due to mechanisms of antibody diversity such as V(D)J recombination class switching and somatic hypermutation. B cells can also function as antigen presenting cells that can activate T cells improving the effectiveness of the immune response. Immune B cell tolerance surveillance through clonal deletion anergy and receptor editing is also necessary to avoid pathological conditions like autoimmune diseases. B cells can contribute to autoimmunity by autoantibody production cytokine synthesis antigen presentation T cell activation and ectopic lymphogenesis. PMID: 18604182
Nat Rev Immunol. 2010 Nov;10(11):778-86. Epub 2010 Oct 15. The importance of natural IgM: scavenger, protector and regulator.
Ehrenstein MR, Notley CA. Centre for Rheumatology, Division of Medicine, University College London, Windeyer Institute of Medical Science, 46 Cleveland Street, London W1P 4JF, UK. Abstract The existence of IgM has been known for more than a century, but its importance in immunity and autoimmunity continues to emerge. Studies of mice deficient in secreted IgM have provided unexpected insights into its role in several diverse processes, from B cell survival to atherosclerosis, as well as in autoimmunity and protection against infection. Among the various distinct properties that underlie the functions of IgM, two stand out: its polyreactivity and its ability to facilitate the removal of apoptotic cells. In addition, new B cell-targeted therapies for the treatment of autoimmunity have been shown to cause a reduction in serum IgM, potentially disrupting the functions of this immunoregulatory molecule and increasing susceptibility to infection. PMID: 20948548
Some of this may be relevant in other articles:
Nature Reviews Rheumatology 6, 622-623 (November 2010) | doi:10.1038/nrrheum.2010.163
Subject Category: Therapy
Therapy: Gut-mediated autoimmune arthritis treated with antibiotics Alan Ebringer About the author
Abstract Bacterial infection is known to trigger a number of autoimmune disorders, an observation that indicates a potentially important role for antibiotics in treating these diseases. Indeed, results from an experimental model of autoimmune arthritis in mice suggest that antibiotics can prevent the onset of disease.
The role of antibiotics in the treatment of autoimmune diseases has been controversial; however, reduction in the incidence of rheumatic fever by treating upper respiratory tract infections with antibiotics1 implies a similar approach might work for other rheumatic conditions. Accordingly, a study by Wu et al.2 suggests that antibiotics might be beneficial in treating gut-mediated autoimmune arthritis.
Experimental autoimmune arthritis in K/BxN mice—which develop symptoms similar to those observed in rheumatoid arthritis (RA)—is known to be strongly attenuated when the animals are housed in germ-free conditions.3 Wu et al. found that serum titers of autoantibody against glucose-6-phosphate isomerase (GPI) decreased in the mice in germ-free conditions, as did the numbers of splenic T helper 17 cells, in comparison to mice housed in a specific-pathogen-free facility.2 GPI is an enzyme of the glycolytic pathway in many animal and bacterial species. Interestingly, in a separate study, synthetic peptides of human GPI (corresponding to amino acids 325–339) were found to induce polyarthritis in DBA/1 mice.4
In the K/BxN mice, interleukin (IL)-17 was found to be necessary for the efficient formation of germinal centers and the promotion of autoantibody production.2 The use of an anti-IL-17 monoclonal antibody blocked the development of arthritis. Furthermore, this disease attenuation could be reversed through exposure of the mice to the segmented filamentous bacteria Candidatus arthromitus, which provoked the rapid onset of arthritis as measured by ankle-thickening.2
Interestingly, the treatment of the K/BxN mice from birth with ampicillin and vancomycin strongly inhibited the onset of arthritis; a weaker inhibition was associated with metronidazole but neomycin treatment actually exacerbated the arthritis.2 The mechanism by which the arthritic disorder was produced was not investigated, although Wu et al. suggest it to be a nonspecific activity of antigen–antibody complexes.2 The contribution of molecular mimicry between joint collagens and GPI to the development of arthritis in these mice remains unclear.
…treatment … from birth with ampicillin and vancomycin strongly inhibited the onset of arthritis…
At the Symposium on Autoantibodies held in Dresden, Germany, in September 2009, Professor Yehuda Shoenfeld from Tel Aviv University proposed that “all autoimmune diseases are caused by external agents (drugs, viruses, bacteria, parasites).” This conjecture implies that sensu stricto there are no 'autoimmune' diseases; rather, these conditions are caused by molecular mimicry or crossreactivity between external agents and self molecules which may even involve a single 'self' amino acid such as tyrosine. Indeed, autoantibodies against red blood cells have been demonstrated in patients who have been prescribed α-methyldopa, a derivative of tyrosine, for the treatment of hypertension.5 Norepinephrine is derived from tyrosine and α-methyldopa competes with this agent for norepinephrine receptors but does not activate them, thereby producing its hypotensive effect. In this study, the presence of autoantibodies against red blood cells was dependent on the dose of the drug taken and could lead to autoimmune hemolytic anemia. Removal of the drug was associated with attenuation of autoimmune hemolytic anemia and a loss of anti-red-blood-cell autoantibodies without further complications.5
The class I MHC molecule HLA-B27 protein is found in 96% of patients with ankylosing spondylitis (AS), as opposed to about 8% of the general population.6 Clearly, this disparity might have something to do with the origin of this disease. Molecular mimicry between a DRED amino acid sequence in HLA-B27 protein and the DRDE sequence found in the pullulanase enzyme of Klebsiella pneumoniae might be an etiologic factor in AS.7 Indeed, antibodies to K. pneumoniae have been found in patients with AS from 16 different countries. In addition, >90% of patients with RA express either the HLA-DR4 molecule or the equivalent HLA-DR1 molecule, but the frequency of these antigens in the general population is about 35%.8 The hexameric sequence EQR(K)RAA at amino acids 69–74 of these proteins is a powerful antigenic determinant, owing to the charged amino acids, and forms the basis of the 'shared epitope' found in these patients. This sequence shows molecular mimicry with the ESRRAL sequence found in the hemolysin protein of Proteus mirabilis; antibodies to this microbe have been found in patients from 14 different countries and have cytopathic properties.9
The findings of Wu et al.2 lead to the question of which human autoimmune arthritic disorders these results could apply to. Tetracycline is useful in the treatment of some patients with RA;10 however, this condition is not associated with the elevated levels of serum IgA antibodies that are characteristic of a disease caused by an agent acting across a gut mucosal surface. This caveat suggests that RA is not a gut-mediated autoimmune disorder but that it is more likely to be associated with an upper urinary tract infection in which the microbe is acting across a ureteric surface.9 In addition, since urinary tract infections are common in women (particularly elderly women), this etiology might account for the greater prevalence of RA in women than in men. Elevated levels of serum IgA are, however, found in patients with AS, and this observation suggests that the Wu et al.2 model might apply to the treatment of this condition.
The demonstration by Wu et al.2 that experimental autoimmune arthritis in mice responds favorably to antibiotics is an important and timely finding that might apply to other rheumatic conditions such as RA. Furthermore, this result suggests that it is time for relevant therapies for P. mirabilis infection to be assessed together with other existing successful modalities, such as inhibitors of tumor necrosis factor, in the management of RA.
Robertson, K. A., Volmink, J. A. & Mayosi, B. M. Antibiotics for the prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc. Disord. 5, 11 (2005). ArticlePubMed Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010). ArticlePubMedChemPort Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996). ArticlePubMedISIChemPort Iwakami, K. et al. Arthritogenic T cell epitope in glucose-6-phosphate isomerase induced arthritis. Arthritis Res. Ther. 10, R130 (2008). ArticlePubMedChemPort Breckenridge, A., Dollery, C. T., Worlledge, S. M., Holborow, E. J. & Johnson, G. D. Positive direct Coombs tests and antinuclear factor in patients treated with methyldopa. Lancet 2, 1265–1267 (1967). ArticlePubMedChemPort Schlosstein, L., Terasaki, P. I., Bluestone, R. & Pearson, C. M. High association of an HL-A antigen W27 with ankylosing spondylitis. N. Engl. J. Med. 288, 704–706 (1973). ArticlePubMedISIChemPort Fielder, M. et al. Molecular mimicry and ankylosing spondylitis: possible role of a novel sequence in pullulanase of Klebsiella pneumoniae. FEBS Lett. 369, 243–248 (1995). ArticlePubMedChemPort Wallin, J., Hillert, J., Olerup, O., Carlsson, B. & Ström, H. Association of rheumatoid arthritis with a dominant DR1/Dw4/Dw14 sequence motif but not with T cell receptor beta chain gene alleles or haplotypes. Arthritis Rheum. 34, 1416–1424 (1991). ArticlePubMedChemPort Ebringer, A., Rashid, T. & Wilson, C. Rheumatoid arthritis, Proteus, anti-CCP antibodies and Karl Popper. Autoimmun. Rev. 9, 216–223 (2010). ArticlePubMedChemPort Stone, M., Fortin, P. R., Pacheco-Tena, C. & Inman, R. D. Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J. Rheumatol. 30, 2112–2122 (2003). PubMedChemPort
Hey Paul, I just came across another new paper strongly linking an 'auto-antibody' to HTLV1. Note that this auto-antibody is strongly associated with neuromeylitis optica.
I think this makes 3 autoantibodies in the past year that have been mapped to pathogens.
Journal of autoimmunity. 2011 Feb 16;
Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes.
Kampylafka EI, Routsias JG, Alexopoulos H, Dalakas MC, Moutsopoulos HM, Tzioufas AG
The autoantibody to aquaporin-4 (AQP4) is a marker and a pathogenetic factor in Neuromyelitis Optica (NMO) (Devic's syndrome). Our aim was to identify B-cell antigenic linear epitopes of the AQP4 protein and investigate similarities with other molecules. To this end, we screened sera from 21 patients positive for anti-AQP4 antibodies (study group), from 23 SLE and 23 pSS patients without neurologic involvement (disease controls) and from 28 healthy individuals (normal controls). Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays. NMO positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1-22 (AQPpep1) (42.9% of patients), aa88-113 (AQPpep4) (33%) and aa252-275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep8' aa257-271, a 15-mer peptide part of the AQPpep8 aa252-275, and the aa219-233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the Human T-Lymphotropic Virus 1 (HTLV-1). Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N = 5) and 31.6% (N = 6) of NMO positive sera (r(s) = 0.81, P < 0.0001). Healthy controls did not react with these peptides, while homologous and cross-inhibition assays confirmed binding specificity. This first epitope mapping for AQP4 reveals that a significant proportion of anti-AQP4 antibodies target linear epitopes localized in the intracellular domains of the channel. One of the epitopes displays high similarity with a portion of TAX1BP1 protein.
PMID: 21333492 URL - http://www.ncbi.nlm.nih.gov/pubmed/21333492?dopt=Citation
I thought that Amy might find this new paper of interest due to her work in connecting autoanibodies to bacteria.Rheumatology (Oxford, England). 2010Dec 11;
Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission.
Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P
Objectives. CpG motifs, which are highly prevalent in bacterial DNA, have been shown to trigger the production of ANCA in vitro by B lymphocytes from patients with active ANCA-associated vasculitis (AAV). Staphylococcus aureus is associated with relapses in AAV, and CpG motifs from staphylococcal DNA may trigger ANCA production in AAV patients in remission. We investigated the presence of ANCA-producing B lymphocytes during quiescent disease and tested the capacity of these cells to produce ANCA in response to CpG. Methods. Expression of Toll-like receptor 9 (TLR9) by B lymphocytes from AAV patients and controls was assessed. Peripheral blood mononuclear cells were isolated from 23 PR3-ANCA and 15 MPO-ANCA patients (33 quiescent, 5 active disease) and 14 healthy controls, and cultured for 12 days in the presence of cytosine-phosphate-guanine oligodeoxynucleotide (CpG-ODN) and IL-2. B-lymphocyte activation, differentiation, immunoglobulin production and in vitro ANCA production were studied. Results. TLR9 expression by B lymphocytes was comparable in AAV patients and controls. B lymphocytes were activated and differentiated towards a plasma cell phenotype in response to CpG-ODN and IL-2. ANCA were produced in vitro by 13 out of 23 PR3-ANCA patients and 3 out of 15 MPO-ANCA patients. Conclusions. We conclude that ANCA-producing B lymphocytes can be present in the peripheral blood of AAV patients during remission. These autoreactive B lymphocytes are triggered by CpG-ODN and IL-2 to produce ANCA in vitro. CpG motifs may trigger the production of ANCA in vivo, contributing to the development of relapses in AAV.
) Actually, just to clarify, the antibody is in fact against a human protein, but its one required for HTLV1 replication. Interesting. This would seem to imply that some autoantibodies dont directly target pathogens and dont accidentaly target human proteins. Rather, they purposefully target human proteins used by the pathogen….
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. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG. Source 1] Department of Pathology, Stanford University, Palo Alto, California, USA.  Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada. . Abstract Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.