Yersinia and Graves' Disease?

Yersinia and Graves' Disease?

Nice to see a bit of UK research at the cutting edge on thyroid issues.

If only I knew enough to properly understand it!

J Immunol. 2013 Jun 1;190(11):5373-81. doi: 10.4049/jimmunol.1203412. Epub 2013 Apr 29.

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves' Disease.

Hargreaves CE, Grasso M, Hampe CS, Stenkova A, Atkinson S, Joshua GW, Wren BW, Buckle AM, Dunn-Walters D, Banga JP.

Source

Division of Diabetes and Nutritional Sciences, King's College London School of Medicine, London SE5 9NU, United Kingdom;

Abstract

Graves' disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves' disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves' disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

PMID:

23630351

ncbi.nlm.nih.gov/pubmed/236...

Yersinia on Wiki:

en.wikipedia.org/wiki/Yersinia

Rod

Image is a slide of Yersinia pestis

8 Replies

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  • Hi Rod, thanks for posting this, very pertinent to me right now, I have an appointment with my Endo today so will be asking if they are up to date with this research. I have read the piece that you have posted, now about to ingest the whole research, better get another coffee!!!

  • Perhaps when you get back, you'll be able to put it into words for everyone to understand? :-)

    Rod

  • I recognised Yersinia from my meat inspection days

    From Wikipedia

    Yersinia enterocolitica is a species of gram-negative coccobacillus-shaped bacterium, belonging to the family Enterobacteriaceae. Yersinia enterocolitica infection causes the disease yersiniosis, which is a zoonotic disease occurring in humans as well as a wide array of animals such as cattle, deer, pigs, and birds. Many of these animals recover from the disease and become asymptomatic carriers. It infects the host by sticking to the cells of the host using Trimeric Autotransporter Adhesins (TAA).

    Acute Y. enterocolitica infections usually lead to mild self-limiting entero-colitis or terminal ileitis in humans. Symptoms may include watery or bloody diarrhea and fever. After oral uptake yersiniae replicate in the terminal ileum and invade Peyer's patches. From here yersiniae can disseminate further to mesenteric lymph nodes causing lymphadenopathy. This condition can be confused with appendicitis and is therefore called pseudoappendicitis. In immunosuppressed individuals, yersiniae can disseminate from the gut to liver and spleen and form abscesses. Because Yersinia is a siderophilic (iron-loving) bacteria, people with hereditary hemochromatosis (a disease resulting in high body iron levels) are more susceptible to infection with Yersinia (and other siderophilic bacteria). In fact, the most common contaminant of stored blood is Y. enterocolitica. See yersiniosis for further details. Yersiniae are usually transmitted to humans by insufficiently cooked pork or contaminated water.

    Yersiniosis is usually self-limiting and does not require treatment. Severe infections (septicemia, focal infection, immunosuppression) can be treated with doxycycline in combination with an aminoglycoside. Other antibiotics that are active against Y. enterocolitica include trimethoprim-sulfamethoxasole, fluoroquinolones, ceftriaxone, and chloramphenicol. Y. enterocolitica is usually resistant to penicillin G, ampicillin, and cephalotin due to beta-lactamase production.

    Y. enterocolitica infections are sometimes followed by chronic inflammatory diseases such as arthritis.

    Y. enterocolitica seems to be associated with autoimmune Graves-Basedow thyroiditis. Whilst indirect evidence exists, direct causative evidence is limited,[6] and Y. enterocolitica is probably not a major cause of this disease, but may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.[7] It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.[8] More recently the role for Y. enterocolitica has been disputed.[9]

    References

    ^ Benvenga S, Santarpia L, Trimarchi F, Guarneri F (2006). "Human Thyroid Autoantigens and Proteins of Yersinia and Borrelia Share Amino Acid Sequence Homology That Includes Binding Motifs to HLA-DR Molecules and T-Cell Receptor". Thyroid 16 (3): 225–236. doi:10.1089/thy.2006.16.225. PMID 16571084.

    ^ Tomer Y, Davies T (1993). "Infection, thyroid disease, and autoimmunity" (PDF). Endocr Rev 14 (1): 107–20. doi:10.1210/er.14.1.107. PMID 8491150.

    ^ Toivanen P, Toivanen A (1994). "Does Yersinia induce autoimmunity?". Int Arch Allergy Immunol 104 (2): 107–11. doi:10.1159/000236717. PMID 8199453.

    ^ Strieder T, Wenzel B, Prummel M, Tijssen J, Wiersinga W (2003). "Increased prevalence of antibodies to enteropathogenic Yersinia enterocolitica virulence proteins in relatives of patients with autoimmune thyroid disease". Clin Exp Immunol 132 (2): 278–82. doi:10.1046/j.1365-2249.2003.02139.x. PMC 1808711. PMID 12699417.

    ^ Hansen P, Wenzel B, Brix T, Hegedüs L (2006). "Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study". Clin Exp Immunol 146 (1): 32–8. doi:10.1111/j.1365-2249.2006.03183.x. PMC 1809723. PMID 16968395.

  • As I am a microbiologist/immunologist: Essentially this is a process called molecular mimicry and it has been implicated in autoimmune diseases (i.e. When your body attacks itself as is the case for Graves and Hashimotos). It is thought to happen when a component of a bacteria or virus is very similar in structure to one of your own body's proteins. Your body fights the invading organism with antibodies, which then inadvertently react against your own body as well. Because the immune system also has a "memory" of structures it has already encountered, this process continues leading to chronic disease. A classic case is also type I diabetes. However there is dispute over the involvement of infectious agents in the establishment of autoimmunity. Put very basically in this case: just because you have an infection in the gut (in this case Yersinia) to which you establish immunity, does that necessarily spark an immune process up in your thyroid gland which is sufficient to cause open disease? The immune system is very complex and it needs a lot of co-factors and different cellular signaling processes (both B-and T-cell adaptive immunity) to be involved if this were to happen. At the momnet our understanding of the immune system is still in it's infancy, and there are so many questions unanswered. We're working on it though.....

  • To make it understandable: In this research they basically purified antibodies from a Grave's disease mouse (a few technicalities involved which are a bit complex but not necessary for lay understanding) and showed that in the lab these antibodies interacted with certain proteins found on the surface of the bacterium Yersinia. They then purified a human antibody and showed the same. I should note here form personal experience in the lab: Just because something binds in cell culture this is not conclusively convincing evidence that this also happens in the body... They will need a lot more work to implicate these antibodies in the development of Grave's

  • There will be 2 experimental approaches to this (sorry guys but this is the harsh reality of proving something in science):

    The first approach will be to infect mice with Yersinia and see if there is a higher incidence of Graves than in a control cohort.

    The second approach will be to inject the purified antibodies from the first experiment into a new cohort of mice and see if there is a higher incidence of Graves than in mice injected with a control antibody.

    And then the argument will be that this may not necessarily be the case in humans. As you can't go around giving people disease you would do population studies to conclude whether say 10 years after hospitalization for Yersinia infection there was a higher incidence of Graves than in those hospitalized for another reason. And then the results may well be skewed as only the tip of the iceberg of cases will require proper diagnosis and hospitalization and those that do may therefore have other underlying medical defects......

    So to be generally accepted you would need both lab and populationevendince by several groups of people all showing the same.

  • Thanks for the posts Nora. It is always helpful to have someone who knows about a subject posting!

    Rod

  • Thanks for this post. It isn't surprising that Yerinia is involved in other auto-immune diseases such as Crohns & reactive arthritis! And we think that because stuff comes from our fridge we ought to be safe!! Great discussion. Sonj

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