The Microbiome and Autoimmunity: Seven Signs of Impending Paradigm Change

The Microbiome and Autoimmunity: Seven Signs of Impending Paradigm Change

Borrelia burgdorferi (top left), Chlamydia trachomatis (bottom left), Mycobacterium tuberculosis (right)Despite an increased understanding of the immune system and the genomes and microbiomes of humans and microorganisms, we still have not defined the etiology of many tissue- and life-altering arthritis and autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, the vasculitides, psoriatric arthritis, and ankylosing spondylitis. However, the evidence of an important connection between microorganisms and these disorders is increasing, and may portend a paradigm shift in our understanding and our response.

We routinely treat these disorders with immunosuppressive drugs. Yet if infection were known to be the root cause, this course of action would seem counterintuitive if not potentially dangerous in the short or long run.

The following results of research over many decades suggest that, as we learn more, many “idiopathic” disorders may be found to be either caused or modulated by microorganisms—some of which have yet to be discovered.1

1.    Infectious disorders (tuberculosis, syphilis, and Lyme disease) share many symptoms with autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa and granulomatosis with polyangiitis (Wegener’s granulomatosis). These include:

•  Fever
•  Fatigue
•  Weight loss
•  Joint inflammation
•  Neurologic disorders
•  Skin lesions

These different condition types also share immunological mechanisms, including liberation of TNF-α, interleukin 1 and 6, and activation of the innate and adaptive arms of the immune system.

2.    In Whipple’s disease, a bowel infection with the organism Tropheryma whipplei causes a rare, chronic complex systemic disorder that can exist for decades before gastrointestinal and malabsorption symptoms, often associated with weakness and polyarthritis, point to a diagnosis and to successful treatment with antibiotics. The organism is able to coexist within the host, due to defects within macrophages and T cells, not in humoral immunity.2, 3

3.    Recent evidence suggests a link between periodontitis and rheumatoid arthritis (RA), mediated by the development of antibodies to peptides that can be citrullinated by the microbes responsible for the mucosal infection. Antibiotics such as tetracycline have been shown to have a mild ameliorative effect, but most therapy today is directed at dampening down the immune system rather than addressing the infection.4, 5

4.    Antibiotic-resistant Lyme arthritis is associated with two histocompatibility types that are also associated with rheumatoid arthritis (RA). T cells from these patients recognize an outer surface protein from the Lyme disease microorganism Borrelia burgdorferi, and inflammation of the synovium may persist long after the spirochete has been nearly or totally eradicated, at times triggering the use of medications commonly used to treat RA, not the Lyme organism.6

5.    Rheumatic fever due to group A beta hemolytic streptococcal pharyngitis is characterized by a migratory “non-septic” reactive arthritis. The term “reactive” here represents an immune response to an organism followed by cross-reaction to host tissue through a process known as “molecular mimicry,” Theoretically, sequence similarities between foreign and self-peptides result in cross-activation of T or B cells and antibodies against body tissues in response to a peptide introduced by a microorganism.7

6.    HLA B27 is a genetic factor associated with  both ankylosing spondylitis and reactive arthritis, and a sequence homology has been identified between B27 and organisms that cause arthritis symptoms.8 Differences of as little as a single nucleotide (SNPs or single nucleotide polymorphisms) were found to confer susceptibility to a reactive arthritis due to Salmonella, suggesting that inflammation can be triggered by the presence of cross-reactive molecules even in the absence of a viable, intact pathogen.9 Indeed, studies of genetically engineered rodents raised in germ-free environments have found that introduction of the appropriate peptide fragment – not the intact microorganism – is sufficient to trigger arthritic symptoms in genetically susceptible animals.10, 11

7.    Reactive arthritis induced by Chlamydia improves significantly after a six-month course of antibiotic treatment specifically targeting that microorganism, according to a recent double-blind prospective trial.8 The authors point out that these pathogens may persist in the synovium, triggering a chronic inflammatory process that may last for years. The subjects of this study had a longstanding seronegative arthritis that had not responded to either NSAIDs or DMARDs. (How many patients with other refractory autoimmune or inflammatory conditions may be harboring silent infections within their joints, and might be treated effectively with the correct antibiotic?)

The practice of rheumatology has assumed that in “nonseptic” inflammatory disorders, the immune response is an over-reaction. Could it instead represent a deficiency in the host’s ability to clear microorganisms?

We may find as this line of research progresses that instead of suppressing immunity, we should be enhancing it.

This article is adapted from a review in Transactions of the American Clinical and Climatological Association.

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