Tiny Doppelgänger Implicated in Autoimmunity
Is this well-known bacteria one of "The Usual Suspects" in Multiple Autoimmune Syndrome?
As hyperbolic as this sounds, my mind is completely blown by what I’ve read so far about Mycobacterium avium subspecies paratuberculosis (referred to as simply Mycobacterium throughout the rest of this post). So much so, that its name now reverberates in my head as a sinister whisper. The more I understand how much this bacteria could underpin the mechanisms of autoimmunity, the more menacing I find it. Implicated in Crohn’s disease (and other types of Irritable bowel disease), Type 1 diabetes, Rheumatoid arthritis, Hashimoto’s Thyroiditis, and Multiple Sclerosis (Garvey, 2018), this bacteria just might be the autoimmune world’s Keyser Söze.
Mycobacterium is considered a serious disease of ruminant livestock, and has been found in milk, infant formulas and treated domestic water supplies (Garvey, 2018). In their previous work, Niegowska et. al have found that antibodies against Mycobacterium cell antigens occur in up to 55.2% of study participants with Type 1 diabetes. In healthy volunteers, they found that the prevalence of antibodies to Mycobacterium cell antigens is only 6.7%.
Mycobacterium has molecules on the surface of its cells that human antibodies bind and react to. It is this binding and reaction that defines the Mycobacterium cell surface molecules as antigens. Prior research has found that human Beta-cell antigen zinc transporter 8 (ZnT8), expressed almost exclusively in the pancreas, and Proinsulin, have portions of cell surface molecules that are identical to portions of the Mycobacterium antigens. Mycobacterium is mimicking Znt8 and Proinsulin cell surface molecules in order to confuse and evade the human immune response.
Mimicry makes the Mycobacterium sound like a chameleon that’s able to change its antigens at will to match its host, but this adaptation is present prior to introduction in any given human host. This mimicry could have evolved within a single host, but has likely become so evolutionarily advantageous to the Mycobacterium that it is now present prior to introduction in any one human host. Based on previous work in a Sardinian population (isolated and homogeneous) with high prevalence rates of both Type 1 diabetes and antibodies to Mycobacterium, Niegowska et. al hypothesize that antibodies that attack identical antigen peptides on both Mycobacterium and self cells could predict the development of Type 1 diabetes in already at-risk children. Their previous study showed that antibodies to Mycobacterium (foreign), and ZnT8 and Proinsulin (self), can be detected prior to other autoantibodies in participants as young as 0-6 months of age, significantly prior to Type 1 diabetes disease onset. The study below explores the prevalence of identical Mycobacterium (foreign), ZnT8 and Proinsulin (self), antigen peptides in a heterogenous Italian population at risk for Type 1 diabetes.
Area of Investigation
Multiple Autoimmune Syndrome: when one person meets the study classification criteria for three or more autoimmune diseases.
Study Title
Type 1 Diabetes at-risk children highly recognize Mycobacterium avium subspecies paratuberculosis epitopes homologous to human Znt8 and Proinsulin
Results
54 Type 1 diabetes at-risk children from mainland Italy, and 42 healthy controls, were included in this study. Eight antigen peptides were assessed in this study and 38 (70.37%) at-risk study participants were positive to at least one of the eight peptides, compared to 16.67% (7) positivity in healthy controls. Of the at-risk children who were positive for the antigen peptides assessed, 30 (78.95%) had antibodies targeting at least four antigen peptides. 11.11% of at-risk participants had antibodies that targeted all eight antigen peptides. Upon four year follow up assessment, eight participants no longer showed immune reactivity after the age of 5. Of the 22 remaining participants, in general, antibodies to antigen peptides shared by Mycobacterium (foreign) and ZnT8 (self) cells decreased with age, whereas antibodies to antigen peptides shared by Mycobacterium and Proinsulin (self) cells increased with age.
Does this study show that antibody reactivity to identical Mycobacterium (foreign), and ZnT8 and ProInsulin (self), antigen peptides is predictive of the development of Type 1 diabetes in already at-risk participants? Not really. This could be due to a small study sample size, or to an age-related, complex evolution of pancreatic autoantibodies, not yet understood. What it does show is that 82.35% of at-risk participants with Celiac disease, or a family history of Celiac disease, had antibodies to the Mycobacterium (foreign), and ZnT8 and Proinsulin (self), antigen peptides analyzed. 100% of participants with autoimmune thyroiditis, either alone or combined with Celiac disease had antibodies to the antigen peptides analyzed. Due to the prevalence of antibodies that react with both Mycobacterium and self cells in participants with pre-existing autoimmune disease, it is plausible that Mycobacterium (MAP) is involved in Multiple autoimmune syndrome. Or in the words of the authors:
Younger age, female sex and concomitant autoimmune disorders contributed to a stronger seroreactivity suggesting a possible implication of MAP in multiple autoimmune syndrome.
Why it Matters
Human exposure to Mycobacterium avium subspecies paratuberculosis may be a common occurrence, and linked to many different autoimmune disorders (Garvey, 2018). In the complex dance between genetic susceptibility and environmental exposures that predispose a person to autoimmune disorders, Mycobacterium could be one of the critical factors that tip the balance toward autoimmune disease. Surveillance of consumer products and drinking water supplies, including milk, other dairy products, infant formula, treated water supplies, and well water monitoring, is essential to understand the ubiquity of this resilient bacteria. It can survive standard water treatment practices in the United States, pasteurization and freeze drying (Garvey, 2018). Determining prevalence is essential to identifying community strategies to reduce exposure.
Study Type
For reference, I have ranked medical study types in order of least likely to be affected by hidden bias to most likely to be affected. Those studies that are most likely to be affected by hidden bias should be taken seriously, but not given the same weight as studies that are less likely to be affected by hidden bias. This study’s type appears in bold below.
Clinical Trial
Observational Study
Prospective
Retrospective
Cross-sectional
References
Garvey M. Mycobacterium avium subspecies paratuberculosis: A possible causative agent in human morbidity and risk to public health safety. Open Vet J. 2018;8(2):172-181. doi: 10.4314/ovj.v8i2.10. Epub 2018 May 19. PMID: 29911021; PMCID: PMC5987349.