Previous discussions on PR re: the use of helminthic therapy in ME patients have usually ended with the observation that helminths (intestinal parasites like whipworm, hookworm) shift the host immune system to a more Th2 response and therefore would not be appropriate for the management of ME, a Th2 dominant condition.
I've been puzzling over this for a few days and have come to the conclusion it is way, way, way more complicated than a simple case of Th1 v. Th2. I am presenting some of the pieces of what I've learned in the hopes that others here might help me make sense of this. I find studies on immunological markers even harder to wade into as a layperson than other areas of research and so @Jonathan Edwards please forgive me for any violence I do to the science!
Helminths are godsends for some autoimmune patients
First there have been both some remarkable anecdotal reports as well as tantalizing preliminary research on helminth infection arresting, diminishing and sometimes even effecting full remission in a wide array of autoimmune diseases.
The preliminary studies in multiple sclerosis have been especially encouraging, including one study showing fewer new lesions in helminth-infected MS patients and a convergence with the control group (i.e., resumption of disease progression) after deworming.
Here is a bibliography of helminth studies in humans and animals: http://wormswell.com/science-research/ (I noticed at least one study on celiac disease and hookworm showing a null result wasn't on here so as always, exercise caution when relying on information someone else has aggregated for you, this post included!)
Many of the diseases in which helminths have been experimentally and anecdotally effective are "Th1 dominant," which supports the paradigm that since helminths induce a Th2 pattern, they are "good" for Th1 diseases.
Helminth/Th2 paradox
The paradox of course is that epidemiologically, there is an inverse correlation between helminth infection and incidence of both Th1/Th2 autoimmune diseases as well as allergic disorders. Despite the Th2 polarization, helminthic infections protect against allergy. Might they also, then, protect against ME?
Helminths increase regulatory T-cells
One of the primary mechanisms through which helminths exert this positive effect is by increasing the production of regulatory T cells, increasing TNF-Beta, and increasing IL-10.
Regulatory T cells are low or malfunctioning in a number of both "Th1 and Th2 dominant" autoimmune diseases. And so whether you have MS (Th1) or Lupus (Th2), correcting low treg numbers may be helpful, even if in general the helminths elicit a Th2–leaning immune response.
But we already have a lot of tregs
However, regulatory T cells have been found to be present in higher than normal numbers in ME patients and are perhaps one of the reasons why we have such low NK function (the treg cells being thought responsible for suppressing NK function).
We also have increased levels of IL-10 and TNF-Beta. Perhaps the presence of helminths might further suppress NK function and only worsen the dysregulation present in ME patients, even as it might help attenuate it in other diseases.
Maybe it's about the B cells?
Helminth infections in MS patients were shown to generate B-cell populations producing high levels of IL-10. IL-10-producing B-cells are called "regulatory B-cells." Bregs are lower in patients with RRMS, especially during flares. However in one mouse study, researchers injected IL-10-negative B-cells from mice with helminths into mice with Experimental Autoimmune Encephalitis (an MS model) and it slowed disease progression, suggesting helminth-altered B-cells may be protective independent of IL-10.
While we have significantly higher levels of regulatory T cells, ME patients like patients suffering from autoimmune diseases have significant decreases in regulatory B cells.
Pregnancy: increased tregs, bregs and has other helminth-like effects
Superficially, hosting a fetus and hosting a helminth seem to share a lot in common! Pregnancy induces a Th2 shift and also increases the number of treg cells and breg cells. A lack of increase treg/breg cells has been associated with spontaneous abortion. It seems the strategies a fetus employs for insuring your body does not reject it are similar to the strategies a hookworm might employ.
We know that pregnancy can temporarily improve symptoms in women with a variety of autoimmune diseases. However, the one study on pregnancy in CFS showed a pretty even split between improvement (30%), worsening (29%), and no effect on symptoms (41%). Anecdotally, the number of women approve seem to be higher. At least according to a panel held at an OFFERUtah conference in 2011, several practitioners including Bateman and Klimas reported that all or nearly all of the patients whose pregnancies they followed reported an improvement in symptoms, will several gaining full remission.
Whether the true number of women who experience improvement is 30% or something higher, it still begs the question of whether "Th2 shift = bad for ME" is too mechanistic a story, especially when you include number of women who experience no change in symptoms as well the fractional (but still hard to ignore!) number of women with ME who experience a complete remission.
Hookworms and NK cells
Hookworms (a species of helminth) increases the number of tregs (at least in patients with low tregs), which would theoretically inhibit NK function. However in vitro they have been found to secrete a protein that binds selectively to NK cells and induces the NK cells to produce more IFN-gamma and in vivo they attract NK cells to their attachment site and stimulate their activity, perhaps as a strategy to evade the host immune system.
IFN-gamma has immunoregulatory, antiviral and anti-tumor properties and promotes NK cell activity as well as macrophage activity.
It also "abundantly" produced by the developing fetus and is decreased in ME patients.
(That said, results of interferon therapy in ME/CFS have been mixed.)
What about hosting helminths while pregnant?
There is very little research on the effects of helminthic therapy on pregnancy. There is a lot of research on the negative effects of helminths in pregnancies where they are endemic because very large parasite burden (much higher than a therapeutic dose) can cause anemia and low birth weight. There are certainly a handful of patients experimenting with inflammatory/autoimmune conditions experimenting with helminth inoculation pre-conception to either try to prevent miscarriage or inflammation-related birth defects in their children. Babies born to women with helminth infections were found to have lower rates of eczema and allergies.
Helminths and the other trillion+ residents of your gut
Helminths may also independently alter the composition of gut bacteria. One study in Malaysia showed villagers infected with helminths had greater gut microbiota diversity than those who did not (while this is an observational study and perhaps helminth-infected people eat more soil or something, one might presume that other diet and environmental factors are more or less similar between among people living in the same village).
I was not able to find any randomized trials on helminths and gut bacterial populations in humans. However, there are studies in animal models. Some helminths increase population of pathogenic bacteria while other helminths increase populations of commensal bacteria.
One animal study showed helminth infection might decrease intestinal inflammation and increase mucus production. This may explain at least part of the benefit in IBD and ulcerative colitis, especially given the importance in those disease of helminths not just to altering systemic immunity but providing "islands of profound calm" localized around their attachment sites.
Many helminths, many effects
Lastly, different species of helminths have different effects on the immune system.
Here are two helpful overviews of the effects of different species of helminths on the immune system:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706953/
http://www.sciencedirect.com/science/article/pii/S156899721400216X
It is also helpful to note that different helminths fill different "niches" in the intestine. That is some colonize the small intestine while others colonize the colon. This means that the optimal therapy for someone with ulcerative colitis might differ for someone with Sjorgen's, for example.
Should ME patients experiment with helminths?
There is zero research and very little patient anecdote to suggest helminths would be helpful to ME patients, particularly given that many of the modifications helminths make to avoid expulsion by the immune system tend toward an expression pattern that is similar in many respects to the immune dysfunction already present in ME.
At the same time, most of the research on the effects of helminths on immune dysregulation in humans and animal models have been in diseases like multiple sclerosis. Helminths are a dynamic intervention – they secrete dozens of immunomodulatory chemicals in response to the host environment, so it is uncertain what they would do in a host with a different pattern of immune dysfunction. My guess is that in a host that already has large numbers of regulatory t-cells, for example, a hookworm would not increase the numbers of regulatory t-cells. Why bother? Rather, it would do the minimum necessary to ensure an environment conducive to its own survival. So it is possible that a helminth infection might positively affect your breg status in a way that could be disease-modifying, while leaving your tcells alone.
The last thing to mention is that there is some evidence that helminth infection might encourage viral reactivation and at least theoretically, inhibit your ability to fight cancer. We should worry about that not only because of our tendency toward viral reactivation but because we have a 4x increased risk of cancer. I've looked and there is not a whole lot of work in this area. The research I have found has not so far found a link between helminth infection and cancer (in fact, certain helminths might reduce your risk of gastric or colon cancer, perhaps by attenuating the damage induced by H. Pylori infection in the case of the former). Moreover, there is no strong evidence that helminths (endemic in many areas with high rates of HIV infection) lead to higher viral loads or more disease progression. In fact, some studies found the opposite. But the results on both are conflicting and the evidence is really not there, either way.
This lack of consistent evidence supporting theoretically negative effects of helminths on cancer or virus suppression may be due to the fact that while much of the helminth research focuses on Th1 dominant autoimmune diseases and emphasizes importance of helminths' effects on tregs, helminths have multiple and dynamic effects on the immune system which probably depend heavily on the host environment and on host-helminth interactions. Put another way, the immunomodulatory "protocol" a helminth would prescribe for your immune system depends a) on the particulars of your immune response and b) on whatever your immune response signals to the helminth it must do in order to ensure its survival. So we just don't know, for better or worse, what a helminth would do when it meets an ME patient's immune system. But I hope someone decides to study it!
I've been puzzling over this for a few days and have come to the conclusion it is way, way, way more complicated than a simple case of Th1 v. Th2. I am presenting some of the pieces of what I've learned in the hopes that others here might help me make sense of this. I find studies on immunological markers even harder to wade into as a layperson than other areas of research and so @Jonathan Edwards please forgive me for any violence I do to the science!
Helminths are godsends for some autoimmune patients
First there have been both some remarkable anecdotal reports as well as tantalizing preliminary research on helminth infection arresting, diminishing and sometimes even effecting full remission in a wide array of autoimmune diseases.
The preliminary studies in multiple sclerosis have been especially encouraging, including one study showing fewer new lesions in helminth-infected MS patients and a convergence with the control group (i.e., resumption of disease progression) after deworming.
Here is a bibliography of helminth studies in humans and animals: http://wormswell.com/science-research/ (I noticed at least one study on celiac disease and hookworm showing a null result wasn't on here so as always, exercise caution when relying on information someone else has aggregated for you, this post included!)
Many of the diseases in which helminths have been experimentally and anecdotally effective are "Th1 dominant," which supports the paradigm that since helminths induce a Th2 pattern, they are "good" for Th1 diseases.
Helminth/Th2 paradox
The paradox of course is that epidemiologically, there is an inverse correlation between helminth infection and incidence of both Th1/Th2 autoimmune diseases as well as allergic disorders. Despite the Th2 polarization, helminthic infections protect against allergy. Might they also, then, protect against ME?
Helminths increase regulatory T-cells
One of the primary mechanisms through which helminths exert this positive effect is by increasing the production of regulatory T cells, increasing TNF-Beta, and increasing IL-10.
Regulatory T cells are low or malfunctioning in a number of both "Th1 and Th2 dominant" autoimmune diseases. And so whether you have MS (Th1) or Lupus (Th2), correcting low treg numbers may be helpful, even if in general the helminths elicit a Th2–leaning immune response.
But we already have a lot of tregs
However, regulatory T cells have been found to be present in higher than normal numbers in ME patients and are perhaps one of the reasons why we have such low NK function (the treg cells being thought responsible for suppressing NK function).
We also have increased levels of IL-10 and TNF-Beta. Perhaps the presence of helminths might further suppress NK function and only worsen the dysregulation present in ME patients, even as it might help attenuate it in other diseases.
Maybe it's about the B cells?
Helminth infections in MS patients were shown to generate B-cell populations producing high levels of IL-10. IL-10-producing B-cells are called "regulatory B-cells." Bregs are lower in patients with RRMS, especially during flares. However in one mouse study, researchers injected IL-10-negative B-cells from mice with helminths into mice with Experimental Autoimmune Encephalitis (an MS model) and it slowed disease progression, suggesting helminth-altered B-cells may be protective independent of IL-10.
While we have significantly higher levels of regulatory T cells, ME patients like patients suffering from autoimmune diseases have significant decreases in regulatory B cells.
Pregnancy: increased tregs, bregs and has other helminth-like effects
Superficially, hosting a fetus and hosting a helminth seem to share a lot in common! Pregnancy induces a Th2 shift and also increases the number of treg cells and breg cells. A lack of increase treg/breg cells has been associated with spontaneous abortion. It seems the strategies a fetus employs for insuring your body does not reject it are similar to the strategies a hookworm might employ.
We know that pregnancy can temporarily improve symptoms in women with a variety of autoimmune diseases. However, the one study on pregnancy in CFS showed a pretty even split between improvement (30%), worsening (29%), and no effect on symptoms (41%). Anecdotally, the number of women approve seem to be higher. At least according to a panel held at an OFFERUtah conference in 2011, several practitioners including Bateman and Klimas reported that all or nearly all of the patients whose pregnancies they followed reported an improvement in symptoms, will several gaining full remission.
Whether the true number of women who experience improvement is 30% or something higher, it still begs the question of whether "Th2 shift = bad for ME" is too mechanistic a story, especially when you include number of women who experience no change in symptoms as well the fractional (but still hard to ignore!) number of women with ME who experience a complete remission.
Hookworms and NK cells
Hookworms (a species of helminth) increases the number of tregs (at least in patients with low tregs), which would theoretically inhibit NK function. However in vitro they have been found to secrete a protein that binds selectively to NK cells and induces the NK cells to produce more IFN-gamma and in vivo they attract NK cells to their attachment site and stimulate their activity, perhaps as a strategy to evade the host immune system.
IFN-gamma has immunoregulatory, antiviral and anti-tumor properties and promotes NK cell activity as well as macrophage activity.
It also "abundantly" produced by the developing fetus and is decreased in ME patients.
(That said, results of interferon therapy in ME/CFS have been mixed.)
What about hosting helminths while pregnant?
There is very little research on the effects of helminthic therapy on pregnancy. There is a lot of research on the negative effects of helminths in pregnancies where they are endemic because very large parasite burden (much higher than a therapeutic dose) can cause anemia and low birth weight. There are certainly a handful of patients experimenting with inflammatory/autoimmune conditions experimenting with helminth inoculation pre-conception to either try to prevent miscarriage or inflammation-related birth defects in their children. Babies born to women with helminth infections were found to have lower rates of eczema and allergies.
Helminths and the other trillion+ residents of your gut
Helminths may also independently alter the composition of gut bacteria. One study in Malaysia showed villagers infected with helminths had greater gut microbiota diversity than those who did not (while this is an observational study and perhaps helminth-infected people eat more soil or something, one might presume that other diet and environmental factors are more or less similar between among people living in the same village).
I was not able to find any randomized trials on helminths and gut bacterial populations in humans. However, there are studies in animal models. Some helminths increase population of pathogenic bacteria while other helminths increase populations of commensal bacteria.
One animal study showed helminth infection might decrease intestinal inflammation and increase mucus production. This may explain at least part of the benefit in IBD and ulcerative colitis, especially given the importance in those disease of helminths not just to altering systemic immunity but providing "islands of profound calm" localized around their attachment sites.
Many helminths, many effects
Lastly, different species of helminths have different effects on the immune system.
Here are two helpful overviews of the effects of different species of helminths on the immune system:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706953/
http://www.sciencedirect.com/science/article/pii/S156899721400216X
It is also helpful to note that different helminths fill different "niches" in the intestine. That is some colonize the small intestine while others colonize the colon. This means that the optimal therapy for someone with ulcerative colitis might differ for someone with Sjorgen's, for example.
Should ME patients experiment with helminths?
There is zero research and very little patient anecdote to suggest helminths would be helpful to ME patients, particularly given that many of the modifications helminths make to avoid expulsion by the immune system tend toward an expression pattern that is similar in many respects to the immune dysfunction already present in ME.
At the same time, most of the research on the effects of helminths on immune dysregulation in humans and animal models have been in diseases like multiple sclerosis. Helminths are a dynamic intervention – they secrete dozens of immunomodulatory chemicals in response to the host environment, so it is uncertain what they would do in a host with a different pattern of immune dysfunction. My guess is that in a host that already has large numbers of regulatory t-cells, for example, a hookworm would not increase the numbers of regulatory t-cells. Why bother? Rather, it would do the minimum necessary to ensure an environment conducive to its own survival. So it is possible that a helminth infection might positively affect your breg status in a way that could be disease-modifying, while leaving your tcells alone.
The last thing to mention is that there is some evidence that helminth infection might encourage viral reactivation and at least theoretically, inhibit your ability to fight cancer. We should worry about that not only because of our tendency toward viral reactivation but because we have a 4x increased risk of cancer. I've looked and there is not a whole lot of work in this area. The research I have found has not so far found a link between helminth infection and cancer (in fact, certain helminths might reduce your risk of gastric or colon cancer, perhaps by attenuating the damage induced by H. Pylori infection in the case of the former). Moreover, there is no strong evidence that helminths (endemic in many areas with high rates of HIV infection) lead to higher viral loads or more disease progression. In fact, some studies found the opposite. But the results on both are conflicting and the evidence is really not there, either way.
This lack of consistent evidence supporting theoretically negative effects of helminths on cancer or virus suppression may be due to the fact that while much of the helminth research focuses on Th1 dominant autoimmune diseases and emphasizes importance of helminths' effects on tregs, helminths have multiple and dynamic effects on the immune system which probably depend heavily on the host environment and on host-helminth interactions. Put another way, the immunomodulatory "protocol" a helminth would prescribe for your immune system depends a) on the particulars of your immune response and b) on whatever your immune response signals to the helminth it must do in order to ensure its survival. So we just don't know, for better or worse, what a helminth would do when it meets an ME patient's immune system. But I hope someone decides to study it!
Last edited: