An exception to every rule: Asthma is not an example of the hygiene hypothesis

[Trieste]

This is a paper I threw together for immunology. It probably has holes in it; I'm not an immunologist. However, I found the topic fascinating, and wanted to share. I would welcome constructive criticism; I feel like I did not have enough time to really dig in and do it.

An exception to every rule: Asthma is not an example of the hygiene hypothesis

The introduction of the hygiene hypothesis with Strachan’s statistical analysis of hay fever and household size⁽¹⁾, and the subsequent exculpatory research and hypotheses, initiated a flurry of investiation that is still going on currently. The relationship between early childhood infections and later autoimmunity has been established as correlative but not causative⁽²⁾. Furthermore, the mechanism of this relationship is still hypothetical, without solid basis in experiment. After Strachan’s publication, the correlation between family size and prevalence of hay fever was extended to include other factors. The factors that were most widely explored were specific diseases and specific allergens.

The specific diseases explored thus far have not been of a traditionally autoimmune family. Inflammatory bowel disease (IBD), also known as Crohn’s disease, has seen a distinct increase in frequency over the last four decades, especially in population centers⁽³⁾. On top of the genetics of IBD, Elliott et al. suggested that the absence of intestinal worms contributed to the prevalence of the disease. They applied it not only to childhood worm infestations, but adulthood infestations as well. In fact, the infection of IBD patients with intestinal parasites has shown a significant decrease in those patients’ inflammatory symptoms due to IBD ⁽⁴⁾.

Literature seems to suggest that incidences of childhood infections can protect against several other diseases. Children who attend day care during their early childhood have been shown to have a lower incidence of both diabetes mellitus and acute lymphoblastic leukemia ^{(5, 6)}. These studies seem to confirm the hygiene hypothesis by adjusting for factors such as parental age, diet, and other factors. Despite these statistical adjustments, the fact remains that children exposed at an earlier age to the infections rampant in early day care centers have a lower incidence of serious infection later in their childhood. The specific mechanism for the protective quality of increased early childhood exposure to infections has not been determined. It has, however, been hypothesized extensively.
The ratio of T_H1 and T_H2 with relation to each other has been implicated in the prevalence of autoimmune and allergic diseases for several reasons. T_H1 production inhibits T_H2 production, and vice versa. T_H1 is specifically linked to inflammation as well as to activation of B cells that produce strongly opsonizing antibodies. T_H2, on the other hand, is essential to the secretion of immunoglobulins, most pertinently IgE. For further discussion of T_H cells in general autoimmune diseases rather than the context of the hygiene hypothesis, refer to the review by Marrack et al.⁽⁷⁾ The emerging explanation with regard to the hygiene hypothesis is that early childhood infection moves the immune system away from the perinatal T_H2-dominated immune profile and stimulates the immune system toward a T_H1-dominated immunological response ⁽⁸⁾.

The literature on allergies and allergens supports this. Childhood asthma and allergies have been linked correlatively and it has been shown that early exposure to allergens such as cat dander produce an immune response without sensitization in young children ⁽⁹⁾. Airway hyperresponsiveness is one component of asthma, but it is only one half of the equation. Inflammatory response is a key component in asthmatic reactions, and it is this component that provides some trouble for the hygiene hypothesis. Exposure to allergens elevates IgE levels in children, and is part of the T_H2 immunological response that predisposes children to asthmatic symptoms ⁽¹⁰⁾.

Further, early childhood attendance to day care, as well as larger family size, has been correlated with more frequent episodes of wheezing in early childhood ⁽¹¹⁾. Respiratory syncytial virus (RSV) infections are more common in children with higher exposure to other children whether through larger family sizes or day care attendance ⁽¹²⁾. These infections result in higher incidences of wheezing and respiratory difficulties in children under the age of 13, which should stimulate their immune systems toward a T_H1-dominated response, according to the hygiene hypothesis. However, these T_H2-mediated infections induce the first part of asthma, airway hyperresponsiveness ⁽¹⁰⁾.

The dendritic cells in the lungs are important in this process. Dendritic cells at rest normally preferentially contribute to the T_H1 pathway, producing a higher T_H1 response. However, mature dendritic cells in the lungs have been shown to preferentially contribute to the T_H2 pathway, creating a prime environment for pulmonary atopic responses ⁽¹³⁾. The lack of uniformity in airway responses can be attributed at least in part to the finding that mature dendritic cells unevenly activate T cell responses, even with large quantities of antigen available ⁽¹⁴⁾. This suggests that it is not the amount of allergen available but the genetic predisposition that matters most in the vehemence of the T_H2 response.

Under these circumstances, later preference toward the T_H1 immunological pathway can prove disastrous. The T_H1-T_H2 ratio hypothesis has been challenged on the basis of findings in, for example, Sheikh et al. on the basis that individuals could report both allergic atopy and asthmatic symptoms. While the study also included diabetes mellitus, the study did not control for differential responses based on the reported autoimmune disorders (e.g. diabetes mellitus versus asthma versus Crohn’s disease). As such, they could not conclude that there is sufficient support for the hygiene hypothesis ⁽¹⁵⁾.

However, in the case of asthma, the T_H1 response has been shown to antagonize already-existing hyperreactivity induced by T_H2 responses ⁽¹⁶⁾. In fact, it produces inflammation in addition to airway hyperreactivity ⁽¹⁶⁾, leading to asthmatic symptoms. While the hygiene hypothesis has proved to be a reliable model for the prevention of some autoimmune conditions, it clearly works counter to the prevention of asthma in particular. (Fig 1)

 
Elliot et al. 2000 ⁽³⁾                                                      Umetsu et al. 2002 ⁽¹⁷⁾

Fig 1. A comparison of the hygiene hypothesis model for Crohn’s disease, compared to the experimental evidence in the formulation of asthma and asthmatic symptoms. The lower branch on Umetsu’s diagram is not supported by literature.

References
1.   Strachan, David P. 1989. Hay Fever, hygiene, and household size. BMJ 299:1259-60
2.   Matricardi, Paolo M., Rosmini, F., Riondino, S., Fortini, M., Ferrigno, L., Rapicetta, M., and Sergio Bonini. 2000. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 320:412-7
3.   Elliott, D. E., Urban Jr, J. F., Argo, C. K., and Joel V. Weinstock. 2000. Does the failure to acquire helminthic parasites predispose to Crohn’s disease?. FASEB J 14:1848-55
4.   Summers, R. W., Elliott, D. E., Qadir, K., Urban Jr, J. F., Thompson, R., and Joel V. Weinstock. 2003. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. American Journal of Gastroenterology 98:2034-41
5.   Gilham, C., Peto, J., Simpson, J., Roman, E., Eden, T. O. B., Greaves, M. F., and F. E. Alexander. 2005. Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study. BMJ 330(7503):1294-1300
6.   McKinney, P. A., Okasha, M., Parslow, R. C., Law, G. R., Gurney, K. A., Williams, R., and H. J. Bodansky. 2001. Early social mixing and childhood Type 1 diabetes mellitus: a case-control study in Yorkshire, UK. Diabetic Medicine 17(3):236-42
7.   Marrack, P., Kappler, J., and Brian L. Kotzin. 2001. Autoimmune disease: why and where it occurs. Nature Medicine 7(8):899-905
8.   Romagnani, S. 1994. Lymphokine production by human T cells in disease states. Annual Review of Immunology 12:227-57
9.   Sears, M. R., Burrows, B., Flannery, E. M., Herbison, G. P., Hewitt, C. J., and M. D. Holdaway. 1991. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. New England Journal of Medicine 325(15):1067-71
10.   Platts-Mills, T., Vaughan, J., Squillace, S., Woodfolk, J., and R. Sporik. 2001. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357:752-56
11.   Ball, T. M., Castro-Rodriguez, J. A., Griffith, K. A., Holberg, C. J., Martinez, F. D., and A. L. Wright. 2000. Siblings, day care attendance, and the risk of asthma and wheezing during childhood. New England Journal of Medicine 343:538-43
12.   Stein, R. T., Sherrill, D., Morgan, W. J., Holberg, C. J., Halonen, M., Taussig, L. M., Wright, A. L., and F. D. Martinez. 1999. Respiratory syncitial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354:541-45
13.   Stumbles, P. A., Thomas, J. A., Pimm, C. L., Lee, P. T., Venaille, T. J., Proksch, S., and P. G. Holt. 1998. Resting Respiratory Tract Dendritic Cells Preferentially Stimulate T Helper Cell Type 2 (Th2) Responses and Require Obligatory Cytokine Signals for Induction of  Th1 Immunity. JEM 188(11):2019-31
14.   Bakocevic, N., Worbs, T., Davalos-Misslitz, A., and Reinhold Forster. 2010. T Cell-Dendritic Cell Interaction Dynamics during the Induction of Respiratory Tolerance and Immunity. The Journal of Immunology 184(3):1318-27
15.   Shiekh, A., Smeeth, L., and R. Hubbard. 2003. There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: Lack of support for the hygiene hypothesis. J Allergy Clin Immunol 11(1):131-135
16.   Hansen, G., Berry, G., DeKruyff, R. H., and D. T. Umetsu. 1999. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. The Journal of Clinical Investigation 103:175-83
17.   Umetsu, D.T., McIntyre, J. J., Akbari, O., Macaubas, C., and R. H. DeKruyff. 2002. Asthma: an epidemic of dysregulated immunity. Nature Immunology 3(8):715-20

[WhiteTigerForever]

This is an excellent paper and findings that though appear more causative, and through my experience, and that throughout human history, may very well back up your research.  The intense exposure when a child is the youngest, when the symptoms are most often the least, is highly functional for the immune system into adult hood. 

I did a paper years ago on Polio(abbreviated) and such findings were similar.  Due to the cleanliness and cultural changes of hygiene, the immune system did not have the chance to develop the defense system to fight off the disease that struck the American populations heavy in the 40's and 50's. 

I too am no immunologist, and been years since I studied such, but I love your paper. :D

[DarklingAlice]

I've hung up my immunologist hat for a few years in order to be a humble ophthalmologist, but I have to say that I think you did a solid job.

Form-wise it is short and to the point, which I always appreciate in scientific literature. Although it does have a little bit of redundant syntax and word choice. Further editing might produce a tighter piece from a style standpoint.

As far as the science goes it's a good review. I found it quite interesting. However, I wonder at the choice of ALL (which as far as I know has no auto-immune component) and the use of the general term 'diabetes mellitus' (since not all forms of it are auto-immune it leaves it ambiguous as to what the data shows e.g. they could just have a lower incidence of type two diabetes which, IIRC, lacks an autoimmune component) as examples. I think there is probably literature more specific to the subject of immune disorders. That said, those examples were background and the main point of your paper is well developed and well taken.

All told, good job! Especially considering your workload <_<

[The Dark Raven]

I do so love lung research in general... <3

Makes me want to dig up papers on the mycoplasma research my Dad's boss did a while back.

[Trieste]

I did a paper years ago on Polio(abbreviated) and such findings were similar.  Due to the cleanliness and cultural changes of hygiene, the immune system did not have the chance to develop the defense system to fight off the disease that struck the American populations heavy in the 40's and 50's. 

That is the basis of the hygiene hypothesis (better hygiene = fewer early childhood infections = weaker immune system), although my paper is discussing how asthma is an exception to that particular flow. :)

I've hung up my immunologist hat for a few years in order to be a humble ophthalmologist, but I have to say that I think you did a solid job.

Form-wise it is short and to the point, which I always appreciate in scientific literature. Although it does have a little bit of redundant syntax and word choice. Further editing might produce a tighter piece from a style standpoint.

As far as the science goes it's a good review. I found it quite interesting. However, I wonder at the choice of ALL (which as far as I know has no auto-immune component) and the use of the general term 'diabetes mellitus' (since not all forms of it are auto-immune it leaves it ambiguous as to what the data shows e.g. they could just have a lower incidence of type two diabetes which, IIRC, lacks an autoimmune component) as examples. I think there is probably literature more specific to the subject of immune disorders. That said, those examples were background and the main point of your paper is well developed and well taken.

All told, good job! Especially considering your workload <_<

The choices of ALL and diabetes mellitus were based on the literature I could find surrounding the hygiene hypothesis. For certain purposes, cancer can be considered an immune dysfunction in that, for example, NK cells don't catch them and then they multiply and form a tumor. I believe that's why ALL was considered relevant by the literature, and why I included it. Diabetes mellitus was the term used by the papers I was using, as well, so I wasn't aware that it was a catch-all term. I'm not familiar with it, but it's my understanding that the autoimmune component is due to the immune system recognizing insulin as foreign and destroying it. That's my rudimentary understanding, anyway. >.>

And thank you!

[WhiteTigerForever]

That is the basis of the hygiene hypothesis (better hygiene = fewer early childhood infections = weaker immune system), although my paper is discussing how asthma is an exception to that particular flow. :)

Indeed and I did forget to put it in as the antithesis, but fabulous!  I hope you do well with it grade wise and research wise!

[Oniya]

I don't know if there's a specific name for it, but there's a form of diabetes where the sufferer develops a tolerance for their own insulin.  It may be one of the 'obesity acquired' forms (that goes away if you lose weight) but I haven't done any research on it.

[WhiteTigerForever]

On par with that, with a host of "other issues", my oldest is allergic to his own adrenaline.  I know it makes no sense what so ever, but neither does his biochemistry at all, in any way.  It is necessary for daily functioning, but when he gets upset, over heated, stress of any kind, his entire body brakes out in horrid hives that cover his entire body.  This in a regular thing for him and must take hydroxazine to keep it at bay.. :(

The random DNA expressions are very often not in a kind way, as the human genome continues to evolve, though taken directly out of nature, which has slowed it for a mass majority.  All for a search for genetic success via mutations, etc.  Most which can hinder the species, but one may take it to the next level of survival.