History and Metabolic Context of Alopecia Areata

Characterization of Alopecia: Areata, Totalis, and Universalis 

Alopecia is a broad term that is used to describe hair loss of many different kinds. In fact, the technical term for male-pattern baldness is actually Androgenic Alopecia. Unlike male pattern baldness, Alopecia Areata (AA) is an autoimmune disorder that targets the anagen (or growing) hair follicle and results in patchy hair loss. As of 2012, there were approximately 4.5 million Americans that were suffering from AA (Gilhar 2012). The prevalence of AA in the world is 0.1-0.2 %, with a calculated lifetime risk of about 1.7-2.0 % (Gilhar 2007/2012, Hordinsky 2004). The disease usually presents itself in patients when they are children, teenagers, and/or young adults, but the onset of symptoms has also been noted in adults in more rare cases.

Autoimmune Alopecia tends to manifest itself in different ways and is named depending on the location and severity of hair loss. Alopecia Areata, as mentioned before, is characterized by patchy hair loss on the scalp, while Alopecia Totalis (AT) results in total loss of scalp hair and Alopecia Universalis (AU) results in complete loss of body hair. While each of these versions of Alopecia are named differently, they all result under the same metabolic conditions. In other words, the generation of hair loss between AA, AT, and AU does not differ depending on the subtype of Alopecia. As such, most papers focus on all three types of alopecia. For the sake of clarity, AA will be used to denote any of these three types unless specifically noted. AA can be easily diagnosed because of its solely physical manifestation. AA separates itself from other skin diseases because it is both non-scarring and non-inflammatory. There are also secondary characteristics by which physicians can recognize AA such as premature graying or whitening of a patient’s remaining hair or the disruption of the nail matrix on patients’ hands. Diagnosing AA with these secondary characteristics, however, is not a perfect method because not all patients experience premature graying or disruption of the nail beds. In rare cases, a skin biopsy may be needed to confirm the diagnosis. This biopsy is generally successful because they search for certain histological features around the hair follicle, as exemplified by figure 1 (Gilhar 2007). There is also epidemiological evidence that suggests AA is associated with lupus erythematosus in 0.6% of patients, vitiligo in 4%, and autoimmune thyroid disease in 8 to 28%. The overall risk of an AA patient being afflicted with a secondary autoimmune disorder is about 16% (Gilhar 2012). This number is small, but not entirely insignificant given the number of those afflicted with AA. Using the statistic from above, this would mean that approximately 720,000 of the 4.5 million diagnosed with AA also show symptoms of other autoimmune diseases.

Gilhar 2007 hair follicle figure
Figure 1: A graphical abstract from Gilhar et. al.’s 2007 review on AA. When performing a skin biopsy to diagnose AA, researchers look for extensive proliferation of CD4+ and CD8+ T cells around the base of the anagen hair follicle. In practice, this is seen as a dark circles around the base of the hair follicle that exist in what is called a “swarm of bees” pattern.

 

Biology of the Hair Follicle

In order to understand the overall impact that AA has on the growth and function of the hair follicle, the normal function of a healthy hair follicle must be examined. Unlike many other parts of the human body, hair follicles undergo cycles of growth and rest throughout their entire lifespan. The typical human hair follicle exists in three separate phases: anagen, a phase characterized by extensive growth and proliferation of the hair follicle; catagen, an apoptosis mediated shrinking of the hair follicle back to its normal size (organ involution); and telogen, a state of rest before re-entering the anagen phase. In AA patients, CD8+ and CD4+ T cells and Natural Killer (NK) cells accumulate and attack only hair follicles that are in the anagen phase. Because of this, hair growth is suppressed rather than completely eliminated because the hair follicle itself is not destroyed and remains entirely intact. While hair regrowth is sporadic and difficult to coerce, the mechanism of AA allows for the possibility as the hair follicle is essentially being held in a state of rest by its own immune system. (Gilhar 2007) A figure from Gilhar et. al.’s 2007 AA review summarizes this information quite nicely (figure 2).

Figure 2: Visual summary of the growth cycle of a normal hair follicle and the hair follicle of an AA patient. (source:  Gilhar A et al. N Engl J Med 2012;366:1515-1525)
Figure 2: Visual summary of the growth cycle of a normal hair follicle and the hair follicle of an AA patient. (source: Gilhar A et al. N Engl J Med 2012;366:1515-1525)

Immune Privilege

The immunology of the healthy hair follicle is also extremely important to understand in the context of AA. In a healthy person, hair follicles are generally granted “immune privilege.” Immune privilege is a term given to any part of the body that can tolerate the presence of an antigen without an extensive inflammatory response from the immune system. Besides for the hair follicle, the eyes, placenta in pregrant women, and testicles are also granted immune privilege (Gilhar 2007). There are a number of mechanisms by which tissues are granted immune privilege, and all act together in order to suppress an immune response. The most common and relevant to AA mechanisms of immune privilege are the low expression of MHC class I molecules, the local production of immunosuppressive molecules (i.e. transforming growth factor-β1 or Interleukin 10), and the absence of lymphatics near the hair follicle (Paus 2005).

In healthy people, all three of these mechanisms grant their hair follicles protection from their own immune system. The normal function of MHC molecules is to recognize and present small parts of an antigen to T cells, which begins the process of specific immunity. Therefore, low expression of MHC class I molecules ensures that auto-active CD8+ T cells cannot recognize the MHC presenting an autoantigen because the MHC is absent, thus preventing an immune response. The low expression of MHC class I molecules opens up the possibility of attack by NK cells, since they generally act to destroy MHC class I negative cells. The hair follicle seems to control this by down-regulating the production of NK stimulating ligands while simultaneously up-regulating the production of molecules that inhibit NK cell function, TGF- β1 amd IL-10 (Gilhar 2012). TGF-β1 and IL-10 also both contribute to immune privilege by acting as secreted agents that maintain the current immune state. In other words, TGF- β1 and IL-10 are both secreted when a harmful autoantigen is not sequestered correctly and work to destroy this autoantigen and prevent it from being recognized by the immune system (Gilhar 2007). It is not surprising, then, to see the onset of AA be linked to the collapse of immune privilege within the hair follicles. There would be no need for immune privilege if there was no danger of developing autoimmunity against specific tissues, which is seen in most parts of the body.

 

More On Alopecia:

Molecular Basis

Treatment

Conclusions and Proposals for Future Work

Annotated Bibliography

6 Replies to “History and Metabolic Context of Alopecia Areata”

  1. Nice page, Matt – very informative. The last two sections were especially well-written. I wanted to ask about two things: 1) Why do T cells attack hair growing in the anagen phase as opposed to the other phases of hair growth? 2) Why does the regrowth of hair in AA patients result in only white hairs growing? Why doesn’t the hair grow back in the normal color?

    1. Hi Zach! There hasn’t been much research that specifically targeted why T cell attack is limited to the anagen hair follicle. When T cells do attack, they cause premature entry to the catagen phase, which is highly apoptotic. Attacking at the catagen or telogen phase would likely cause premature entry into the anagen phase instead. Research has implicated that the act of melanogenesis (produced by melanocytes on the bottom layer of the skin) triggers both entry into the anagen phase and the accumulation of T cells.
      As for your second question, I should have been more clear in my post. It’s not that the hair grows back white, it’s that the remaining hair may turn white seemingly overnight. Researchers who conducted a genome-wide association study to identify frequently mutated genes in AA found a mutation in a gene called STX17 that was associated with premature hair greying. Not all patients experience this, however.

      Thanks for reading!

  2. Hey Matt…

    I appreciate that you took the time to edit this properly. Your discussion is well organized and flows very nicely from one topic to the next. I’m going to make a short comment here and then on another page because I only have technical suggestions at the moment.

    Do you think you could hyperlink the articles on the doi or the reference itself instead of the picture? The pictures are hard to see on the blog page itself, so typically when you click on them it will open it up and zoom in for you, but instead yours took me to the paper. Then i have to go through the paper and click on that figure to enlarge it and etc. and etc. It would be more user friendly if I could click on the picture in this page for a zoom and then you leave the link elsewhere in the caption. Also, if you want to throw in some more detail on the page that’s up to you, but could you explain to me a little more of figure 2? I don’t think I am completely understanding what the difference is between those two follicles.. Is the idea that one follicle is in place and another comes from underneath and pushes it out?? So in the disease state you have attack of the cytokines which prevents the underlying follicle from coming in properly? I can visually see the difference but I’m trying to dynamically imagine how these players are interacting with one another. Just need a bit of clarification. Thanks buddy. I’ll leave another short comment elsewhere in a minute.

    1. Hey Ryan! Thanks for your feedback, I’m glad you gave me some stylistic pointers on top of your questions. As for the figures, I went through and checked the rest of my figures (other than figure 2 here) and they seem to be linked to the picture instead of the paper. I’m not sure why this isn’t linking to the image, but I can’t change the hyperlink because we don’t own the paper. I have the pdf file on my computer, but it won’t let me view the image to get its link. Sorry about that!
      As for your question on AA pathogenesis, the difference between the hair follicles is caused by the cytokine and T cell accumulation at the base of the anagen hair follicle. T cell attack triggers the hair follicle to enter the apoptosis driven catagen phase prematurely. The catagen phase is apoptotic because during mealnogenesis (which triggers hair follicles to return to the anagen phase from the telogen phase) the follicle swells because of a higher rate of cell division in that microenvironment that is necessary for hair growth. AA causes hair loss, then, by preventing the return the the anagen phase, forcing the hair follicle to spend more time in the apoptotic catagen phase or the resting phase, telogen. This is better explained in the molecular basis section of my report if you need further clarification.
      Thanks for reading

  3. Hey Matt! I really liked your site- I feel like I learned a lot. I have a couple questions. First (and I don’t know if you came across anything about this), is there an evolutionary reason why hair follicles enjoy immune privilege? It seems to make more sense that the other areas of the body that you mentioned as having immune privilege would possess it. I’m just curious why hair follicles also (usually) maintain this ability to tolerate antigens.

    Speaking of antigens, I think it would be helpful if you clarified what an “autoantigen” is. I think I understand what it is, but since you go from discussing how immune-privileged areas of the body can tolerate antigens, I think that it would be more cohesive if this new term were defined before explaining how it functions in immune privilege.

    Good job!

    1. Hey Gabby! As I was doing my research, I did not find anything on why hair follicles enjoy immune privilege, just about how they manage immune privilege. Nontheless, I was also curious about this simply because the hair follicle doesn’t seem as important, evolutionarily speaking, as something like the eyes or testis. My best guess is because of the mechanism of hair growth and the cycle of the hair follicle, which leads well into your next question about autoantigens. Hair growth in humans occurs in cycles, as seen in figure 2. The catagen phase is characteristically apoptotic, because of the swelling of the follicle during hair growth (anagen phase). The best explanation for this, and also your evolution question, is that the phagocytosis of apoptotic cell fragments and self-peptide processing present unique opportunities for recognition by the immune system (Paus 2005). Unfortunately, there is yet to be hard evidence on this subject that has proven this. An autoantigen, then, would be something that originates from one’s own body (like the apoptotic cell fragments) that are recognized and presented on the surface of MHC-I expressing cells, leading to an immune response against the antigen as if it were foreign. Part of immune privilege is a low expression of MHC-I cells, thus physically preventing the presentation of the autoantigen. I hope this helped clarify your question rather than make it more confusing. Thanks for the interesting questions!

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