Alopecia Areata: A Review of Disease Pathogenesis

F. Rajabi; L.A. Drake; M.M. Senna; N. Rezaei

Disclosures

The British Journal of Dermatology. 2018;179(5):1033-1048. 

In This Article

What Causes Immune Privilege Collapse?

What causes IP to fall apart is a matter of debate. There are two main theories explaining the initial events: one theory emphasizes local defects in HFs and the other implicates a dysregulated immune system (Figure 2).

Figure 2.

The two distinct scenarios for alopecia areata development. (a) Immune privilege collapse starting at hair follicles. Stressors provoke expression of MICA proteins on keratinocytes, leading to activation of NK cells and secretion of IFN–γ. MHC-I protein expression is induced by IFN–γ, revealing the previously obscured antigens to T cells. (b) Immune privilege collapse could result from large amounts of CD8+ NKG2D+ effector memory T cells, which upregulate in regional lymph nodes and then invade the hair follicles. These cells produce IL–15 and IFN–γ. IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; MICA, MHC class I chain-related A; NK, natural killer; TCR, T-cell receptor; TGF, transforming growth factor.

Local Disturbances in Hair Follicles as the Initiators of Immune Privilege Collapse

This hypothesis states that environmental stress can lead to build-up of reactive oxygen species in HF keratinocytes.[79,80] Genetically susceptible individuals are unable to surpass this effectively, so stress builds up in the cells, promoting MICA expression.[43,44,49,81] MICA-positive cells, aside from their MHC presentation state, become visible to NKG2D receptors on NK cells, causing activation of the innate immune system and the cascade of events following it.[9,49] The stressed environment could also downregulate IP guardians and MIF.[25,82] These factors were shown to correlate negatively with IFN production, NK cell accumulation and, most importantly, MHC presentation. When HF cells begin to present MHC-I molecules, a vast group of secured antigens becomes visible to the immune system and subsequent immunological events thereafter become unstoppable.[25,49,79,80,83]

Several antigens have been proposed to be targeted, mainly melanocyte-associated molecules[84] and some HF structural proteins such as trichohyalin and keratin 16.[85,86] There is significant evidence supporting this theory. HF cells in AA show strongly positive MICA expression, while normal HFs, except for a small region in the proximal matrix, are usually MICA negative; this zone is suggested to be the primary site involved in AA.[49,87,88] The MICA and NKG2D receptors are also involved in other autoimmune diseases such as rheumatoid arthritis[89] and type I diabetes.[90,91] Genetic studies have also provided ancillary clues to the involvement of MICA, ULBP and antioxidant enzymes in the pathogenesis of AA.[92–94]

The Hair Follicle as an Innocent Bystander in a Dysregulated Immune System

The second hypothesis of AA indicates that the initiating step occurs in the lymphatic system with activation of immune cells. These cells may later invade HFs and induce expression of MHC and MICA molecules via IFN–γ. This would infer that IP collapse is a normal anticipated response in HFs, which is under the influence of IFN–γ–producing immune cells.[95–97] A number of animal, genetic and immunological studies have provided evidence to support this theory.

There are two famous mouse models for AA, one of which is the C3H/HeJ mouse provided by the Jackson Laboratory (Bar Harbor, ME, U.S.A.). This mouse lineage spontaneously develops hair loss clinically and histologically resembling AA, in up to 20% of cases.[98,99] The other mouse model is the SCID mouse (homozygous for the severe combined immunodeficiency mutation) bearing a normal human skin graft.

Placing a full-thickness skin graft from normal C3H/HeJ mice on alopecic C3H/HeJ recipients would result in hair loss in the graft, while grafting AA-affected C3H/HeJ skin onto immunodeficient recipients results in hair regrowth.[100,101] More specifically, AA may be induced solely by transfer of immune cells from naturally affected mice such as CD8+ cells, cells cocultured with IL–15 and CD8+ NKG2D+ T cells.[95,100,102] As IL–15 upregulates NKG2D receptors,[103] and lymph node cell populations depleted of CD8+ NKG2D+ T cells are incapable of AA induction, this cell line is thought to be crucial in disease pathogenesis.[77] In the SCID mouse model, injection of activated T cells, harvested from human scalp AA lesions, into the graft induces hair loss. A tissue homogenate containing HFs and antigen-presenting cells is responsible for T-cell activation.[104,105]

Hair loss similar to AA may be induced in SCID mice by exposing them to IL–2–rich peripheral blood mononuclear cell cultures from healthy individuals. High doses of IL–2 promote expression of NKG2D+ CD56+ cells.[49,106–108] Studies on these models emphasize the primacy of immune activation over the HF disturbance theory by demonstrating the ability of AA induction solely by transferring immune cells. This is more evident for the SCID model because its lacks inherited susceptibility for AA.

Another study in favour of this hypothesis demonstrated higher expression of activating receptors such as NKG2C and fewer inhibitory receptors such as KIR on NK-cell surfaces in patients with AA.[49] This means that NK cells are more susceptible to activating stimuli in patients with AA. This increases their chance of breaching the IP via engagement of the NKG2C with nonclassical MHC or by recognition of MHC-negative HFs by NK cells that could now escape their suppressive environment.

Investigations around the AIRE gene could also be viewed as evidence in favour of this theory. The AIRE mutation causes an autosomal recessive disease called autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED). AA is one of the features of APECED, occurring up to 40 per cent of patients.[109] The AIRE protein initiates the transcription of a diverse set of peripheral-tissue antigens in thymic epithelial cells.[110–113] Any self-antigen expressed in thymic epithelial cells is secured from autoimmunity due to negative selection of T cells expressing reactive T-cell receptors.[114] AIRE dysfunction allows a range of naive autoreactive T cells (possibly against HFs) to go on unrecognized, increasing the possibility for autoimmune diseases.[115,116] Several studies have revealed the association of AIRE gene polymorphisms with non-APECED AA.[116–119]

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