Alopecia areata: a review of disease pathogenesis

Abstract

Summary Alopecia areata is a disease that causes hair loss, although it does not always look the same and its course is unpredictable. It typically presents as small spots of reversible hair loss on the beard or scalp that can easily be treated. It can also result in total scalp baldness (called alopecia totalis) with devastating psychological impacts for some patients, inadequate treatment options, and frequent relapses. This article is a narrative review of the main events that cause alopecia areata, conducted by researchers based in Iran and the U.S.A. Many environmental and genetic factors are involved in the development of alopecia areata but the mainstream event is an attack on hair follicles by the immune system, which usually serves to protect the body from harmful ‘foreign’ substances or illnesses. In a normal state, hair follicles are kept in a sanctuary out of reach of the immune system. A breach in this sanctuary activates the immune cells against hair follicles. This happens because the immune system has never been exposed to the hair follicles so it recognizes them as foreign material. What causes this breach is a matter of debate. It could happen as a result of a problems in the central immune system or a disturbance in the follicular environment, i.e. close to the follicles. Psychological stress has also been linked to both the initiation and exacerbation of alopecia areata. A cell line called the mast cells is the link between the immunologic (immune system) events and psychological stress. Stress activates mast cells leading to the release of histamine and other inflammation‐causing factors. Multiple treatment strategies have emerged in recent years aiming at immunological targets, called biologic agents, but most of them have not been able to establish long‐lasting remissions. This may be due to the complex nature of the immunologic events which cannot be targeted with a single agent. Overlooking strategies that aim to kick‐start the regrowth of hair, after treatments that restore the immune sanctuary, might be another reason for treatment failures.

What is behind the ‘swarm of bees’ in alopecia areata

“…In this issue of the BJD, Rajabi et al present a comprehensive review of recently proposed pathogenic mechanisms of AA. 3 In 1993, Paus et al first suggested the collapse of hair follicle (HF) immune privilege (IP) in AA. 4 Past observations suggested that HFs, especially the proximal portion including the bulb, enjoy IP that is enabled by several mechanisms: the absence or low-expression of major histocompatibility complex (MHC) class Ι and its pathway-related genes; the downregulation of interferon regulatory factor-1; the upregulation of immunosuppressive or proapoptotic molecules (IP guardians) such as transforming growth factor (TGF)-b, a-melanocyte-stimulating hormone (MSH), indoleamine-2,3-dioxygenase (IDO), protein red encoded by the IK gene (red/IK), interleukin (IL)-10, calcitonin gene-related peptide (CGRP), insulin-like growth factor (IGF-1), somatostatin, Fas ligand and programmed death-ligand 1 (PD-L1); the absence of MHC class ΙΙ + cells or Langerhans cells; the sparse distribution of T cell and natural killer (NK) cells; NK cell prevention machinery [low MHC class I polypeptide-related sequence A (MICA) expression, production of macrophage migration inhibitory factor (MIF), downregulation of NKG2D and upregulation of killer cell Ig-like receptor (KIR) on local NK cells]; the absence of lymphatics and the presence of relatively rich extracellular matrix, etc.…”

“…The uniqueness of the work by Rajabi et al lies in the way that the authors distinguish and discuss two individual scenarios for initial triggering of IP collapse. 3 One theory centres on environmental stress (e.g. reactive oxygen species) locally promoting MICA expression that activates the innate immune system via NKG2D + NK cells, which leads to subsequent interferon production and MHC class Ι upregulation to break HF-IP.…”

“…3 In this scenario, interferon (IFN)-c-producing immune cells play an initial role in the breakdown of IP aside from MHC class Ι upregulation or IP guardian downregulation. 3 Past studies adopting AA animal models favour this theory. In C3H/HeJ AA model mice or severe combined immunodeficiency (SCID) mice with human skin grafts, transplantation of AA-affected mice skin or introduction of activated human T cells were sufficient to elicit an AA phenotype.…”

“…15 IL-2 and IL-15 were also upregulated around HFs. 3 Importantly, IL-15 stimulates the NKG2D signalling pathway eventually leading to Janus kinase (JAK) activation. 13 Probably because the review focused on the pathogenesis of AA not pathophysiology, the authors did not particularly focus on a description of this; however, the local IFN-c-IL-15-JAK axis ('loop' would be more appropriate) should be more clearly featured as JAK inhibitors hold promise and feature in clinical trials for treating patients with intractable AA.…”

“…With regards to future therapies, greater emphasis could have been placed on re-establishment of IP, as the mechanism triggering IP collapse is important and I would like to add IGF-1 and tacrolimus as potential reagents to recover HF-IP. 5 The work by Rajabi et al 3 illustrates the complexity of AA pathogenesis for those unfamiliar with recent advances in the immunological, molecular and cellular understanding of this autoimmune disease and therefore is useful. To fully dissect how IP collapse contributes to AA development, genetically engineered mouse models, for instance a conditional knockout mouse enabling HF-specific downregulation of MHC class Ι with AA prone C3H/HeJ background, would be necessary.…”