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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 263-266

A perspective on predictive markers of alopecia


1 Department of Psychiatry, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka, India
2 Yenepoya Research Centre, Yenepoya University, Mangalore, Karnataka, India
3 Department of Pharmacology, Yenepoya Pharmacy College and Research Center, Yenepoya University, Mangalore, Karnataka, India
4 Consultant Psychiatrist, Parmod Clinic, Chandigarh, India
5 Consultant Psychiatrist, Chandigarh, India

Date of Submission27-Aug-2020
Date of Decision28-Nov-2020
Date of Acceptance10-Dec-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Dr. Anil Kakunje
Department of Psychiatry, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_228_20

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  Abstract 


Hair is a primary characteristic of mammals and is an immune-privileged structure. Autoimmune attack of the hair follicle characterizes a disease called alopecia areata (AA), an auto-immune disorder, targeting the anagen-stage hair follicle. Erythroid differentiation regulator 1 is one of the presently investigated biomarkers for hair loss disorders. There are majorly two types of AA, namely diffuse and focal. Androgenetic alopecia (AGA) is a common androgen-induced progressive disorder, the pathways of which are regulated by local genetic codes and hormonal control. AA incognita is a type of diffuse hair fall with no confirmatory diagnostic test. AGA in women is a common pathology, the systemic inflammation in AGA has not been extensively studied, but it raises the possibility of identifying new cardiovascular risk factors among female patients with AGA. Other biomarkers for hair loss disorders are C-reactive protein, fibrinogen, VSH, tumor necrosis factor-α, and interleukin-6. This review attempts to give a perspective on the predictive markers of alopecia, their significance, and implications for future research.

Keywords: Alopecia, auto-immune disorder, biomarkers, hair


How to cite this article:
Kakunje A, Prabhu A, Pookoth R, Sindhu Priya E S, Karkal R, Kumar P, Gupta N. A perspective on predictive markers of alopecia. Arch Med Health Sci 2020;8:263-6

How to cite this URL:
Kakunje A, Prabhu A, Pookoth R, Sindhu Priya E S, Karkal R, Kumar P, Gupta N. A perspective on predictive markers of alopecia. Arch Med Health Sci [serial online] 2020 [cited 2021 Jan 17];8:263-6. Available from: https://www.amhsjournal.org/text.asp?2020/8/2/263/304718




  Introduction Top


Hair is a primary characteristic of mammals and exerts a wide range of functions. Hair follicle development takes place during fetal skin development and relies on tightly regulated ectodermal–mesodermal interactions.[1] It is an immune-privileged structure and the features responsible for this characteristic include the suppression of natural killer group-2 member D receptors found on the surface of natural killer cells and cytotoxic T-lymphocytes.[2] Autoimmune attack of the hair follicle characterizes a disease called alopecia areata (AA).[3] It is an auto-immune disorder with a transient, nonscarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair bearing sites. Patchy alopecia affecting the scalp is the most common type. AA affects nearly 2% of the general population at some point during their lifetime.[4] Autoimmune disorders such as atopy and autoimmune thyroiditis are well correlated with AA.[5] Interferon-α (IFN-α), interleukin (IL), and tumor necrosis factor-α (TNF-α) are the cytokines that are well known to play a major role in the pathogenesis of the disease, while several studies have shown that many more pathways exist.[6]


  Molecular Mechanisms Contributing to Alopecia Areata – Preclinical Evidence Top


IL-2 is a cytokine with leukocyte activating and regulatory properties. Mice that produce increased levels of IL-2 due to heterozygosity for IL-2 deletion gene were grafted with skin from mice affected with AA. Results indicated that 47% of the grafted animals developed AA against 88% in the wild subtype (homozygous) that is positive for IL-2 deletion. Due to the failure of activated leukocyte recruitment, AA resistance of IL-2–positive/negative mice is occurred, which points to an involvement of IL-2 in AA pathogenesis.[7] Genes that modulate AA causal are found to be located on human leukocyte antigen class II.[8] Biopsies of pretreatment lesional and nonlesional (NL) scalp and posttreatment (intralesional steroid injection) lesional scalp of six patchy AA patients using immunohistochemistry and gene expression analysis were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) showed, in the pretreatment lesional scalp (compared to NL), a significant increase (P = 0.05) in the expression of inflammatory markers (IL-2, IL-2RA, Janus kinase 3 [JAK3], IL-15, T helper type 1 [Th-1], Th-2, IL-12/IL-23p40, and IL-32). This study showed concurrent activation of Th-1 and Th-2 immune axes.[9] The experimental stress mimicking prolonged life stress exposure increased neurogenic inflammation-induced adaptive immunity cytokine imbalance, which was characterized by a shift to Th-1 cell cytokines and increased apoptosis of epithelial cells. [Table 1] shows the various factors involved in alopecia.
Table 1: Molecules involved in alopecia

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In C3H/HeJ mouse model for AA and heart tissue response to adrenocorticotropic hormone (ACTH) exposure, histology, immunohistology, qPCR, and ELISA are used to assess heart health. Both atrial and ventricular hypertrophy and increased collagen deposition were exhibited by mice with AA as compared to normal haired littermates. Significant increases in IL-18 (4.6 fold), IL-18 receptor 1 (IL-18r1; 2.8-fold), and IL-18 binding protein (IL-18bp; 5.2 fold) were recorded in the hearts of mice-bearing AA. IL-18 was found to be downregulated in acute AA compared to controls, while IL-18r1, IL-18bp and Casp 1 remained similar to that of chronic AA. Atria from chronic AA showed increased localization of IL-18 as indicated by immunohistochemical analysis. The levels of cardiac troponin-I (cTnl) were increased significantly in AA heart tissue as well as in serum. The release of cTnl into the culture medium was enhanced for both AA and control mice in a dose-dependent manner. It was concluded that in preclinical mouse models, AA is associated with molecular, biochemical, and genetic changes consistent with cardiac hypertrophy in response to ACTH exposure.[10]


  Molecular Mechanisms Contributing to Alopecia Areata – Clinical Evidence Top


During a stressful final examination period at three points in time (T) 12 weeks apart, 33 (18 exam appearing, 15 comparison) female medical students with comparable socio-biological status were analyzed. T1 was before the start of learning period, T2 between the 3-day written examination and an oral examination, and T3 after a 12-week rest and recovery from the stress of examination period. Time-wise comparison revealed that stress level Th-1/Th-2 cytokine balance and hair parameters changed significantly from T1 to T2 in the examination group and not in the control. Thus, in humans, neuralistic stress as perceived during participation in a major medical examination has the potential to shift the immune response to Th-1 and transiently hamper hair growth, but these changes stay within a physiological range.[11] Studies were conducted to investigate the putative role of erythroid differentiation regulator 1 (ErDr 1) in alopecia. Skin samples from patients with hair loss disorders (n = 21) and control subjects (n = 5) were evaluated to assess their expression levels of ErDr 1. Results revealed that expression of ErDr 1 was significantly downregulated in the epidermis and hair follicles of patients with hair loss disorders when compared to that in the control group. Hence, ErDr can be considered as a predictive biomarker for alopecia.[12] The genetic architecture of male pattern baldness using data from over 52,000 male participants of the UK Bio bank aged 40–69 years was explored. 250 independent loci with severe hair loss were identified. A prediction algorithm is developed based on common genetic variants which discriminated those with no hair loss from those with severe hair loss by splitting a cohort into a discovery sample of 40,000 and target sample of 12,000.[13] Features of balding scalp have high levels of potent androgen dihydrotestosterone and increased expression of androgen receptor gene. To determine if the androgen receptor gene is associated with male pattern baldness, allele frequencies of androgen receptor gene polymorphism (Stul restriction fragment length polymorphism and two triplet-repeat polymorphisms) in cases with cosmetically significant baldness (54 young and 392 older men) and 107 older men as controls with no indication of baldness were compared. The androgen receptor gene Stul restriction site was found in 98.1% of the young bald men and in 92.3% of older balding men but in only 76.6% of nonbald men. These markers are very close to a functional variant that is a necessary component of the polygenic determination of male pattern baldness.[14]


  Causative Factors for Hair Loss Top


The causative factors of hair loss are broadly categorized into diffuse and focal hair loss. Nonscarring or scarring alopecia (cicatricial) is predominantly caused by focal hair loss. Conditions such as traction alopecia, tinea capitis, or trichotillomania may contribute to patchy nonscarring hair loss. Discoid lupus erythematosus is generally considered responsible for scarring alopecia. Male or female pattern hair loss or androgenetic alopecia (AGA) contributes to hair thinning and diffuse hair loss contributes to shredding of the hair.[15]

[Figure 1] shows a simple classification of hair loss, and [Table 2] shows distinguishing features of various alopecia causes.
Figure 1: Simple classification of hair loss

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Table 2: Distinguishing characteristics of alopecia types

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The pathways of AGA, a common androgen-induced progressive disorder, are regulated by local genetic codes and hormonal control. Thirty biopsies were taken from frontal (bald) area and occipital (hair-bearing) area of 15 male patients with AGA, and five specimens were taken from the frontal area of five age-matched controls. Perifollicullar lymphocytic infiltrate of the bald area showed significant expression of Bcl-2.[16] AA incognita (AAI) is a type of diffuse hair fall with no confirmatory diagnostic test. The UL 16 binding protein-3 (ULBP-3) is ligand for natural killer group 2, member D receptor. It is a key regulator of both innate and adaptive immune responses. ULBP-3 is turned off in case of normal hair follicles. However, its increased levels in AA have been reported by many studies.

Biopsy specimens from females suffering from AAI (n = 36), with FPHL (n = 15), with TE (n = 9) and healthy female controls (n = 10) were analyzed for the immunogenetic detection of ULBP-3 levels using qRT-PCR. AAI patient group showed statistically significant increase in the levels of ULBP-3 compared with FPHL, TE, and normal hair. Age and duration of the disease were positively correlated with this marker. Hence, this evidence suggest that ULBP-3 can be a predictive biomarker for the detection of AAI with further validation in larger cohorts.[17] A case of acute diffuse and total alopecia of the female scalp in a 65-year-old female was studied. Elevated thyroid peroxidase and thyroglobulin antibodies are reported, and vitamin deficiencies were also revealed upon laboratory investigations. The condition was associated with Borrelia infection and Vitamin D deficiency as specific constraints.[18]

Individuals with trichotillomania provided saliva sample for analysis of inflammatory cytokines. In addition, these participants were examined on a variety of demographic variables (including body mass index, previously found to relate to inflammation) along with clinical measures (symptom severity, functioning, and comorbidity). Thirty-one participants, with a mean age of 24.7 (±10.2) years and 27 (87.1%) being females were included. Compared to normative data, the mean inflammatory marker levels in the trichotillomania sample had the following Z-scores: IL-1β Z = -0.26, IL-6 Z = -0.39, IL-8 Z = -0.32, and TNF-α Z = -0.83. The relatively low level of inflammatory saliva cytokines observed indicates that evaluation of blood inflammatory levels in trichotillomania versus matched controls would be valuable in the future work.[19] AGA in women is a common condition with a low success rate of chemotherapeutics. The local inflammation is mainly responsible for the pathogenesis of the disease, therefore investigation into the anti-inflammatory markers/agents look promising in its treatment. A group of 30 female patients with AGA (age range of 30–60 years) and a control group of 30 patients without injuries of skin appendages were selected. To evaluate the systemic inflammation (C-reactive protein [CRP], fibrinogen, VSH, TNF-α, and IL-6), venous blood samples were collected between 8 and 9 a.m., 12 h after the last meal, the consumption of alcohol being prohibited for 24 h before collecting specimens. Statistically, CRP levels were significantly higher in the alopecia group compared to the control group (P = 0.05). No statistically significant differences were observed for the other analyzed parameters (P > 0.05). IL-6 and TNF-α were not correlated with any of the other inflammatory markers. This study has revealed the presence of a certain degree of systemic inflammation through high ESR and CRP values in the AGA group compared to the control group. IL-6, the serum TNF-α, and AGA in women could not be correlated.[20]


  Conclusion Top


Hair loss is a common problem worldwide, and molecular mechanisms underlying the condition need to be elucidated to develop newer drug targets. Although genetic and environmental causes are considered as the predominating factors in its development, the actual causes with established mechanistic insights are still lacking. This review attempts to pave an insight into the possibility of indicating different cytokines and genetic and immune markers as predictive markers of hair loss, which can be exploited further for advances in diagnostic and therapeutic perspectives.

Acknowledgment

The authors would like to acknowledge the financial grant from Indian Association of Private Psychiatry for the IAPP project titled 'Association of valproic acid levels, biotinidase activity, and hair loss in Indian population'.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132-42.  Back to cited text no. 1
    
2.
Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol 2017;8:1124.  Back to cited text no. 2
    
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Jabbari A, Cerise JE, Chen JC, Mackay-Wiggan J, Duvic M, Price V, et al. Molecular signatures define alopecia areata subtypes and transcriptional biomarkers. EBioMedicine 2016;7:240-7.  Back to cited text no. 3
    
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Pratt CH, King LE Jr. Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primers 2017;3:17011.  Back to cited text no. 4
    
5.
Darwin E, Hirt PA, Fertig R, Doliner B, Delcanto G, Jimenez JJ, et al. Alopecia areata: Review of epidemiology, clinical features, pathogenesis, and new treatment options. Int J Trichology 2018;10:51-60.  Back to cited text no. 5
    
6.
Ito T. Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. Clin Dev Immunol 2013;2013:348546.  Back to cited text no. 6
    
7.
Gregoriou S, Papafragkaki D, Kontochristopoulos G, Rallis E, Kalogeromitros D, Rigopoulos D, et al. Cytokines and other mediators in alopecia areata. Mediators Inflamm 2010;2010:928030.  Back to cited text no. 7
    
8.
Barahmani N, de Andrade M, Slusser JP, Wei Q, Hordinsky M, Price VH, et al. Human leukocyte antigen class II alleles are associated with risk of alopecia areata. J Invest Dermatol 2008;128:240-3.  Back to cited text no. 8
    
9.
Freyschmidt-Paul P, McElwee KJ, Hoffmann R, Sundberg JP, Kissling S, Hummel S, et al. Reduced expression of interleukin-2 decreases the frequency of alopecia areata onset in C3H/HeJ mice. J Invest Dermatol 2005;125:945-51.  Back to cited text no. 9
    
10.
Peters EMJ, Müller Y, Snaga W, Fliege H, Reißhauer A, Schmidt-Rose T, et al. Hair and stress: A pilot study of hair and cytokine balance alteration in healthy young women under major exam stress. PLoS One 2017;12:e0175904.  Back to cited text no. 10
    
11.
Woo YR, Hwang S, Jeong SW, Cho DH, Park HJ. Erythroid differentiation regulator 1 as a novel biomarker for hair loss disorders. Int J Mol Sci 2017;18(2):316.  Back to cited text no. 11
    
12.
Hagenaars SP, Hill WD, Harris SE, Ritchie SJ, Davies G, Liewald DC, et al. Genetic prediction of male pattern baldness. PLoS Genet 2017;13:e1006594.  Back to cited text no. 12
    
13.
Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol 2001;116:452-5.  Back to cited text no. 13
    
14.
Wang E, Chong K, Yu M, Akhoundsadegh N, Granville DJ, Shapiro J, et al. Development of autoimmune hair loss disease alopecia areata is associated with cardiac dysfunction in C3H/HeJ mice. PLoS One 2013;8:e62935.  Back to cited text no. 14
    
15.
Mounsey AL, Reed SW. Diagnosing and treating hair loss. Am Fam Physician 2009;80:356-62.  Back to cited text no. 15
    
16.
El-Domyati M, Attia S, Saleh F, Bassyouni M, Barakat M, Abdel-Wahab H, et al. Evaluation of apoptosis regulatory markers in androgenetic alopecia. J Cosmet Dermatol 2010;9:267-75.  Back to cited text no. 16
    
17.
Moftah NH, El-Barbary RA, Rashed L, Said M. ULBP3: A marker for alopecia areata incognita. Arch Dermatol Res 2016;308:415-21.  Back to cited text no. 17
    
18.
Bhardwaj EK, Trüeb RM. Acute diffuse and total alopecia of the female scalp associated with borrelia-infection. Int J Trichology 2015;7:26-8.  Back to cited text no. 18
    
19.
Grant JE, Chamberlain SR. Salivary inflammatory markers in trichotillomania: A Pilot study. Neuropsychobiology 2017;76:182-6.  Back to cited text no. 19
    
20.
Sarac F, Brihan I, Micle O, Sava M. Inflammatory markers in androgenetic alopecia in women. Dermato-Venerol 2018;63:7-11.  Back to cited text no. 20
    


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