Alopecia and Periodontitis: Exploring the connecting dots

Abstract

Alopecia areata is a systemic disease with nonscarring hair loss from the scalp, face, or any part of the body. The disease with undetermined etiology and pathogenesis has a considerable impact on the social life of patients which gradually builds up stress and expedites further deterioration of their condition. Interestingly, in such patients, besides stress-relieving exercises and immunomodulators, well-timed dental assessment and prompt treatment have contributed to improving the prognosis of alopecia. This depicts an interrelationship between alopecia and oral foci of infections. Over the past few decades, periodontitis has remained to be one of the predominant forms of oral focus of infection for systemic diseases. The present review throws light on the role of stress and autoimmunity in establishing a possible correlation between alopecia and periodontitis. It is augmented with documented case reports, demanding a complete oral examination in patients with the unexplained origin of alopecia. An interdisciplinary approach is the need of the hour which can prevent the progression of both the diseases as well as other oral infections.

INTRODUCTION

The evidence-based medicine in the present aeon is largely substantiated by various reports determining the role of oral foci in causing systemic diseases. Customarily, a broader term “oral primary foci” was introduced to include a vast number of oral diseases such as periodontitis, dentoalveolar abscesses, partial or complete pulpal necrosis, cellulitis, and metastatic spread of the microbes leading to various sequelae of pulpal and periodontal pathosis of graded severity.^[1] These conditions are considered to be among the multiple predisposing factors leading to different systemic conditions and associated complications.^[2] Currently, periodontitis has established itself as one of the predominant forms of oral focus of infection for systemic diseases.

Being a complex infectious disease in nature, periodontitis stems from the interplay of bacterial infection and the host’s response to it, further modified by genetic susceptibility, environmental, and acquired risk factors. It is one of the most common oral infections in India with a prevalence rate of 67.7%, 89.6%, and 79.9%, respectively, among the 15-, 35–44-and 65–74-year age groups, whereas the worldwide onus of this sixth most prevalent disease escalated by 57.3% since the past three decades.^[3,4]

It is primarily a Gram-negative anaerobic infection springing in rigorous inflammation, with a probable vascular spread of the microbiota and their virulent factors systemically thus producing a cascade of immune reactions at the cellular level. Apart from this, most of the research indicates the presence of antibodies to host components (mainly collagen), double-stranded DNA, and aggregated IgG in peripheral blood samples, gingival biopsies, and gingival crevicular fluids, suggesting the role of autoimmunity in periodontitis.

Autoimmunity is a double-edged sword in the sense that its exaggerated response leads to the destruction of the cell, at the same time, it has a protective role too (anti-idiotype antibodies). Its role in the etiopathogenesis of periodontitis was initially posited by Brandtzaeg and Kraus in 1965.^[5] Since then, this whole concept and its associations with other probable autoimmune diseases are intriguing.

Alopecia areata (AA) is one of the most common autoimmune conditions one comes across in today’s stressful world. It usually begins with well-demarcated round-to-oval bald patches on the scalp which may progress to grievous manifestations such as alopecia totalis (absolute hair loss exclusively from the scalp) or alopecia universalis (deprivation of hair in toto). Although this disease is not fatal, it has a devastating effect on the emotional health of the patient. It becomes difficult for them to cope with the new appearance and thus their social life gets inhibited.

AA is also known as “pelade” or “area celsi” as recognition to Cornelius Celsus, who outlined two variants of alopecia depending on the affected age group-one in any age group whereas the second is exclusively in children. The original term “AA” was first used by Sauvages in 1760. Later in the 1800s, two theories evolved based on:

1. Parasitic infection (Gruby 1843 and Radcliffe-Crocker 1903)
2. Nervous disorder (Von Barensrung 1858).

Interestingly, Jacquet in 1902 noticed flawed and unhealthy teeth as the nerve irritants which triggered AA. This fact was established by Decelle in 1909. Over the period of time, newer associations were seen with AA such as endocrinal disorders (mainly thyroid), hormonal disturbances, noxious agents, and syphilis, all of which presented unforeseen, swift, patchy hair loss similar to AA (Ormsby 1948 and Roxburgh 1950) before the evolution of relatable lesions.^[6,7]

The lifetime incidence of AA is shown to increase from 1.7% in the early 1970s to 2.1% in the 1990–2009 epidemiological report, while the prevalence is reported to be around 0.1%–0.2% worldwide.^[8,9]

Till date, this disease is known to be linked with a number of contemporaneous diseases counting mental illnesses such as depression or anxiety, and other autoimmune diseases such as lupus, psoriasis, atopic dermatitis, rheumatoid arthritis, and lichen planus, but the exact etiology is still unknown.^[10]

The present review has thrown light on the possible interrelationship of periodontitis and other dental infections with AA as they have a common factor of autoimmunity and foci of infection, thus demanding in-depth knowledge of the various underlying mechanisms to comprehensively investigate the correlation between them.

AUTOIMMUNE MECHANISM OF ALOPECIA

Multiple observations suggest alopecia to be a tissue-specific autoimmune disease as it has a localized disease pattern contradictory to other systemic involving diseases such as lupus and autoimmune thyroiditis. Lymphocytic interpolate in and around the hair follicles (HFs) is the key feature of AA, depicted histologically, mainly consisting of CD4+ and CD8+ T-lymphocytes of Th1 cytokine bias.^[11]

Humans, as well as mice, have an ongoing peculiar phenomenon in their body defense known as “immune privilege” (IP), which is a protective mechanism to guard some of our vital organs of finite regenerating capacity.^[12] HFs are one of the important immune-privileged sites apart from eyes, placenta, testes, and central nervous system. The mechanism behind this concept as shown in Figure 1, is that the epithelial lining of nether(lower) HFs desist from expressing major histocompatibility complex (MHC) Class I and II molecules, in turn decreasing the abundance of antigen-presenting cells such as Langerhans dendritic cells.^[13] IP guardians such as alpha-melanocyte-stimulating hormone, transforming growth factor-β, insulin-like growth factor 1, calcitonin gene-related peptide (CGRP), interleukin (IL)-10, and somatostatin are also produced by the HFs to repress MHC expression, which in due course inhibits macrophages thus suppressing interferon-gamma (IFN-ɤ) production.^[14,15]

Figure 1: The main mechanisms of immune privilege preservation and disruption in normal hair follicles.^{[ 13–19 ]} IL-10 – Interleukin-10; TGF-beta – Transforming growth factor-beta; IGF-1 – Insulin-like growth factor 1; CGRP – Calcitonin gene-related peptide; IFN-gamma – Interferon-gamma; HLA-DR – Human leukocyte antigens-DR; alpha-MSH – alpha-melanocyte-stimulating hormone; IP – Immune privilege; MHC – Major histocompatibility complex; ICAM – Inter cellular adhesion matrix; MICA – Major histocompatibility complex class I chain-related gene A; CXCLS – Chemokine (C-X-C motif) ligand; CD – Cluster of differentiation

“Immune privilege” disruption in alopecia areata

AA is mainly believed to be a result of the collapse of this immune-saving phenomenon where the peribulbar area of HFs depicted the presence of lymphocytes, dendritic cells, and NK cells and a greater expression of MHC Class I and II.^[11,16] The level of IP guardians presumably falls and an upregulated MICA, chemokines (CXCLs), intercellular adhesion molecules (ICAM 2 and 3), and IFN-ɤ were evinced in AA lesions as explained in Figure 1.^[17,18]

IFN-ɤ is a potent inducer of these aforementioned receptors as well as MHC I and II. CD8+ cells under the influence of IFN-ɤ, impels human leukocyte antigens (HLAs)-DR on the affected HFs to bring out a subsequent wave of CD4+ cells.^[19] The role of ICAM is also noteworthy as they concentrate the lymphocytes at the inflammatory sites.

ROLE OF STRESS IN ALOPECIA

Stress is defined as physiological and metabological perturbations caused by various aggressive agents and the psychophysiological response of an organism facing the perception of a challenge or a threat. It is an adaptable key factor that poses a threat to both mental and physical ailments.^[20]

It is true that almost everyone experiences stress but not all lose their hair, it is the genetic makeup that differentiates these individuals. About 2.1% of the world’s population have associations with HLA-DR and HLA-DQ and mutation in the AIRE (autoimmune regulator) gene, making the individuals more susceptible to inflammatory cascade and subsequent hair fall. Stress may not always be the causative factor of AA but acts as a trigger, misguiding the immune system to attack its own HFs.^[21] Numerous studies have reported the exacerbation of AA due to stress, ranging from 6.7% to 96%, thereby playing an influential role in the immunopathology of AA.^[22,23]

A possible explanation to understand the pathogenesis of stress in AA is through the “neuroendocrine-immune axis” which is a collection of “hypothalamus–pituitary–adrenal axis” in the skin and web of nerve fibers around the HFs.^[24] Immunoregulatory neuronal signaling molecules, such as substance P, corticotropin-releasing hormone, nerve growth factor, and vasoactive intestinal peptide which are the stress advocates, cause a release of histamine along with other inflammatory cytokines tumor necrosis factor-alpha (TNF-a), IL-6, and IL-1 from mast cells. An augury of IP collapse is seen by the uprooted expression of Class I MHC on anagen HFs under the influence of substance P. Another immunomodulator CGRP plays an important role in the hair cycle as it is an effective inductor of vasodilation of skin vessels, thus deficit of it probably leads to constriction of vessels and exaggerated immune response which altogether has a key role in the focalization of AA.^[25,26]

AUTOIMMUNITY IN PERIODONTITIS

The exact etiopathogenesis of periodontitis has still remained unclear and the role of autoimmunity is still an arena to be explored well enough to draw final conclusions. Dental plaque is imperative in initiating periodontal disease but is not the sole determinant of its progression. The inflammatory process in the disease is a combination of innate and adaptive immunity, mainly mediated by T and B lymphocytes, neutrophils, monocytes, and macrophages. Innate immunity plays the primary defensive response to a bacterial attack by producing a cascade of proinflammatory cytokines such as IL-8 (produced by gingival fibroblasts and endothelial cells), IL-1, IL-6, macrophage inflammatory protein-1 alpha, and receptor activator of nuclear factor-κβ ligand (by pdl fibroblasts and neutrophils) which are the regulators of periodontal inflammation and alveolar bone resorption.^[27] Whenever the inflammation does not subside by innate immunity mechanisms, adaptive immunity comes into play. The microbial end products trigger the dendritic cells to deconstruct and submit the antigen on its surface through MHC Class II molecules which get identified by the CD4 T-helper cells. A sequence of events thus follows upon activation of these lymphocytes, leading to differentiation of the natural T-helper cells (Th0) into various subclasses – Th1, Th2, Th17, and regulatory T lymphocytes (Treg), and also extend a helping hand to B cells in producing distinct antibodies.

Probable reasons for a thorough look out into the concept of autoimmunity in relation to periodontitis.^[28–31]

1. Overexpression of nonantigen presenting cells, i.e., IgA
2. Modified roles of T helper and T suppressor cells
3. Excessive build-up of natural autoantibodies to B-cell stimulators such as bacterial lipopolysaccharide in dental plaque
4. A whimsy notion with regard to a web of anti-idiotype antibodies resembling the self-antigens, thus producing anti-idiotype antibodies (secondary antibodies) whose existence has no direct evidence in periodontitis as of now
5. The presence of bacterial and viral noxious agents in a periodontal pocket actuates the autoreactive T cells of the immune system
6. Genetic propensity of HLA to periodontal disease and various autoimmune diseases.

ROLE OF STRESS IN PERIODONTITIS

Psychological stress has usually been considered to be a prospective contributor to the pathogenesis of periodontitis. It shares a similar mechanism in periodontitis to that observed in alopecia as depicted in Figure 2. It leads to impaired sleep, depression, and dysregulated neuroendocrine as well as sympathetic nervous systems which activate the hypothalamus–pituitary–adrenal axis to release the immunomodulatory cytokines mainly IL-1 beta, TNF-a, and IL-6 which cause profound immunosuppression. This causes a decrease in the lymphocytic count and its proliferation, antibody generation in response to the activity of natural killer cells, and recrudescence of dormant viral infections thus increasing the susceptibility to infections eventually affecting the onset, duration, course, and progression of periodontal disease.^[32,33] Reduced bacterial clearance rate leads to delayed wound healing of oral mucosa and tissues.^[34]

Figure 2: Stress as a common factor in the pathogenesis of periodontitis and alopecia areata^{[ 25 , 26 , 32 , 33 ]}. ^VIP – Vasoactive intestinal peptide; ^CRH – Corticotropin-releasing hormone; ^IP – Immune privilege

EVIDENCE SUPPORTING CORRELATION OF ALOPECIA AREATA WITH ORAL FOCI OF INFECTION

1. Douki Nabiha in 2018 reported a case of complete remission of AA upon extraction of a pericoronitis-infected mandibular third molar tooth in a 47-year-old female patient. Thus, an association between the two disease entities is anticipated possibly due to common pro-inflammatory mediators.^[35]
2. Fatemi et al. in 2016 published a case report of a young male patient with a diagnosis of localized mild chronic periodontitis with AA and observed hair regrowth in the focal spot after complete periodontal treatment. This finding suggests a plausible role of periodontitis as an essential factor to be considered in the course and development of AA.^[36]
3. Dinkova et al. in 2014 emphasized on a case of AA originating from a dental focus in their report. In that, a 55-year-old female was examined to understand the possible etiology of alopecia. It was observed that only after the extraction of decayed and faulty root canal treated teeth, did the patient’s alopecic spots showed signs of hair regrowth. This finding strengthens the concept of focal infections playing a major role in the contribution to immunologic diseases.^[37]
4. Gil Montoya et al. in 2002 reported a case of AA in a 37-year-old male patient associated with an oral fistula apical to a central incisor with pulpal necrosis. The bald spots completely disappeared following root canal therapy suggestive of considering an insight into focal infections in alopecic cases to be important^[38]
5. Lesclous and Maman in 1997 observed a mechanical irritant (rather than bacterial) to be a triggering factor in AA. It was observed that a 35-year-old male patient who reported bilateral dull retromandibular pain in the jaws due to impacted mandibular third molars, had a complete remission of AA subsequent to the extraction of both the wisdom teeth.^[39]

DISCUSSION

Although the exact etiology of AA has not been completely established yet, there are many theories pursued to arrive at the nearest possible conclusion. While most of the published data emphasize an autoimmune cause depicting circulating autoantibodies and inflammatory infiltrates around the HFs, dental origin, or foci of infection linked to the origin of AA cannot be overlooked. The multidimensional interplay between the oral irritants (mechanical, chemical, or microbial) and the host protector cells brings about the advent of endogenic immunoinflammatory agents such as cytokines, kinins, complement fragments, neuropeptides, lysosomal enzymes, and fibrinolytic peptides dividing such immune responses into cell-mediated and antigen-antibody-mediated immune responses. Since some of the research reported the existence of immune complexes widespread in the systemic circulation (elementally in acute oral infections but also in AA), the dental origin of AA seems to be well supported.^[40]

However, there are few studies that show a different explanation for the dental origin of AA which is based on a trigeminal-sympathetic reflex mechanism. A distant mechanical or an infectious stimulus initiates a centripetal response comprising a triple-neuron system, whereas the centrifugal conduction involving the sympathetic nucleus in proximity to the terminal branches of the trigeminal nerve might impel vasoconstriction of the pilosebaceous follicle, stimulating multiple alterations with subsequent hair loss.^[39]

In the current scenario, where the prevalence of lifestyle diseases is at an all-time high, the role of stress in such idiopathic diseases cannot be understated. In terms of AA, along with the already described mechanisms, stress too has a major contribution. It acts as a common link between AA and periodontal as well as other dental infections.

Thus, AA requires a multicentric approach to arrive at a particular etiology, taking all the possible factors into consideration. However, the above evidence of case reports clearly supports the role of focal infection in the pathogenesis of the disease demanding an in-depth understanding of this pathway.

CONCLUSION

AA is a rare autoimmune disease with an undetermined cause yet many theories revolve around coming to a possible conclusion such as stress, focal infection, and autoimmunity involving destructive cells such as IL-1 alpha and beta and TNF-α. Various dental infections such as periodontitis are the ignitors of this inflammatory cascade which interrupt the synthesis of hair or promotes its destruction by hindering the cellular increase in a number of pilar follicles. This warrants the medical practitioner to have a consultation or a referral of such patients to the dental clinic. However, long-run clinical trials are needed to arrive at a final diagnosis.

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Conflicts of interest

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