Alopecia or pathological hair loss is different than the normal hair loss or hair fall that everybody has to a certain degree, specially as aging. The illness Alopecia if it is limited to a small patch or patches, mostly on scalp that can happen in other areas of the body as well, is called “Alopecia areata”. Alopecia that often is areata or localized as a small patch or patches and most often self-limited and improves, could also rarely lead to the total hair loss of the scalp that is called “Alopecia totalis”, or the total hair loss of the body, called “Alopecia universalis. (1)
Alopecia in its three types is an autoimmune disease, where the body immune system by mistake attacks its own hair follicles for wrongly being recognized as foreign. If there is no inflammation, scars or fibrosis at the site of alopecia areata, the condition is mostly reversible and self-limited, specially in children and adolescents. Alopecia like any other autoimmune diseases could be partly hereditary and runs more in the families with such history or other immune disorders. But like any other immune disorders or any so called “genetic disorders”, Alopecia can occur in anyone for the first time with no hereditary background history of any autoimmune disorders. So what would be the primary cause or trigger of “T cell lymphocytes” as the defenders of the body or our immune system to attack its own?! (2)
The secret behind Alopecia:
As it has been discussed in detail in other articles on autoimmune disorders such as MS (Multiple Sclerosis) and Diabetes Melitus Type 1 on this site, the trigger to the autoimmune disorders are external and caused by microbial invasions. Metabolic defects in the endogenous retinoids, a chemical compound that are vitamers of vitamin A and important in immune function and activation of tumor suppressor genes have been shown to play a key part in the pathogenesis of the alopecia areata. This defect is not only seen in alopecia but also in skin cancers as well. (3) Moreover other than the T lymphocytes, specially the interferon gamma (IFNG) and other T helper cells, cytokines and substance p, all important members of our immune system are involved in alopecia. (4-5)
While there is a well consensus among the experts in the autoimmune pathogenesis of Alopecia, the research has rarely gone behind the scene to identify the primary cause or enemy of our immune system that defects it so it attacks itself! This is despite many evidential reports since late 1940’s and 1950’s, confirming the link between different focal infections from parasitic Tineas to syphilis and fungal infections. (6-9) There have also been surprisingly early reports in 1950’s and 70’s of the reversal of alopecia areata with antibiotics. (10-11)
It was not until humans were hit largely and gravely by HIV (Human Immunodeficiency Virus), attacking our immune system at large and causing AIDS (Acquired Immunodeficiency Disease) that to only some degree we realized the extent of the damage to our being by the microbial invasions. AIDS as the term delineates and even lay people know it well, caused by a virus that knocks down all the immune system at large to the last day of life. The symptomatic manifestations of AIDS are all across the immune and autoimmune disorder domains, and could include different skin diseases such as alopecias of areata, totalis and even universalis types, through attacking our CD4 lymphocytes, helper T-cell lymphocytes, IFN-γ, IL-1, IL-2, IL-12, IL-18, TNF-α, other cytokines and the rest of our immune protecting agents.(12-15)
Soon other infections such as Cytomegalovirus and even hepatitis virus were linked with Alopecia and other autoimmune diseases. (16-17) By 1990’s, the epigenetic theory of autoimmune disorders such as Alopecia were proposed so that genetics alone were not causative of these maladies, but an interplay between the gene susceptibility and environmental factors, basically the microbial invasions. (16, 18-19) Certain polymorphisms in the genes regulating our immune system such as cytokines and HLA (Human Leukocyte Antigens) as susceptibility to different microbial invasions in causation of these autoimmune diseases including Alopecia were explained and documented. It was shown a high concordance rate of 55% among a sample of monozygotic twins, while 0% in fraternal twins, all inflicted with Alopecia areata, being linked to HLA class 2 typing and Cytomegalovirus infection. (19)
Finally over years conviction and popularity of enormous reports in the literature of the link between alopecia and infections, one of the most common human bacteria, Helicobacter pylori, the cause of peptic and gastric ulcer, seen in more than 50% of the world population was also linked to this condition among other autoimmune disorders. (20) There came reports of improvement of alopecia after eradication of the H.Pylori. Still to this day, infection after infection are adding to the list of assaulting agents causing alopecia among other autoimmune diseases. (21-22) There have also been reports of antibiotics reversing alopecia even the universalis type. (23)
The occurrence of more than one autoimmune disease has been reported as early as 1948, when Addison’s disease and diabetes mellitus and hypothyroidism were observed altogether. (24) Over time the associations of many autoimmune diseases together in different combinations such as alopecia, vitiligo, Addison’s disease, polyglandular autoimmune disease (PGA), acquired hypoparathyroidism, juvenile onset pernicious anemia, primary hypogonadism, insulin requiring diabetes or type 1, rheumatoid arthritis, autoimmune thyroid disease, Juvenile autoimmune polyendocrinopathies, systemic lupus erythematosus, Crohn’s disease and other inflammatory bowel diseases (IBD) including ulcerative colitis, and so many more were reported. (25-30) Some studies even reported alopecia as possible extraneous manifestations of the primary autoimmune disease, such as extra-intestinal manifestation of IBD, e.g. Crohn’s disease. (31-32)
In many of the above-mentioned research studies across time and globe, there have been footsteps of microbial invasions in the causation and pathogenesis of all autoimmune diseases including alopecias. As outlined earlier, the microbial invasions of different kinds find the susceptible victims with weak immune protection, such as defected HLA haplotypes invade the body and fooling the immune system to recognize wrongly their own as enemies and destroy its own tissues and organs. The weaker the immunity, the harsher attacks and invasions resulting in longer, irreversible or multiple organ damages.
As discussed in the case of other autoimmune diseases and cancers throughout this site, genetics or even genetic susceptibility are only means of transcription and inheritance, not causative factors. Again the environmental factors such as microbial invasions through mutations to our genomes causing such susceptibilities to different diseases that could be passed on to the next generations and look like the genetic is the cause or pathology. Most recently through a genetic association analyses of phenotypic variation in circulating white blood cell (WBC), such mutations and variations in causation of many autoimmune disorders has been shown. This unique exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies, identified 16 common variants associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Although some overlaps in the WBC variations caused by SNP (Single Nucleotide Polymorphism) mutation by microbial invasions were observed among different autoimmune and inflammatory disorders, some have specific variants.(33) This recent large study completing the previous GWAS (Genome Wide Association Studies) of while blood cells, the backbone of our immune system, is a major step forward to identifying the susceptible individuals to any of the common autoimmune and inflammatory diseases such as alopecias, and paving the path for the future preventions and treatment.
Alopecia either as a small patch or patches (areata), or total baldness or hair loss of the skull (tolalis), or the total loss of all body hairs (universalis) is known consensually to be an autoimmune disorder. This common autoimmune disorder could be acute and self-limiting, but it could relapse and turn to a chronic condition and advance from areata to totalis or universalis. It could also be comorbid with other autoimmune conditions, from a simple vitiligo (loss of the skin pigment) that can cover a few spots to the whole body, or other more serious autoimmune disorders such as inflammatory bowel diseases of Crohn’s and Ulcerative colitis, etc.
Therefore while reassuring the inflicted individuals that alopecia is mostly self-limited, but they have to be warned that is can progress to a chronic and also comorbid and more severe condition. More importantly it needs to be noted from the start that alopecia is an autoimmune disease, it could run in the family or will be heritable to the offspring.
While the autoimmune nature of alopecia like other autoimmune diseases are clear to many physicians and researchers, the origin of where, how and why the immune system of body instead of protecting self, attacking self has not been well explored and explained. Here in this article, I attempted such exploration and explanation briefly and revealed the role of microbial invasions on triggering such self-destruction of the human immunity so to cause autoimmune disorders such as alopecia. It seems that generation(s) ago, the microbes that could be of different types, like the Trojan horse enter the body, with or without an acute damage or footstep, cause some mutations in the genes of specific body tissue, in this case the white blood cells associated to the hair follicles. This gene mutation renders the offspring susceptible to the development of alopecia in this case, triggered by re-entry of the same microbe or a different one, stress or any other situation that precipitates an inflammatory process or weakening of the immune system. These different susceptibilities have well been shown in the phenotypic variations in our circulating white blood cells in a most recent genetic association meta-analysis. The hope is that soon the medical science will be able to identify these genetic variations, mutations and polymorphisms leading to genetic diseases such as autoimmune disorders including alopecia.
Dr. Mostafa Showraki, MD, FRCPC Lecturer, School of Medicine, University of Toronto, Author: “ADHD:Revisited” book adhdrevisited.com”/”medicinerevisited.com”
- Odom, Richard B.; Davidsohn, Israel; James, William D.; Henry, John Bernard; Berger, Timothy G.; Clinical diagnosis by laboratory methods; Dirk M. Elston (2006). Andrews’ diseases of the skin: clinical dermatology. Saunders Elsevier.
- Martinez-Mir, Amalia; Zlotogorski, Abraham; Gordon, Derek; Petukhova, Lynn; Mo, Jianhong; Gilliam, T. Conrad; Londono, Douglas; Haynes, Chad; Ott, Jurg; Hordinsky, Maria; Nanova, Krassimira; Norris, David; Price, Vera; Duvic, Madeleine; Christiano, Angela M. (2007). “Genomewide scan for linkage reveals evidence of several susceptibility loci for Alopecia areata”. The American Journal of Human Genetics. 80 (2): 316–28.
- Duncan, F Jason; Silva, Kathleen A; Johnson, Charles J; King, Benjamin L; Szatkiewicz, Jin P; Kamdar, Sonya P; Ong, David E; Napoli, Joseph L; Wang, Jinshan; King, Lloyd E; Whiting, David A; McElwee, Kevin J; Sundberg, John P; Everts, Helen B (2012). “Endogenous Retinoids in the pathogenesis of Aloepcia areata”. Journal of Investigative Dermatology. 133 (2): 334–43.
- Hoffmann R. J. The potential role of cytokines and T cells in alopecia areata. Investig Dermatol Symp Proc. 1999 Dec; 4(3):235-8.
- Siebenhaar F, Sharov AA, Peters EM, Sharova TY, Syska W, Mardaryev AN, Freyschmidt-Paul P, Sundberg JP, Maurer M, Botchkarev VA. Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata). J Invest Dermatol. 2007 Jun; 127(6):1489-97.
- Carrasco CM. The athlete’s foot from the scalp of adults, a case report of cicatricial alopecia. Gaz Med Port. 1949 Jan-Mar;2(1):123-7.
- Knierer W. Circumscribed alopecia following furunculosis. Dermatol Wochenschr. 1950;122(27):654.
- Strauch JH. Coexisting tinea capitis and alopecia areata. Arch Derm Syphilol. 1950 May;61(5):863-4.
- Perin L, Sissmann R, Vieu JF. Small multiple alopecia and syphilitic roseola. Bull Soc Fr Dermatol Syphiligr. 1951 Nov-Dec;58(5):484-6.
- Lotte F. Diffuse alopecia as first manifestation of a secondary syphilis; original occurrence cured by penicillin ointment. Bull Soc Fr Dermatol Syphiligr. 1956 Mar-Apr;(2):138-9.
- Cöster C, Tyrenius A. Reversible hair loss with nitrofurantoin treatment. Lakartidningen. 1971 Jun 21;68(30):3366. S
- Staughton R. Skin manifestations in AIDS patients. Br J Clin Pract Suppl. 1990 Sep;71:109-13.
- Ruiz-Rodriguez R, Longaker M, Berger TG. Anetoderma and human immunodeficiency virus infection. Arch Dermatol. 1992 May;128(5):661-2.
- Stewart MI, Smoller BR. Alopecia universalis in an HIV-positive patient: possible insight into pathogenesis. J Cutan Pathol. 1993 Apr;20(2):180-3.
- Taisuke I. Recent advances in the pathogenesis of Autoimmune hair loss disease, Alopecia Areata. Clin Dev Immunol. 2013.
- Skinner RB Jr, Light WH, Bale GF, Rosenberg EW, Leonardi C. Alopecia areata and presence of cytomegalovirus DNA. JAMA. 1995 May 10;273(18):1419-20.
- Paoletti V, Mammarella A, Basili S, Paradiso M, Di Franco M, De Matteis A, Musca A. Prevalence and clinical features of skin diseases in chronic HCV infection. A prospective study in 96 patients. Panminerva Med. 2002 Dec;44(4):349-52.
- Cork MJ, Crane AM, Duff GW. Genetic control of cytokines. Cytokine gene polymorphisms in alopecia areata. Dermatol Clin. 1996 Oct;14(4):671-8.
- Jackow C, Puffer N, Hordinsky M, Nelson J, Tarrand J, Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol. 1998 Mar;38(3):418-25.
- Magen E, Delgado JS. Helicobacter pylori and skin autoimmune diseases. World J Gastroenterol. 2014 Feb 14;20(6):1510-6.
- Bhardwaj EK, Trüeb RM. Acute diffuse and total alopecia of the female scalp associated with borrelia-infection. Int J Trichology. 2015 Jan-Mar;7(1):26-8.
- Nadesalingam K, Goodfield M, Emery P. Halo naevi, vitiligo and diffuse alopecia areata associated with tocilizumab therapy. Oxf Med Case Reports. 2016 Aug 9;2016(8):omw027.
- Kartal ED, Alpat SN, Ozgunes I, Usluer G. Reversible alopecia universalis secondary to PEG-interferon alpha-2b and ribavirin combination therapy in a patient with chronic hepatitis C virus infection. Eur J Gastroenterol Hepatol. 2007 Sep;19(9):817-20.
- Bernstein DE. Diabetes mellitus followed by Addison’s disease and hypothyroidism, simulating panhypopituitarism. J Clin Endocrinol Metab. 1948 Aug;8(8):687-93.
- Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981 Sep;60(5):355-62.
- Brun JM. Juvenile autoimmune polyendocrinopathy. Horm Res. 1982; 16(5):308-16.
- Al-Rawi Z, Al-Shaarbaf H, Al-Raheem E, Khalifa SJ. Clinical features of early cases of systemic lupus erythematosus in Iraqi patients. Br J Rheumatol. 1983 Aug;22(3):165-71.
- Goddard CJ, August PJ, Whorwell PJ. Alopecia totalis in a patient with Crohn’s disease and its treatment with azathioprine. Postgrad Med J. 1989 Mar;65(761):188-9.
- Seibold F, Klein R, Jakob F. Polymyositis, alopecia universalis, and primary sclerosing cholangitis in a patient with Crohn’s disease. J Clin Gastroenterol. 1996 Sep;23(2):121-4.
- Sobolewska-Włodarczyk A(1), Włodarczyk M(2), Fichna J(3), Wiśniewska-Jarosińska M. Alopecia areata in patients with inflammatory bowel disease: an overview. Folia Med Cracov. 2016;56(1):5-12.
- Ganzetti G, Campanati A, Offidani A. Alopecia Areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis. 2012 Oct;6(9):962-3.
- Patel KV, Sanderson JD, Irving PM. Alopecia areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis. 2013 Nov;7(10):e503.
- Tajuddin SM, et al. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet. 2016 Jul 7;99(1):22-39.