Introduction:

The world even the medical filed are all terrified by the cancers, while the autoimmune disorders are more prevalent across the globe. While the incidence of all cancers world wide is about 17 millions cases in 2018 that makes it .22%, the prevalence of only very common autoimmune disorders is over 3.45% or over 266 millions internationally, making them more than 15 times prevalent than the cancers. (1-2) The common autoimmune disorders that to some including physicians might not be recognized as such diseases in the above estimate of prevalence (with an average prevalence per 100,000 in brackets) are as follow: Diabetes type 1 in all ages (946); Hypo- and Hyper-Thyroidism (691); Rheumatoid Arthritis (381); Ulcerative Colitis (378); Crohn’s Disease (225); Psoriasis (197); Multiple Sclerosis (182); Uveitis (149); Polymyalgia Rheumaica (112), Celiac Disease (50); Sjogren Disease (48); Chronic active Hepatitis (45); SLE (Systmeic Lupus Erythematosus) (32); Vilitigo (29); Systemic Sclerosis (23); Alopecia (21); Addison’s Disease (18); Myasthenia Gravis (18); Primary Billiary Cirrhosis (12); and Systemic Vasculitis (10). (1)

 As discussed in a few articles on different cancers such as breast, prostate, ovarian and endometrial, lung, colorectal, skin cancers and leukemia on this site, cancers are mostly epigenetic than genetic (3-10). Of the epigenetic factors, microbial invasions are the frontiers on the assaults and causation of different cancers. The epigenetic factors such as infections as part of their offensive strategies, weaken the defensive power of the targeted organ, causing dysplasia, polyps or other benign forms of tumours before progressing to malignant cancers that are the killers of the assaulted organs. In a relatively similar process, autoimmune disorders are caused by epigenetic factors including microbial invasions. While cancers are localized assaults, autoimmune disorders are more generalized attacks of epigenetics to our living system.

 

It is not yet very clear to our scientific strive to differentiate at the onset of the invasion which disease will ensue at the end. It seems so far to our limited knowledge that the pathogeneses of either cancers or autoimmune disorders, or the impact of what organ or system of the body are multi-factorial. This depends on the invader, what organ or system it attacks or what is its specialty, and also on the condition of the targeted organ or body system. The control of the invaders is by avoidance (e.g. too much exposure to the sun in skin cancer), prevention (e.g. vaccinations when possible and available), early recognition of he early stages of the attack and recovery (e.g. surgical removal of polyps or benign tumours). But more importantly is the fostering of our body system to be more immune and protective against such invasions that are all around us and often could not be avoided. This strategy is about reinforcing our immune system that is perhaps the major defense against autoimmune disorders (3-15).   

 It is suspected that the incidence of autoimmune disorders are on the rise that could be due more to our less defensive immune system than the stronger environmental factors such as microbial invasions. It also seems that single autoimmune diseases are rising up to multiple autoimmune diseases or syndromes. This makes the hypothesis of increasing the rate of autoimmune disorders due to our poorer immune system seem more right as multiple autoimmune syndromes occur more in the subjects with less defensive or weaker immune system. In this article through a search into our available scarce knowledge data on this growing monster, I will attempt to bring these syndromes and their pathogenesis more to the light of recognition and hope to the arena of prevention (16-18).

 

Humans: More Knowledge, More Tools, More Vulnerable:

For the sake of simplicity and unified terminology with the rest of the field, the term of Multiple Autoimmune Syndrome (MAS) for any multiple autoimmune disorders that occur together in a person. The condition is so on the rise due to our defenseless immune system that the expert consider MAS when there are three or more of autoimmune disorders clamp together in an individual. About 25 percent of patients with autoimmune diseases have a tendency to develop additional autoimmune disorders. Surprisingly for whatever reason, MAS often involves one dermatological or skin condition such as alopecia, vitiligo or psoriasis (19).

 For long and before the discovery of MAS, the medical field was acknowledged of a few systemic autoimmune disorders, spreading to more than one organ of the body, and the most commonly known is SLE (Systemic Lupus Erythematous) that is a progression from skin lupus but spread beyond to the joints and more. Later on in the course of the history of medical knowledge, we recognized more concurrent autoimmune diseases in autoimmune hepatitis autoimmune bowel diseases, e.g. ulcerative colitis and crohn’s disease. Association of skin autoimmune diseases such as vitiligo and alopecia in MAS is another important and significant observation that could one day lead us to more understanding of the pathogenesis of these metastatic autoimmune disorders. Moreover on the epigenetic or the invader’s front, some such as cytomegalovirus by producing multiple autoantibodies are capable of spreading into different organs and causing MAS (20-21).

 

Epigenetic factors mostly microbial invasion by invading an immunologically weakened or vulnerable body, mainly in an early age, as discussed in other posts here (e.g. Autoimmune Disorders, Diabetes Melitus), deceives the immune system to produce HLA (Human Leukocyte Antigen) against different body tissues and organs and cause autoimmune disorders. Many autoimmune disorders that co-occur in MAS, that is on the rise, share the same type of HLA, which is an evidence their common pathway(s) in the host, the epigenetic source or both (22-24).    

While there are 18 DR isotopes of HLA, HLA-DR 1-18, only four are mostly associated with autoimmune disorders as following:

HLA-DR 1: Rheumatoid Arthritis (RA, Seropositive); Systemic Sclerosis, Crohn’s and Ulcerative colitis; Lichen Planus; Nephritis (Tubulointerstitial); Pemphigus (Foliaceous); Psoriasis (Vulgaris); Papilomatosis (Respiratory); Myasthenia (Penicillamine-induced); & Uveitis (Tubulointrestitial).

HLA-DR 2: Autoimmune Hepatitis, Primary Billiary Cirrhosis; Multiple Sclerosis.

HLA-DR 3: Juvenile Diabetes; SLE (Systemic Lupus Erythematous); Myasthenia Gravis; Sclerosis (Bout onset Multiple); Hashimoto’s Thyroiditis & Grave’s Thyroiditis or Disease, Addison’s Disease.

HLA-DR 4: Alopecia; Vitiligo; Hypertrophic cardiomyopathy; Juvenile Rheumatoid Arthritis; IgA-mediated nephropathy; Pemphigus Vulgaris; systemic Scelrosis(25-35).

 

On the host side, viral infections such as Epstein-Barr and Cytomegalo viruses are the invaders triggering the production of common HLAs, mostly the same DR isotopes to lead to co-occurrence of autoimmune disorders or MAS. There are three principal types of MAS, based on the co-occurrence of the autoimmune disorders as follow:

Type 1 MAS: Myasthenia Gravis; Thymoma; Polymyositis; Giant Cell Myocarditis.

Type 2 MAS: Sjogren’s Syndrome; SLE; Rheumatoid Arthritis; Primary Biliary Cirrhosis; Scleroderma; Autoimmune Hypothyroidism.

Type 3 MAS: Sjogren’s Syndrome; Myasthenia Gravis &/or Thymoma; Addison’s Disease; Type 1 Diabetes Melitus; Autoimmune Haemolytic Anaemia; Pernicious Anaemia; ITP; Autoimmun Hypothyroidism; Dermatitis Herpetiformis(25-36).

The primary function of HLA-DR in general is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Increased abundance of DR ‘antigen’ on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation. HLA-DR is most responsible for graft rejections within the first six months, while HLA-B responsible for such reaction within the first two years, and HLA-A could protect help the long-term survival of the grafts. Therefore HLA-DR is on the forefront of immune stimulation and defense of the body, that at times is defeated by the strong microbial antigens at the face of a weak immune system, so involved in several autoimmune conditions, disease susceptibility and disease resistance. HLA-DR is also closely linked to HLA-DQ physically on the HLA region of the chromosome 6 and also functionally in our immune system and in autoimmune disorders. Moreover HLA-DR among all HLA isotopes is evolutionary in humans and generally have evolved through the process of gene conversion or evolution. In this evolution HLA-R has formed new alleles, and frequently new functionally different DR Isoforms. Many of HLA isotopes in humans since his evolution have undergone fixation within the last 600,000 to 100,000 years except the HLA-DR with variants in different racial populations (37-38).

 HLA-DR1 that is involved in many autoimmune disorders and in MAS is also an antigenic response to the common human viral infections such as different strains of influenza, from the Spanish flu of 1918 to the modern H1N1 strain, and the new Caledonia/20/99 virus. The HLA-DR1-positive humans that have been previously exposed to H1N1 influenza virus may have circulating CD4 T cells (T-helper immune cells defending again foreign invasions such as viruses) that recognize and can be activated by confrontation with different strains H5 or H2 of influenza virus (39-41). Influenza in its different strain is mostly an acute respiratory infection and any of its complications, if the afflicted individual survives, could not be observed in short period. But if the immune system is weak or aged like in old people, the virus through invading the immune system and releasing HLA-DRs or antigen against the body own tissues and cells could cause in a longer-term autoimmune diseases, such as Waldenstrom’s macroglobulinemia, angioimmunoblastic lymphadenopthy, multiple myeloma, amyloidosis and certain autoimmune diseases, that occur in old people much more frequently than in the young (42). In immune weak population even influenza vaccinations have been shown to cause autoimmune diseases, e.g. autoimmune hepatitis (43). Moreover the more immediate and direct burden of influenza in susceptible population could be myocarditis and encephalitis (44). Experimental studies have also shown that the injection of influenza A virus grown in human pancreatic cells could cause pancreatitis and diabetes in animal models (45).  

 

Another common human’s viral infection is Epstein-Barr virus (EBV) infects B cells and ~95% of adults are infected, through binding of the toxin or the glycoprotein (gp42) of the virus to HLA-DQ and HLA-DR (46-47). EBV has also been shown to trigger autoimmune thyroid and liver diseases (48-49). This common human virus is also heavily involved in Systemic Autoimmune Diseases (SADs) such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren’s syndrome (SS) (50). Influenza and EBV are very common viral infections, but other common and less common viruses, e.g. cytomegalovirus (51-54), coxsackie virus (55-56), HIV (57-58), Hepatitis virus (59-63), and many more. Adding other microbial invasions such as bacteria in the causation of autoimmune disorders including MAS would be a staggering list, that needs to awaken us of the dangerous natural environment we live in, while it could be symbiotic(64-68)!

 

Conclusion:

Autoimmune diseases seem to be on the rise and more common than cancers and haunting us more. As cancers spread or metastasize when not discovered and treated early, the autoimmune diseases seem to be so. A very well known for long type of autoimmune disease that disseminate is Systemic Autoimmune Diseases (SADs) such as SLE (Systemic Lupus Erythematous), RA (Rheumatoid Arthritis) and Sjogren’s Syndrom that start from one tissue such as skin or joints then spread to other tissues and parts of the body. Although these systemic autoimmune diseases were known for long, almost for a century, we did not label and other SADs as such until more recently. In the same token is the Multiple Autoimmune Syndrome (MAS) that have existed for long, but we came to recognize them more recently as combination of more than two or three autoimmune diseases. Although we have classified MAS into three groups, but these are only arbitrary and any combinations could occur.

 The field of medicine knows relatively well the autoimmune pathogenesis of autoimmune disorders (e.g. the involvement of MHC and HLAs), though may not know well this in the etiology of cancers. But what we have not recognized well at least clinically to translate as educational material to the public is what triggers the HLAs to turn the immune system against itself and lead to autoimmune diseases, one or multiple within an individual. As detailed in this article, the etiology of autoimmune disorders is bi-factorial, and an end reaction to an internal vulnerable immune system of the host, and the environmental insults principally microbial invasions. The rise in the prevalence of autoimmune disorders globally, and the spread of some autoimmune diseases such as SLE and RA, and the rise of MAS, involving more than one or two of such diseases in one individual are evidence of more vulnerable hosts and more environmental invasions. Perhaps the future of medicine in this regard would be fostering our immune system and warding off or protecting us from the environmental insults such as prevention from microbial invasions.     

 

Dr. Mostafa Showraki, MD, FRCPC

Lecturer, School of Medicine, University of Toronto

Author: ADHD: Revisited Book

Adhdrevisited.com/medicinerevisited.com      

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