(“I went to see an old woman with asthma, a customer at La Gioconda. The poor thing was in a pitiful state, breathing the acrid smell of concentrated sweat and dirty feet that filled her room, mixed with the dust from a couple of armchairs, the only luxury items in her house. On top of her asthma, she had a heart condition. It is at times like this, when a doctor is conscious of his complete powerlessness, that he longs for change: a change to prevent injustice of a system in which only a month ago this poor woman was still earning her living as a waitress, wheezing and panting but facing life with dignity. In circumstances like this, individuals in poor families who can’t pay their way become surrounded by an atmosphere of barely disguised acrimony; they stop being father, mother, sister or brother and become a purely negative factor in the struggle for life and, consequently a source of bitterness for the healthy members of the community who resent their illness as if it were a personal insult to those who have to support them….In those dying eyes there is a submissive appeal for forgiveness and also, often a desperate plea for consolation which is lost to the void, just as their body will be soon lost in the magnitude of mystery surrounding us.”)
Ernesto Che Guevara,
Asthma that is the narrowing of the airways of lung, causing difficulty in breathing with sound of wheeze, is a chronic disease often starts in childhood and is an interaction between the environmental allergens or pathogens and the individual lung’s susceptibility or genetic make up. This early onset asthma that often leads to asthma attacks, frightening the person and the relatives for the fear of inability in total breathing and death, is usually due to an allergic eosinophilic reaction of the lung airways, causing their narrowing due to thickness of their smooth muscle walls and also obstruction caused by reactive sputum (1-3).
But not all asthma is an allergic eosinophilic reaction of the lung airways and there is a heterogeneity even in the inflammatory asthma known and reported since 1922 by Huber and Koessler (4). It has been shown and reported that any problems with the lung function such as reduced its function even as early as infancy could lead to late on obstructive lung disease such as asthma (5-6). At the same time, having a history of allergy or atopic sensitization as long as not related to such sensitivity in the lung airways, it will not necessarily lead to asthma in childhood. (7) Following an epigenetic model of causation in asthma, the airway hyper-responsiveness or sensitivity or overwhelming the lung airways with too much dust mites, heavy smoking specially at an early age could prolong the childhood asthma into adulthood and also cause exacerbations and further attacks (8).
Other than the common allergic or eosinophilic asthma with an early onset in life and running a chronic course, microbial invasions of the lungs and respiratory airways, also contribute to asthma. There have been reports on neutrophilic and lymphocytic infiltrations of the lung airways among others causing the narrowing of the airways, hence asthma (9-10). Such infiltrations of other white blood cells even in the airways or sputum of allergic or eosinophilic asthma that for long thought to be due to T helper type 2 disease and as an allergic reaction, has more recently been shown to have an underlying immunologic susceptibility. This is the beginning of a new understanding of asthma and its genetic susceptibility as an immune or perhaps an early autoimmune disease (11-12).
Che Guevara: An Iconic Asthma Sufferer
Ernesto Guevara was an Argentine physician, who later on by his Cuban comrades was popularized as “Che”, meaning comrade or friend, and since then he has been known as Che Guevara. Before joining the Cuban revolution along with Fidel and Raul Castro and other guerillas, since he suffered from a severe asthma with frequent attacks from his childhood, causing him staying home sick often, he spent all his sick time reading a lot of everything from literature, poetry, philosophy, politics and else. He was also in love of photography and travelling, that his trip across South America, that he called one nation, on a motorcycle with his friend Alberto Granado, under the title of “The Motorcycle Diaries”, before his graduation from medical school and becoming a revolutionary, has been a popular book and film. Despite his severe asthma in his continental trip, he swam at night across Amazon river, a considerable distance of 4 kilometers (2.5 miles) when visiting and helping the lepers in a leper colony in Peru. He unlike the doctors and nurses in the colony, did not wear gloves to shake hands and touch the lepers, but bravely did so with his bare hands.
His thoughtful observation of the South American people in his nine months trip, struggling with poverty and oppression, made up his mind to be a revolutionary to free people of his continent from dictatorships who were franchises of American imperialism. “ I knewthat when the great guiding spirit cleaves humanity into two antagonistic halves, I will be with the people.” Returning home to Buenos Aires, after his adventurous and eye-opening motorbike trip, he finished his medical school and went back for another journey across different Latin Americas countries that he had not the chance to visit the first time. Through these trips that evolved his revolutionary mind, and learning about the only revolutionary efforts happening in Cuba, he set out for Mexico to join these revolutionaries in exile, where for the first time he met Castro and his comrades. Setting out with 82 men, on the “Granma” boat from Mexico back to Cuba, everyone was lost in a surprise attack by the Batista regime, except the 22 survivors including Che, who started the Cuban revolution.
After the success of the revolution and a few years working in different posts for the new Government, and despite the disagreement of his wife, and Cubans, including Castro, he set out to the rest of the world, first Africa then Bolivia for assistance in their struggles for freedom. “Above all, always be capable of feeling deeply any injustice committed against anyone, anywhere in the world. This is the most beautiful quality in a revolutionary”. Jean Paul Sartre and his wife Simon Bolivar, the influential French philosophers and writers who visited Cuba after the revolution a few times, called Che Guevara “the most complete human being of our age.”
After failing his revolutionary venture in Bolivia, he was captured by the Bolivian army with the aid of American CIA and executed right away without any trials at an early age of 39, on October 9, 1967. After his execution, his body was lashed to the landing skids of a helicopter and flown to nearby, Vallegrande, where his body was laid on a concrete slab for identification and viewing of the locals, who believed him looking like Jesus Christ, and some clipped locks of his hair as divine relics. A declassified memorandum on October 11, 1967 to the time US president Lyndon Johnson from his National Security advisor called the decision to kill Che Guevara “Stupid, but understandable from a Bolivian standpoint”! Some of Che’s belongings are still on display at the CIA.
After a military doctor amputated his hands, Bolivian army officers transferred Guevara’s body to an undisclosed location and refused to reveal whether his remains had been buried or cremated. The hands were sent to Buenos Aires for fingerprint identification. They were later sent to Cuba. On October 15 in Havana, Fidel Castro publicly acknowledged that Guevara was dead and proclaimed three days of public mourning throughout Cuba. On October 18, Castro addressed a crowd of one million mourners in Havana’ Plaza de la Revolucion:
“If we wish to express what we want the men of future generations to be, we must say: Let them be like Che! If we wish to say how we want our children to be educated, we must say without hesitation: We want them to be educated in Che’s spirit! If we want the model of a man, who does not belong to our times but to the future, I say from the depths of my heart that such a model, without a single stain on his conduct, without a single stain on his action, is Che!”
In late 1995, the retired Bolivian General Mario Vargas revealed to Jon Lee Anderson, the author of “Che Guevara: A Revolutionary Life” that Guevara’s corpse lay near Vallegrande airstrip. The result was a multi-national search for the remains, which lasted more than a year. In July 1997 a team of Cuban geologists and Argentine forensic anthropologists discovered the remnants of seven bodies in two mass graves, including one man with amputated hands (like Guevara). Bolivian government officials with the Ministry of Interior later identified the body as Guevara when the excavated teeth “perfectly matched” a plaster mold of Che’s teeth made in Cuba prior to his Congolese expedition. The “clincher” then arrived when Argentine forensic anthropologist Alejandro Inchaurregui inspected the inside hidden pocket of a blue jacket dug up next to the handless cadaver and found a small bag of pipe tobacco. Nino de Guzman, the Bolivian helicopter pilot who had given Che a small bag of tobacco, later remarked that he “had serious doubts” at first and “thought the Cubans would just find any old bones and call it Che”; but “after hearing about the tobacco pouch, I have no doubts.”
On October 17, 1997, Guevara’s remains, with those of six of his fellow combatants, were laid to rest with military honors in a specially built mausoleum in the Cuban city of Santa Clara, where he freed and had commanded over the decisive military victory of the Cuban Revolution.
Asthma: An Early Autoimmune Disease?
Eosinophilic asthma that is the most common type of this disease with an early onset from childhood and has been linked to allergy, it may not be so, but an early autoimmune disease! Eosinophils come to the defense of the body against allergens or pathogens, prompted by T-helper cells of immune system, a known mechanism of allergic reaction that has made the scientists and clinicians to believe asthma being only an allergic disease. But the persistence of eosinophils in the airways even after an episode of asthma through generating eosinophilopoietic cytokines in response to epithelial-derived alarmins, denote of an autoimmune pathophysiology. Another mechanism of persistent airway eosinophilia is glucocorticosteroid insensitivity, which is linked to recurrent airway infections and presence of local autoantibodies (13).
Autoimmune factors interleukins (IL), particularly IL-33 have been recently recognized in the susceptibility and pathogenesis of allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, allergic keratoconjunctivitis, and even food allergy. These allergic diseases that are characterized by refractory inflammation and T2-helper cells mediated immune responses, have been discovered to be helped by IL-33 to promote the inflammation, for example in the lung airways, hence prolong the disease. Increasing genomewide association studies have also reported the loci of IL-33 gene plays important roles in susceptibility of several diseases such as asthma and allergic rhinitis (14).
Even in non-allergic or non-eosinophilic asthma with no or low level of immunoglobulin E (IgE) and Th2 cells, the involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils, have been recently discovered. Protease allergens have been shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses (15).
Semaphorin-3E (Sema-3E), a member of a large family of proteins originally identified as axon guidance cues in neural development in 2007 (16) and later on being shown in different cell types, such as immune, cancer, neural and epithelial cells, has also been shown that its dysregulation having an important pathogenic role in various biological processes, ranging from cancers to autoimmune and allergic diseases. Most recently, 10 years after its discovery in 2017, this molecule has been revealed to have a critical immunoregulatory role in experimental allergic asthma (17).
Microbial invasion that has a significant role in the pathogenesis of many autoimmune diseases, has also been shown to contribute to the causation and prolongation of asthma. It has been shown that absence of early antibiotic exposure, exclusive breast-feeding for the first 4 months of life, vaginal delivery, furry pets in the home during infancy, lack of maternal antibiotic use during pregnancy, and maternal animal exposure during pregnancy all have been associated with lower rates of allergic diseases, including asthma (18-22).There is also study suggesting microbiota (together with bacterial metabolic products) during early infancy affects the risk of childhood asthma (23). In addition, in genetically comparable populations, environmental exposures linked to varied microbial content affect the development of asthma by shaping the innate immune response (24).
Microbes have also been postulated to play a role in the heterogeneity of asthma, through the early-life exposure to microbially rich environments on susceptibility to childhood asthma; in immune system development; and the potential role of bronchial colonization by particular bacteria in the phenotypes of asthma (25-26). Evidence for a direct effect of the microbiota on asthma has been obtained from animal models, particularly in the context of development of allergic responses and allergic airway inflammation. An exaggerated susceptibility to allergic responses that is normally seen in germ-free mice is reversed by colonization of germ-free animals with a microbiota before allergen sensitization. Interestingly, there appear to be key postnatal steps through which microbial colonization educates the immune system and influences disease susceptibility, the so-called window of opportunity (27). The clinical parallel is earlier landmark epidemiologic studies from Europe in 2011 showing that living in a farming environment, which is linked to exposures to a diverse microbial community, is associated with a lower incidence of allergies (28).
Asthma, a chronic suffering condition with an early onset in childhood that has been thought until recently to be an allergic disease, is now regarded more an immune or even an autoimmune disorder. The eosinophilic asthma that is the most common, severe and chronic type of asthma, has been thought to be allergic due to the secretion of eosinophils and IgE as a body reaction to allergens. But recent studies that were described in this article have shown that even in the eosinophilic asthma, the other immune mechanisms such as lymphocytes, basophils and others also contribute to the pathogenesis of asthma.
Moreover the microbial invasions have also significant role in the susceptibility, pathogenesis and prolongation of asthma. The autoimmune pathogenesis of asthma that detailed in the article has been suggested in many recent studies through the discovery of the involvement of many autoimmune factors such as Interleukines (IL), IL-33/TSLP-basophil-ILC2-IL-5/IL-13. Semaphorin-3E (Sema-3E) that has also been shown in other autoimmune disorders and cancers, has been discovered in the pathogenesis of allergic diseases such as asthma. All these discoveries should soon translate to immune therapy and shorten the duration and lessen the sufferings by asthma and above all open the path to its final prevention.
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Dr. Mostafa Showraki, MD, FRCPC
Lecturer, School of Medicine, University of Toronto
Author: ADHD:Revisited Book