History and Current Epidemiology of Disease. Leprosy is literally an ancient disease, one that has been around several millennia, beginning with the Ancient Greek and Egyptian civilizations. To gain better idea of what the current status of the leprosy is in this day and age, it is necessary to investigate where it came from, and how it evolved into the disease it is today. Gordon Grice (2000), author of "Where Leprosy Lurks", an article in the November 2000 issue of Discover Magazine, cites that the leprosy has gone back as far as 200 BC in Egypt, where four skulls were discovered to been infected the leprosy. Dr. Grimm (2005), author of "The Global Spread of Leprosy Tied to Human Migration", also believes that leprosy first originated in Egypt based on the comparative study he conducted on the origin of different strains of leprosy.
The spread of the disease to other parts of the world was heavily aided by the major conquests of empires such as that of Alexander the Great, who conquered East Africa and the Middle East and brought the disease back to Greece along with various spices and silks (Grice, 2000). From Greece, the disease spread around the Mediterranean basin as Romans introduced it into Western Europe (Grice, 2000). Over time, this process was further carried out as war, trade, and colonialism established a complex route of transmission for leprosy that involved the migration and influx of many people in many different parts of the world. Throughout Africa, Europe, and parts of Asia, much stigma developed around people affected with disease. Many were often persecuted and isolated from the rest of the community based on their condition, giving rise to the term "lepers" (White, 2009). During the colonial era, many European missionaries believed that a degree of shame should be put on the disease because it was considered unholy (Vaughan, 1991). Furthermore, the popular belief among societies at this time was that leprosy was a hereditary condition that could only be contracted by relatives of lepers, and not anyone else (Grice, 2000). This assumption was contradicted in 1870 when Father Damien, a Christian missionary on the Hawaii Island of Molokai, contracted the disease while he was working with Lepers (Grice, 2000). His case was particularly intriguing because it was evident that he had contracted the disease from infected individual, since he did not have family history of the disease. This lead to a severe scare among European societies as many people believed one could contract the disease just by standing next to some one else. Although, this assumption was put to rest in 1873, when Hanson discovered that the disease was caused by an infection of bacteria called Mycobacterium leprae (Grice, 2000). In 1940, Dr. Guy Faget, a physician at Carville Treatment Center, a specialized institution designed for leprosy patients in the U.S., discovered a cure of leprosy by testing the kill rate of sulfone on the bacillus (White, 2009). This treatment was very successful until M. leprae began to grow resistant to dapsone, a sulfone derivative. This prompted the usage of multidrug therapy, which began in 1981 when it was administered by the WHO using a combination of dapsone, clofazimine, and rifampcin (White, 2009).
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Since 1981, the combination of these drugs has approximately decreased 90% of leprosy's prevalence, and the number of registered cases of leprosy worldwide has dropped from 5.4 million to 211,903 cases in 2010 (World Health Organization, 2010). Furthermore, since 2000, 4 million leprosy patients have been cured, and over 14 million patients have been cured in the last twenty years with the help of WHO, who now provide the multidrug therapy for free around the world (World Health Organization, 2010). While the effectiveness of these treatments has helped to significantly decrease leprosy rates around the world, there are still areas of high leprosy prevalence in a select few developing countries. Dr. Felisa Lewis (2010), a physician at the Madigan Army Medical Centers, reports that 86% of today's worldwide cases occur in Brazil, India, Indonesia, Ethiopia, Philippines, Nepal, Tanzania, Thailand, Bangladesh, and Congo. The two countries with the highest leprosy rates are Brazil and India respectively, and between the two, they contain approximately 150,000 cases, over 71% of the current 211, 903 cases (World Health Organization, 2010). Based on these statistics, it would interesting to investigate this disparity through a evolutionary model by determining if these select populations exhibit any type of genetic susceptibility to the leprosy.
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Etiology/ Symptoms of Leprosy
Before constructing an evolutionary framework to why humans are vulnerable to leprosy, it is necessary to fully understand the causes of the disease. The most familiar symptoms of leprosy are the appearance of one or more lesions on the skin. Marcia Gaudet (2009), the author of the groundbreaking book Carville: Remembering Leprosy in America, concludes that one of the major misconceptions of leprosy is that there is a immediate loss of limbs, but this is not true as untreated leprosy initially starts out by disrupting nerves in the body, which eventually cause a loss of temperature sensation, loss of muscle control, and above all else, skin lesions. Most of these skin patches are not painful, and because the disease grows very slowly compared to other bacteria (doubles every 14 days), it can become dormant for months and even years, showing no signs of symptoms. Leprosy transmission is primarily based in the respiratory, and is passed from person to person through the expulsion of nasal droplets when one sneezes or coughs (Lewis, 2010). Once it enters the body, the bacilli replicate within the Schwann cells and attack the peripheral nervous system, consequently damaging nerve endings, which leads to reduced sensitivity and numbness in the body's extremities (White, 2009). As a result, a person afflicted with leprosy could further complicate his or her condition by walking around barefoot and exposing themselves infections through open wounds. Unfortunately, once leprosy is left untreated, it can result in more severe complications that include deformities in the limbs such as the "claw hand", where the fingers become paralyzed in a claw-like position, "penciling", which give the hands and feet a shrunken and swollen appearance (White, 2009). Leprosy eventually causes the deterioration of limbs and external body parts, for example, in many parts of Africa, leprosy is referred to as "leonine" or "lion face" because the bacilli can localize in the forehead and give the outward appearance of lion's face (White, 2009). Leprosy can also cause destruction in the nasal bones, cartilage, as well as the area surrounding the eyes. Dr. Brand and Dr. Yancey (1993), authors of Pain: The Gift Nobody Wants, concluded that until a decade ago, leprosy was one of the leading causes of blindness in developing countries as the disease's bacilli accumulate in the cornea and cause major damage in the eyes.
Proximate Explanation: Immunological Response of Leprosy
The proximate mechanisms that underlie leprosy primarily revolve around the immune system of the infected individual. Once M. leprae enters the body, the immune system engages a response against the bacilli that result in number of reactions, such as pain, fever, and inflammatory skin lesions. These responses are known as type 1 reactions because they result in an spontaneous increase in cell-mediated immunity, which becomes activated when the invading bacilli's antigens stimulate the body's defense cells. These cells, called lymphocytes, attack the M. leprae antigens and producing an inflammatory response to the body that cause the various skin patches associated with leprosy (White, 2009). The lymphocytes main function is to secrete certain chemicals that attract larger macrophages to the antigen build-up site, and assist the macrophages in digesting the bacilli since they cannot actually perform phagocytosis themselves. The bacilli have a particular affinity to cooler areas of the body such as the peripheral nerves, which is why deformities in the extremities are the most distinct symptom of leprosy. Type 2 reactions of leprosy are inflammatory responses that are more comprehensive in their interactions within the body. It mediates a humoral immunity, which is also known as antibody mediated immunity, because it involves generating certain antibodies that aim to destroy foreign antigens that invade the immune system. While humoral immunity is particularly effective in fighting various forms of pathogens, it uncharacteristically has little effect against M. leprae, and usually increases with the severity of the disease (Lewis, 2010).
Both the type 1 and type 2 reactions form the basis of the two main forms of leprosy: tuberculoid leprosy and lepromatous leprosy (White, 2009). Tuberculoid leprosy is a paucibaccillary condition because it contains a small number of skin lesions (less than 5), while lepromatous leprosy, a multibaccillary condition, can contain more than six skin lesions (World Health Organization, 2010). Lepromatous leprosy is the most contagious form of the disease because individuals who have it contain a strong humoral response, but a weak immune response. As a result, their bodies are unable to stop the proliferation of bacilli, and they cannot help but release the bacteria into the environment (Scollard, 2004). Tuberculoid leprosy, on the other hand, is characterized by a stronger cell-mediated response because it allows individuals to fight the bacilli so that they don't persist in the body. This form is much less milder, less contagious, and unfortunately, less common because of its passivity (Scollard, 2004).
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Ultimate Explanation: Why We Are Vulnerable to Leprosy
Based on what has been discussed about the history, epidemiology, etiology, and immunology of leprosy, the question still remains why people in countries such as Brazil and India are exceptionally susceptible to leprosy in comparison to other Third World countries,. Evidence has shown that the rates of leprosy infections are significantly higher than rates of actually developing the clinical form of the disease (Lewis, 2010). This disparity has shown that while initial exposure is a major factor that can determine whether an individual will develop leprosy, it is not the only cause. For quite some time, it has been suspected that there is genetic predisposition to leprosy as shown by the history of the disease, which was commonly referred to as a hereditary condition before Dr. Hansen's discovery of its mycobacterial source. Finally, in 2001, the leprosy genome was decoded and a link was identified which showed that a specific stretch of DNA in 5% of the world's population contained a significant susceptibility to the leprosy based on a lack of innate immunity to the disease, something that most individuals have (Gaudet, 2004). Dr. Han (2008) et al, leprosy researchers at the National Allergy and Infectious Disease Institute in Washington, D.C., believe that leprosy's pathogenicity is inherently connected to an individual's cell-mediated immunity, which as noted earlier, is a vital defense needed to protect individuals against M. leprae antigens. Fortunately, approximately 90% of the human race has cell-mediated immunity to leprosy, which has led researchers and evolutionary biologists to believe that people who develop leprosy have a certain genetic predisposition to the leprosy because they do not have the proper immunological defenses that provide them the ability to fight off the disease and prevent it from worsening (Comeu, 2003). So while the disease may not be hereditary, there may be an inherited susceptibility to the disease that may weaken a person's immune response to leprosy.
This genetic predisposition has been synonymous with researchers around the world, particularly McGill University's leading genetic scientists Erwin Scharr and Tom Hudson. With the help of a team of researchers, Scharr and Hudson (2003) were successfully able to isolate a section in human chromosome 6 that has shown to make people more vulnerable to leprosy. Schurr (2003) lead the team to India, Brazil, Thailand, and Ethiopia to study and collect DNA samples from members of affected families. The research team used gene mapping techniques to look for common similarities in genetic makeup between families affected with leprosy. They noticed that many brothers and sisters were both afflicted with leprosy because they inherited the same pieces of chromosome 6, and since siblings share 50% of the same genes, there appeared to be parallels between heredity and leprosy susceptibility (Comeu, 2003). While the actual gene has not been identified yet, Schurr and Hudson found that a specific area on chromosome 6 contains genetic information that provides M. leprae a friendly environment to coexist in, essentially providing a selection for it over other bacteria (Comeu, 2003).
Furthermore, the Major Histocompatibility Complex (MHC), which is located on the short arm of chromosome 6, has shown to have a important interaction with CMI as it contains specific HLA type genes, which are human leukocyte antigens that contain genes related to the immune response in humans (Silva et al., 2009). These genes have recently shown to regulate the clinical progression of leprosy, and most importantly, increase the susceptibility of infection (Silva et al., 2009). Silva et al. (2009) studied the polymorphic MHC genetic system by conducting a cross-cultural genome analysis on which HLA polymorphism has the greatest susceptibility to leprotamous leprosy. The populations studied were Brazil, India, and Bangladesh. The results showed that a particular HLA gene, specifically the HLA-DR2 locus, was present in nearly 90% of the sample, concluding that the gene showed a discernable vulnerability to leprosy (Silva et al., 2009). Interestingly, Fitness et al. (2002) also found out that the adjacent HLA-DR3 locus was mapped among a majority of patients in South American populations such as Surinam and Venezuela. The genetic susceptibilities in these studies were due to a malfunction in the HLA system, as the mutant HLA genes failed to relay peptides from the bacilli to human T cells, thereby giving the body the inability to protect itself from the infected M. leprae cells (Silva et al., 2009). Consequently, an individual with this susceptibility would be less likely to resist the invasion of the M. leprae antigens because of faulty genes in the HLA system. As shown by these studies, it is apparent that there is a genetic vulnerability to leprosy among individuals living in number of developing countries, specifically Brazil and India. Is it a coincidence that both of these countries have the highest rates of leprosy in the world? Why is it that both of these countries have proven genetic predispositions to leprosy when there are many other developing countries like Brazil and India that do not display any evidence of susceptibility? While the answer is still uncertain, there are a few underlying factors that may provide insight as to why these phenomenon is occurring. The first step might be to analyze the risk factors associated with leprosy, such as poverty, low social status, and poor living conditions such as a lack of sanitation (White, 2009). While these factors are associated with both developed and developing countries, they are more problematic in developing countries, which may explain why leprosy is more prevalent in the developing world. Consequently, determining what risk factors are selective for leprosy in Brazil and India is irrelevant, because these elements are consistent throughout other developing countries as well, particularly ones that don't exhibit any susceptibilities.
Although, on an evolutionary level, one may be able to explain Brazil and India's genetic vulnerability to leprosy based on the disease's history of migration. Gene flow, which is the shift of alleles from one population to another, may be the most fit in explaining why countries such as Brazil and India have high rates of leprosy. As one of the four main processes of evolution, gene flow explains why migration and intermixing between one or more population can lead to abnormalities in gene pools. Brazil is a country characterized by an exceptional diversity that stems from the mixing Black slaves that migrated from Africa to work for European settlers, most notably the Portuguese, during the 1500s (Geographia, 2006). Based on these migration patterns, it may be possible that the gene pools of both these populations mixed, creating a genetic vulnerability to leprosy over time as both populations may have been exposed to the disease prior to coming in contact with each other. This may be very plausible based on the origin of leprosy, as it originated in East Africa and was brought over to Europe by migration through trade routes and empire conquests like the Greek empire of Alexander the Great. The case can even be made for India as Alexander's empire stretched over to Punjab, a northwest part of India, leaving behind many of his generals to establish Greek rule (Marshall, 2010). This could have lead to a transfer and intermixing of allele frequencies within the two populations, which may have also occurred when the British Empire came in and ruled India from 1858 to 1947.
While the answer is still unknown, Dr. Randolph Nesse and Dr. George Williams (1994), authors of Why We Get Sick, providing an alternative ultimate explanation as to why mutant genes, such as the ones identified in the populations of Brazil and India, did not die out. They argue that because natural selection selects for reproductive success, and not health, a mutant gene may remain common if it does not decrease the average number of offspring, even if it may cause debilitating effects (Nesse & Williams, 1994). Such is the case of leprosy, which can often to be hard to analyze because it exists in multiple forms which determine if the disease is serious enough to persist. Tuberculoid leprosy may take more than four years for the symptoms to develop, while the fatal lepromatous form develops much slower, taking as long as 10 years for the initial skin lesions to become visible (Lewis, 2010). Since there are no current statistics on the average age of leprosy, and whether adult leprosy patients have children before they are diagnosed, it is difficult to determine if this mutate gene hypothesis applies to leprosy. In any case, there is no evidence that shows that leprosy affects fertility, so an individual could very well have children before they even know they have disease. Thus, as long as the mutant gene can passed itself off to the next generation of offspring, the forces of balancing selection will continue to allow it to spread. While it is still uncertain why this disease continues to persist in a select number of developing countries, the forces of gene flow and migration, as well as the host gene pathway proposed by Nesse and Williams, provides a more knowledgeable evolutionary insight as to why leprosy continues to pervade throughout certain parts the developing world.
While there might be a variety reasons why the HLA-DR genes are only exhibited in minority of developing countries such as Brazil and India, it is evident that there is indeed a genetic susceptibility to leprosy. By examining the proximate mechanisms of the body's immune response to leprosy, it was concluded that individuals who contained a mutant form of the HL-DR gene on chromosome 6 lacked a proper cell-mediated immunity. Based on this abnormality, they are more vulnerable to contract the more fatal, lepromatous form, putting themselves at a selective disadvantage in comparison to other individuals who do not have this genetic predisposition. By analyzing the history and origin of leprosy, a explanation on why this vulnerability persists in only a select few populations. Whether this hypothesis is plausible or not, the important thing to take away is that in order to fully analyze a infectious disease, one needs to evaluate all aspects of the disease, including its' history, epidemiology, etiology, and most importantly, its proximate causes ultimate causes. Just like a puzzle, a disease cannot be looked in its entirety until all of its parts are connected and put together. Furthermore, while the data in these studies only provided explanations about the population as a whole, it would be interesting to determine which individuals within the vulnerable population are at more risk based on factors such as family genealogy.