6. Immunology

M. leprae is an acid-alcohol-fast, Gram-positive obligate intracellular bacillus that shows tropism for cell and endothelial system and peripheral nervous system (Schwann cell). The leprosy bacillus has a predilection for macrophages, collecting intracellular globus. The bacteria never cultured in vitro but have been grown in the foot pads of 9-banded armadillos. Predisposed to infect cold areas of the body surface such as the skin, nasal mucosa, and peripheral nerves, the best temperature for M. leprae grows is 27 and 30C. The efficacy of this pathogen within a narrow ecological niche is primarily explained by the properties conferred by two structural elements: the capsule and the cell wall [17]. The capsule is composed of two lipids, phthiocerol dimycoserosate and a phenolic glycolipid-1, which is the main target of humoral immune response, like immunoglobulin M-mediated [18]. Another important component of the cell wall is lipoarabinomannan, which is an antigen for the macrophage. M. leprae has a predilection for Schwann cells, for specific binding to the G domain of the laminin alpha-2 chain, which is expressed specifically in the basal lamina of peripheral nerves [19]. Development of the disease depends on the immune status of patients. The role of genetics, associated with a susceptibility locus at chromosome 10p13, near the mannose receptor on the surface macrophages, is important in the phagocytosis. The other role of major histocompatibility complex (class II HLA) genes at chromosome 6 has been implicated in the clinical type of patient leprosy. The lepromatous form affects the skin and peripheral nerve, causing well-defined infiltrated plaques that are annular or ovoid form. Immunohistochemical findings in skin biopsies show mainly interleukins 4 and 10. The immune response to M. leprae is variable and gives rise to spontaneously changing clinical manifestations that may present as type 1 or 2 leprosy reactions [17].

immune reports focus on the role of regulatory T cells and cytokines secreted by T helper cells in leprosy. Finally, a newly identified species named M. lepromatosis has been detected in

Based on two types of extreme immune responses, two polar forms (tuberculoid at one end and lepromatous in the other) of the clinical presentation of the disease occur. The disease may present with a clinical picture representing severity, anywhere in the continuous/variable spectrum between these two polar forms (see Appendix No. IV for Ridley's general overview and Jopling Hardness classification on leprosy, in the form of a continuous spectrum and Appendix III for differential diagnosis leprosy). People with a "good" CMI response develop a milder and localized form of disease (tuberculoid) with fewer bacterial loads, whereas people with weak or absent CMI develop a widespread spread of disease (lepromatous) with a high

The transmission of leprosy exactly is still understood. The human being is the main reservoir of leprosy infection, although by history, transmission through African green monkeys and Armadillos has been reported [15]. Other dissemination routes were suspected, but their role in the transmission of leprosy was not clearly defined [16]. M. leprae has a tropism for the skin and Schwann cells of the peripheral nerves. The primary sign appears as sensory neuritis, but in untreated patients seeking medical treatment at a late phase with severe motor impairment. Plantar ulcers, lytic bone lesions and ulnar nerve paralysis or lagophthalmos are frequent

Leprosy diagnosis remain based clinical findings and easy make for health workers to treat patients. Various clinical signs can be known during the early phase of leprosy, defined as

M. leprae is an acid-alcohol-fast, Gram-positive obligate intracellular bacillus that shows tropism for cell and endothelial system and peripheral nervous system (Schwann cell). The leprosy bacillus has a predilection for macrophages, collecting intracellular globus. The bacteria never cultured in vitro but have been grown in the foot pads of 9-banded armadillos. Predisposed to infect cold areas of the body surface such as the skin, nasal mucosa, and peripheral nerves, the best temperature for M. leprae grows is 27 and 30C. The efficacy of this pathogen within a narrow ecological niche is primarily explained by the properties conferred by two structural elements: the capsule and the cell wall [17]. The capsule is composed of two lipids, phthiocerol dimycoserosate and a phenolic glycolipid-1, which is the main target of humoral immune response, like immunoglobulin M-mediated [18]. Another important component of the cell wall is lipoarabinomannan, which is an antigen for the macrophage.

indeterminate phase, so that it is difficult to diagnose the disease.

patients with severe leprosy and erythema nodosum leprosum [8].

10 Current Topics in Tropical Emerging Diseases and Travel Medicine

5. Clinical appearances

complications in leprosy patients [16].

bacterial load.

6. Immunology

The steps in the transmission of the disease are not entirely clear. However, it is acceptable that the mycobacterium reservoir is exclusively human, and it is most often transmitted through the spread of basil aerosol. In many cases, the infection appears to occur during childhood, with an incubation period ranging from 6 months to several years. Rarely, very long incubation periods of up to 40 years have been reported, although infection rates in adults with close contact with infected individuals (e.g. spouse) are as low as 5% even in long-term investigations [20].

Leprosy usually begins as an indeterminate form that can heal spontaneously, remain unchanged for long periods, or progress to a more severe form. About 95% of contact with the bacillus will result in spontaneous resolution without the development of clinical symptoms. This initial indefinite form can produce patches or macules of the skin, which is not clear with little hypopigmentation. In parallel, such patches may coincide with hypoesthesia of the corresponding skin nerve. If the disease develops, tuberculoid leprosy can develop as long as the host immune response is preserved enough. At this stage, rapid skin sensation loss due to severe neurological damage can occur, as well as local paralysis, loss of sweat and sebaceous glands, and hair loss. The skin shows macular lesions with significant hypopigmentation; peripheral nerves are infiltrated and may present as thick subcutaneous bundles. Secondary symptoms include bruised skin under hypoesthesia due to local external damage and superinfection with poor healing ulcers [21].

The lepromatous stage occurs in individuals with poor immune reactions. Clinically, this is the most severe form and can lead to mutilation. Skin lesions may appear as macules, papules, or plaques with hypopigmentation. The most affected areas are the ears, the central face, the fingers, and toes, but the distal extremities, such as the extensor surfaces of the thighs and forearms, can also be affected. Severe skin infiltrations in the peri-nasal and periorbital areas lead to "facies leonine" or lion face, associated with loss of eyelashes and lateral eyebrows ("facies leprosy"). Often, blindness can occur when the eye is exposed. Osseous resorption of the nostrils and destruction of the bridge of the nose result in severe facial mutilation. The Mycobacterium leprae affected throat can cause a distinctive hoarseness. In fact, all other body areas can also be affected, leading to varying clinical features. The fourth stage, called the borderline stage, also exists, which is somewhat intermediate between tuberculoid and lepromatous stages in clinical symptoms. Considering the various clinical symptoms, especially the early stages and stages of minor illness, leprosy can easily be confused with various other diseases. This is often important for historical

reconciliation, since evidence previously interpreted as supporting the diagnosis of "leprosy" should be carefully considered. In contrast, typical skeletal mutilation in the form of severe leprosy leaves a distinctive footprint of disease that may be identified in historic relics with high levels of certainty [21].

e. Skin smear on new case samples can provide quality control. Research into laboratory tests (e.g., serological or skin tests) that may be useful in the field in identifying M. leprae infection, diagnosing active disease, and classifying leprosy cases should be continued [25].

Leprosy: The Ancient and Stubborn Disease http://dx.doi.org/10.5772/intechopen.79984 13

Leprosy patients have been traditionally classified based on the number and type of skin lesions into various clinical groups. However, according to current WHO guidelines, only the number of skin lesions determines the length of therapy patients received for leprosy. Various studies have reported and highlighted the differences between clinical and skin classification and nerve biopsy findings of leprosy patients [26]. The WHO classification (1988) for leprosy control program has differences with the 1998 WHO classification. The patients are categorized into PB and MB leprosy depending upon whether the slit skin smears demonstrate any bacilli or not. Earlier, the cases with a bacterial index of 2 or less had been categorized as PB, but later on, for feasibility and operational difficulties, all the patients with demonstrable bacilli in slit skin smear without any reference to bacterial index were to be categorized as MB, whereas 1998 WHO Classification for leprosy control program was based on the total number of leprosy lesions in the patient. This is a corollary to the fact that PB patients have good immunity and present with only limited number of lesions. Furthermore, the single lesions leprosy was also segregated on the ground that this can be treated with the limited amount of chemotherapy. On the practical side, the WHO expert committee's conclusions

about new classification based on the number of lesions are translated as [27]:

3. Multi-bacillary leprosy six or more skin lesions and also all smear positive cases

Pauci-bacillary leprosy is found in people with good CMI. The disease remains localized to produce single or little skin lesions with or without peripheral nerve involvement. The skin lesion may be macular (flat) or papule (slightly raised) and plaque. People with strong immune responses are capable of destroying large amounts of normal organisms and skin normally

Multi-bacillary leprosy is found in people with poor CMI. Bacilli multiply and spread more widely resulting in a common disease: usually accompanied by widespread lesions in the skin, nerves, and at lower levels in other organs such as the eyes, respiratory mucosa, testes, and reticuloendothelial system in men and usually the central nervous system and the upper reproductive system in women. The skin lesions may be multiple (borderline) or uncountable (lepromatous). Lepromatous lesions may be symmetrical and unclear bilateral macules or

1. Pauci-bacillary single lesion leprosy (SLPB)

most of them exhibit negative skin examinations.

2. Pauci-bacillary leprosy (2–5 skin lesions)

7. Pauci-bacillary

8. Multi-bacillary

More advanced leprosy presentations have been reported and classified as tuberculoid leprosy and lepromatous leprosy. Many other clinical presentations, known as intermediate or borderline leprosy, have been identified and classified among the two types. The Ridley and Jopling System (RJ) defines five clinical presentations of leprosy: polar tuberculoid leprosy (TT), borderline tuberculoid leprosy (BT), borderline-borderline leprosy (BB), borderline lepromatous leprosy (BL), and polar lepromatous leprosy (LL) [22].

But according WHO classification, leprosy is divided into two major groups: pauci-bacillary subtype and multi-bacillary subtype. The WHO system is based on the quantity of skin lesions and the number of bacilli on skin smear. Skin smears are made by squeezing a fold of skin and making a shallow slit in the skin with a scalpel [23]. The two main categories of the WHO classification system are: (1) pauci-bacillary (PB) leprosy: ≤5 skin lesion with no bacilli on skin smear and (2) multi-bacillary (MB) leprosy: ≥6 skin lesion and may have bacilli on skin smears.

The Ridley-Jopling classification system is based on the histopathology of skin lesions and essentially represents a spectrum of disease. The spectrum of leprosy classification is not static. For example, in some cases, untreated TT can progress into LL, given a long enough time and the proper immunologic environment. There are the two classification systems that are mutually exclusive. Indeterminate and tuberculoid leprosy (TT) are commonly referred to as PB leprosy, while BB and LL are commonly referred to as MB leprosy [23, 24]. This was confirmed by the WHO Expert Committee on Leprosy at the seventh meeting in 1997, which defined a case of leprosy as follows: A case of leprosy is someone who has one or more of the following features and who still needs to complete a complete treatment: skin lesions hypopigmentation or redness with a definite loss of sensation, peripheral nerve involvement, as shown by neural thickening accompanied by loss of sensation, as well as positive skin-smears for acid-fast bacilli [24].

The following recommendations are based on the evidence just described:


e. Skin smear on new case samples can provide quality control. Research into laboratory tests (e.g., serological or skin tests) that may be useful in the field in identifying M. leprae infection, diagnosing active disease, and classifying leprosy cases should be continued [25].

Leprosy patients have been traditionally classified based on the number and type of skin lesions into various clinical groups. However, according to current WHO guidelines, only the number of skin lesions determines the length of therapy patients received for leprosy. Various studies have reported and highlighted the differences between clinical and skin classification and nerve biopsy findings of leprosy patients [26]. The WHO classification (1988) for leprosy control program has differences with the 1998 WHO classification. The patients are categorized into PB and MB leprosy depending upon whether the slit skin smears demonstrate any bacilli or not. Earlier, the cases with a bacterial index of 2 or less had been categorized as PB, but later on, for feasibility and operational difficulties, all the patients with demonstrable bacilli in slit skin smear without any reference to bacterial index were to be categorized as MB, whereas 1998 WHO Classification for leprosy control program was based on the total number of leprosy lesions in the patient. This is a corollary to the fact that PB patients have good immunity and present with only limited number of lesions. Furthermore, the single lesions leprosy was also segregated on the ground that this can be treated with the limited amount of chemotherapy. On the practical side, the WHO expert committee's conclusions about new classification based on the number of lesions are translated as [27]:

