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As in other areas, the TNF gene has been the gene predominately examined for associations to infectious diseases. One of the earliest disease associations to be reported was that of the TNF-308A allele to cerebral malaria. The TNF-308 polymorphism was examined in malaria, as high levels of the cytokine have been associated with disease severity, and in particular with fatal cerebral malaria. McGuire et al. (1994) reported that homozygotes for the TNF-308A allele had a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria.

Similarly, another study reported two to three times greater odds in carrying the TNF-308A allele among individuals with severe malarial disease (Wattavidanage et al., 1999). Furthermore, a TNF polymorphism at position -238 has been associated with severe malarial anaemia characterised by low TNF levels (McGuire et a!., 1999). The TNF-308A allele has also been associated with other infectious diseases such as mucocutaneous leishmaniasis (Cabrera et a!., 1995) and brucellosis (Caballero etal., 2000).

Cytokine gene polymorphisms have also been examined for associations with viral infections. An association between the TNF-238 polymorphism and the development of chronic hepatitis B infection has been reported. However, there was no association with TNF-308 polymorphism (Hohler et al., 1998). This polymorphism has however, been found to be associated with hepatitis C infection. The TNF-308A allele was found to associate with a shorter time to, and greater severity of, hepatitis C recurrence following liver transplantation (Rosen et al., 1999). Furthermore, a recent study found that the TNF-238A and TNF-308A alleles conferred a greater risk of cirrhosis from hepatitis C infection (Yee et al., 2000). Other cytokine polymorphisms that have been found to associate with viral infection include those of the IL-10 gene. For example, IL-10 alleles have been found to associate with EBV infection (Helminen et al., 1999) and with the response to IFNa therapy in chronic hepatitis C (Edwards-Smith

1.3.2.1 Leprosy

Background

Leprosy is a chronic disease caused by the pathogenic bacillus

Mycobacterium leprae. In 95% of subjects, the infection is subclinical as T

cell mediated immunity eradicates the infection. In some subjects, however the infection disseminates to the skin and nerves. Leprosy forms a spectrum of clinical states that correlate with the extent of bacterial dissemination and the type of immunopathological response mounted against the organism. The disease mainly affects the skin, the peripheral nerves, the mucosa of the upper respiratory tract and the eyes, apart from some other structures.

The immune response to the bacterium may be predominantly cellular resulting in the tuberculoid form of the disease, or it may be biased to a humoral response that leads to the development of lepromatous leprosy (Abulafia & Vignale, 1999). In addition, there are a number of intermediate variants that may develop such as borderline tuberculoid, borderline lepromatous and borderline borderline leprosy (Abulafia & Vignale, 1999). The borderline types of leprosy are often unstable and with time, the disease develops towards either one of the two dichotomous forms i.e. tuberculoid or lepromatous (see Figure 1.5).

Infection by the aerosol route is common in areas with a high prevalence

numbers of bacteria. High numbers in the nasal mucosa may allow the disease to spread via nasal droplets, the tuberculoid form however, is generally considered non-contagious.

Tuberculoid

Borderline

Lepromatous

cell mediated immunity

'resistance'

Figure 1.6 The clinical spectrum of leprosy

'susceptible'

Immunopathology

The two principal targets of the microorganism are the Schwann cells of the peripheral nervous system and cells of the monocyte/macrophage system. Initially M. leprae infects Schwann cells where it multiplies and forms perineural granulomas. From here, the microorganisms can migrate to the perivascular connective tissue and be ingested by macrophages. The macrophages completely destroy the bacilli, and then by acting as APCs induce cell-mediated immunity. In these circumstances the epithelioid granulomas characteristic of tuberculoid leprosy arise. Alternatively, only partial lysis of the bacteria occurs in the macrophages

and the bacterial phospholipids persist forming lepra cells and lepromatous granulomas (Abulafia & Vignale, 1999).

It is the level of cell-mediated immunity that correlates with the clinical manifestations of leprosy. The standard measure of cell-mediated immunity against the pathogen is the Mitsuda reaction. Mitsuda reaction positive patients exhibit a nodular lesion after 3 to 4 weeks following an intradermal injection of M. leprae. Lepromatous patients are Mitsuda negative.

Th1/Th2 Responses in Leprosy

The Th1/Th2 dichotomy seen in CD4+ T cells has a crucial and determining influence in leprosy. Patients with the tuberculoid form of leprosy have in their skin lesions predominantly CD4+ T cells that secrete Thi-type cytokines. These patients are more resistant to infection. The skin lesions of lepromatous leprosy patients are characterised by infiltrating CD8+T cells that secrete the Th2 type cytokines IL-4 and IL-10 (Modlin, 1994; Yamamura et a!., 1992). These patients are largely unable to combat M. leprae and the infection becomes widely disseminated. It is likely that the Thi cytokines contribute to the more efficient control of infection seen in tuberculoid leprosy. Furthermore, it has been reported that administration of IL-2 or IFNy to lepromatous patients results in the clearance of some bacilli from the lesions (Nathan et al., 1986; Kaplan et al., 1989).