Genetic factors in leprosy involve the human leukocyte antigen (HLA) system as well as non-HLA genes. These genes affect the individual’s susceptibility to the disease, including bacillary transmission and clinical features. The chromosomes involved in these aspects include 6p21, 10p13, 17q22, and 20p13.
The markers associated with leprosy are termed MRC1 and are in chromosome 10. This region codes for receptors in cells of the innate immune system such as macrophages and dendritic cells.
Another candidate gene group is the PARK2 and PARCRG genes found on both Schwann cells and on macrophages, which regulate macrophage response to the leprosy bacillus Mycobacteria leprae. Another nucleotide polymorphism called LTA+80 is associated with a lower expression of lymphotoxin alpha (LTA) which is an inflammatory cytokine belonging to the tumor necrosis factor (TNF) group. It plays an important part in lymphocyte activation.
Other related polymorphisms include the gene promoters for TNF-α and interleukin-10, some of which alter a person’s susceptibility to leprosy. Other genes which show variations which may be associated with an increased risk of contracting the disease have been identified in a genome scan conducted over a population group in China. These include seven genes (CCDC122, CD13orf31, NOD2, TNFSF15, HLA-DR, RIPK2, and LRRK2), of which CD13orf31, NOD2, RIPK2, and LRRK2 genes are linked to MB leprosy.
Other polymorphisms seem to protect against the infection as well as the clinical disease. For instance, the -308A allele of the TNF gene is protective and also regulates the level of TNF during leprosy reactions.
Among the changes identified, certain are linked to leprosy, particularly the multibacillary (MB) end of the spectrum. TNFα gene promoter alleles and Nramp1 (macrophage protein 1 associated with natural resistance) polymorphisms are related to a higher risk of MB leprosy. On the other hand, the 10p13 region is associated with the development of paucibacillary (PB) leprosy.
The vitamin D receptors (VDR) gene may also have a link with which form of disease develops, namely, tuberculoid and lepromatous leprosy. Upregulation of this gene is found to predict increased macrophage killing of M. leprae intracellularly. Class II antigens of the HLA complex that are associated with tuberculoid and lepromatous leprosy respectively include HLA-DR2 and HLA-DQ1 respectively.
Similarly, polymorphisms in the TLR1 and TLR2 genes may predict the occurrence of a reversal reaction, but not with ENL.
Interestingly enough, different polymorphisms are associated with different states of resistance or susceptibility to leprosy, when they are found in different populations. Whether this is due to differences between studies in relation to their size, their design, or simply the genetic make-up of the population involved remains to be clarified.
Immune Response in Leprosy
The wide range of clinical manifestations of leprosy occurs due to the variation in the host’s cellular immune status and response. Initial infection is met by innate immune response in the form of intact epithelium, bacteriocidal secretions from epithelial surfaces, and IgA antibodies which mop up the body surface antigens. These natural defences are complemented by natural killer (NK) cells, cytotoxic T cells, and activated macrophages.
The innate immune response is important in that it does not take account of the existence or strength of adaptive immunity. A strong innate immune response may thus be the key to clinical resistance to infection with M. leprae, in addition to the organism’s low virulence.
Even after infection occurs, initial immunity is non-specific. Inflammatory cytokines and chemokines are released which attract T helper 1 (Th2) or T helper 2 (Th2) cells, which leads to the initiation of specific cellular or humoral immunity, respectively. According to which subset of cells is activated the clinical manifestations may tend towards the tuberculoid or lepromatous form.
Adaptive immunity is ineffective in preventing clinical disease and in fact allows the bacilli to disseminate throughout the body in the case of humoral (IgM) antibodies produced in lepromatous patients. Cellular immunity leads to tuberculoid lesions which show mostly CD4+ cells, of which memory cells outnumber naïve cells in a ratio of 14:1, with a predominance of T-cytotoxic cells among the CD8+ population. The memory cells are bound to macrophages inside the granuloma surrounded by peripheral CD8+ cells.
On the other hand, lepromatous lesions have a CD4+:CD8+ ratio of 0.6:1, with half the CD4+ cells being naïve and most CD8+ cells being T-suppressor cells. In lepromatous granulomas, CD8+ cells are intermingled with macrophages and CD4+ cells.
Tuberculoid patients show high levels of cytokines such as interferon-gamma, interleukin-2, and TNF-α, produced by CD4+ cells, which lead to higher levels of cell-mediated immunity, macrophage activation, and suppress the proliferation of the bacilli. Bacillary destruction and granuloma formation are associated with these molecules.
High levels of these cytokines lead to increased damage of involved tissues as well as the type 2 leprosy reaction, also called erythema nodosum leprosum. In addition, tuberculoid lesions have high levels of interleukins 7 and 12, which promote T cell growth and differentiation. Interleukin 13 is thought to suppress lepromatous lesions.
In lepromatous cells, on the other hand, CD8+ cells lead to increased production of interleukins 4, 5, and 10 which inhibit macrophage activity. Interferon-gamma levels are low. These cytokines result in B cell activation and high humoral immunity response, which increases the susceptibility to leprosy. Transforming growth factor-beta is also absent in tuberculoid leprosy but elevated in the lepromatous form, inhibiting macrophages and thus preventing the production of TNF-α, and interferon-gamma. This helps establish leprosy.
In the type 1 leprosy reaction, the cellular immune response is exacerbated, with CD4+ cells flooding into the granuloma to produce more interleukin 1 and 2, TNF-α, and interferon-gamma. In the type 2 reaction, or erythema nodosum leprosum, immune complexes produce an inflammatory reaction, with interleukins 6, 8, and 10, and TNF-α.