Lepromatous leprosy is a deadly form of leprosy that is the result infection by M. leprae and subsequent TH1 activation failure, typically accompanied by overexpression of TH2 cells. This differentiation of cell type has a major impact on the progression of the disease, and understanding it is crucial for treatment of the disease.To track the naïve T-cell in the progression of Lepromatous leprosy, we must begin in the thymus. One fully developed in the thymus, naïve T-cells are released into the bloodstream to be carried around the body by circulation. These naïve T-cells travel through the bloodstream until they encounter a peripheral lymphoid tissue which include the lymph nodes and the spleen.
To enter the lymphoid tissue, the naïve T-cells cross a specialized vein called the high endothelial venule (HEV). These peripheral lymphoid tissues experience a constant flow of both naïve T-cells and a combination of whole pathogens and pathogen components. The pathogenic components are the result of the lymph of the infected tissue draining from the sight of infection and carrying these antigenic molecules back to the lymph nodes.
Within the lymphoid organs are specialized cells responsible for capturing antigen — either deposited by the lymph or from the site of infection — and presenting it to the naïve T-cells. The innate immune response is primarily responsible for the migration of antigen-presenting cells (APCs) to the peripheral lymphoid tissues. Dendritic cells at the site of infection are collecting particulate matter and antigens from the pathogen and will soon travel to the peripheral lymphoid tissue. Migration from the site of infection to the peripheral lymphoid tissue is induced by a combination of presence of bound antigen, and various cytokines produced for induction of the inflammatory response.
Macrophages and B-cells can be activated in a similar fashion to macrophages, resulting in binding to components of the infectious agent, producing additional APCs. Once all the appropriate signaling has occurred, both naïve T-cells and APCs congregate in the lymphatic tissues where T-cell activation will occur.Once the peripheral lymphoid tissue contains both APCs and naïve T-cells, the process of T-cell activation can begin. The physical interaction between APCs and the naïve T-cell are crucial in the formation of a fully activated T-Cell and is promoted by the actin skeleton of the dendritic cell. When the dendritic cell and naïve T-cell come in contact, the glycoprotein B7.2 on the dendritic cell interacts with the CD28 receptor present on the naïve T-cell, increasing the affinity of the MHC-TCR interaction. The MHC on the dendritic cell is then capable of interacting weakly with the TCR on the TH0 cell, inducing differentiation into T2H cells rather than T1H cells. These newly created T2H cells then produce IL-4, which acts to suppress differentiation into T1H cells while simultaneously promoting producing of T2H cells.
The overexpression of T2H cells results in an excessive production of antibodies that are not only ineffective against M. leprae, but also result in distribution of the bacterium to varies sites of the body, ultimately resulting in further tissue damage. Furthermore, because the overproduction of T2H cells results in an underproduction of T1H cells, macrophages cannot be sufficiently activated by the T1H cells, resulting in high rates of bacterial survival. The overproduction of the ineffective antibodies also proves problematic, as the antibodies can bind to antigens on the bacterial cells, inhibiting CD8 T-cell function. These CD8 T-cells thenperform their non-cytolytic function of IL-10 and LT secretion, both of which further inhibit TH1 differentiation and response.
This cycle insures that patients with lepromatous leprosy are incapable of illuminating the bacteria through immunological means, and so these patients must be prescribed antibiotics if they are to survive.
