The choice between Thl and Th2 responses in humans nature versus nurture

Racial differences, twin and adoption studies show that host genetics contribute to susceptibility to infectious diseases such as tuberculosis. HLA-A10, -B8 and DR2 are associated with tuberculosis, whereas recently identified polymorphisms in the vitamin D receptor and mannose binding protein genes confer resistance to

FIG. 1. Factors that regulate the development and effector functions of T helper (Th) 1 and Th2 cells. The most important factor for the induction of Th1 cells is the presence of interleukin (IL)-12 (produced by macrophages and dendritic cells), whereas IL-4 (produced by CD4+ NK1.1+ T cells, mast cells and basophils) is the most potent stimulus for the development of Th2 cells. The transcription factors Stat4 and IRF-1 are required for the development of Th1 cells, whereas Stat6 is needed for the development of Th2 cells. y-Interferon (IFN-y) inhibits the growth and effector functions of Th2 cells; IL-4, IL-10 and IL-13 inhibit Th1 cells. APC, antigen-presenting cell; DC, dendritic cell; DHEA, dehydroepiandrosterone; M0, macrophage; R, receptor.

FIG. 1. Factors that regulate the development and effector functions of T helper (Th) 1 and Th2 cells. The most important factor for the induction of Th1 cells is the presence of interleukin (IL)-12 (produced by macrophages and dendritic cells), whereas IL-4 (produced by CD4+ NK1.1+ T cells, mast cells and basophils) is the most potent stimulus for the development of Th2 cells. The transcription factors Stat4 and IRF-1 are required for the development of Th1 cells, whereas Stat6 is needed for the development of Th2 cells. y-Interferon (IFN-y) inhibits the growth and effector functions of Th2 cells; IL-4, IL-10 and IL-13 inhibit Th1 cells. APC, antigen-presenting cell; DC, dendritic cell; DHEA, dehydroepiandrosterone; M0, macrophage; R, receptor.

tuberculosis (Bellamy & Hill 1998, this volume). Newport et al (1996) identified a mutation in the IFN-y receptor gene in a Maltese family with extreme susceptibility to infection with mycobacteria and other intracellular organisms. A host of other genetic defects lead to primary immune deficiencies. These rare genetic defects are beyond the scope of this review.

Asthma and atopy have been linked to genes on chromosome 11q13 (FceRI), 5q31 (cytokine gene cluster) and 14q (TCR-a genes; Sandford et al 1996). Total serum IgE links to markers in chromosome 5q31.1, where the genes of IL-3, -4, -5, -9, -13, interferon regulatory factor 1 (IRF-1) and the p chain of the IL-12 receptor are clustered (Marsh et al 1994). The occurrence of atopic disease is also regulated by environmental factors. The prevalence of asthma has doubled in the western world over the last two decades. Increased exposure to environmental allergens such as house dust mite may contribute to the asthma epidemic. Several studies indicate that childhood infections may regulate cytokine responses and confer a degree of protection to atopy, while modern vaccination strategies induce predominantly Th2 responses (Shirakawa et al 1997). In Third World populations chronic intestinal parasite infestation has been shown to induce Th2 immune deviation. Bentwich et al (1995) proposed that chronic parasite-induced Th2 activation, manifested by increased secretion of Th2 cytokines, high serum immunoglobulin (especially IgE) levels and an eosinophilia, contributes to a greater susceptibility for HIV and to greater viral loads following infection. Parasite infestation also exacerbates asthma and in a recent interventional study, regular anti-helmintic treatment reduced IgE levels and led to clinical improvement of asthma (Lynch et al 1997).

Neuroendocrine factors have a powerful effect on immune responses. Populations stressed by war or natural disasters have an increased incidence of infections such as tuberculosis and typhus, but under these circumstances it is difficult to estimate the relative contributions of defective public health and of increased host susceptibility to infection. Bernton et al (1995) studied the immunological and endocrine changes in military recruits under conditions of 'mental and physical stress approaching that found in combat', and found raised cortisol levels and reduced DHEA/cortisol ratios in these recruits. Testosterone levels, delayed-type hypersensitive responses and T cell mitogenic responses decreased, while IgE levels increased. The authors suggested that stress induced a Th1 to Th2 shift.

Another steroid that modulates immune responses is the active metabolite of vitamin D, calcitriol, of which a deficiency enhances susceptibility to tuberculosis (Davies 1985). Calcitriol activates monocytes and stimulates cell-mediated immunity, and vitamin D metabolites enhance the killing of intracellular M. tuberculosis by monocytes (Rook et al 1986).

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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