transforming-growth-factor-beta and Helminthiasis

The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFβ may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context.

Topics: Animals; Asthma; Dioxygenases; Disease Models, Animal; Genetic Loci; Genetic Variation; Helminthiasis; Histone Demethylases; Humans; Inflammation; Mice; Neoplasm Proteins; Nuclear Proteins; Th2 Cells; Transforming Growth Factor beta

In this article, the authors review current and latest evidence linking helminth infections and the development of atopy. Although there is intense ongoing investigation and debate on this issue, the review of experimental, clinical and epidemiological data apparently shows that helminth infections can have beneficial aspects in regard to the pathogenesis of atopy and allergic diseases. Despite the fact that simplistic views are not recommended, it seems that polyclonal IgE production and mainly the stimulation of host immunoregulatory networks leading to synthesis of anti-inflammatory cytokines (IL-10, TGF-beta and others) can provide new insights into how mechanisms that helminths have developed throughout their evolution and that are useful for parasite evasion and persistence, could also be used in humans in order to provide new approaches in atopy prevention.

Topics: Animals; Disease Susceptibility; Eosinophilia; Helminthiasis; Host-Parasite Interactions; Humans; Hypersensitivity, Immediate; Immunity, Cellular; Immunoglobulin E; Inflammation; Interleukin-10; Interleukins; Mast Cells; Mice; Mice, Knockout; Models, Immunological; Signal Transduction; Th2 Cells; Transforming Growth Factor beta

The only vaccine available against tuberculosis (TB), BCG, so effective in experimental animal models, has been under scrutiny for a long time owing to its variable efficacy against pulmonary tuberculosis in adults. In this study, we evaluated whether anti-helminthic therapy prior to BCG vaccination could increase the immunogenicity of BCG vaccination in helminth infected population. We recruited volunteers with evidence of prior mycobacterial infection and who were asymptomatic carriers of helminths. The subjects were randomized to receive either anti-helminthic drugs or placebo. Three months later, BCG vaccination was administered to volunteers. Mycobacterial antigen-specific cytokine responses were assessed 2 months after vaccination. The results show that peripheral blood mononuclear cells obtained from the placebo group were found to have a lower frequency of IFN-gamma (129 vs 191, p=0.03) and IL-12 (149 vs 243, p=0.013) producing cells per 2 x 10(5) PBMC (peripheral blood mononuclear cells) when stimulated in vitro with a mycobacterial antigen mixture (purified protein derivative (PPD)) compared to those from the dewormed group. On the other hand the placebo group had higher frequency of TGF-beta producing cells in response to PPD (152 vs 81.3, p=0.002) or the T cell mitogen concanavalin A (Con A) (210 vs 157, p=0.03). However, no detectable IL-4 or IL-5 producing cells were observed when cells were stimulated with PPD. Comparable numbers of both cytokine producing cells were induced in both groups upon stimulation with concanavalin A (IL-4 217 vs 191, p=0.08) and IL-5 (131 vs 103, p=0.14). The data presented here demonstrate that chronic worm infection reduces the immunogenicity of BCG in humans and this was associated with increased TGF-beta production but not with enhanced Th2 immune response.

Topics: Adolescent; Adult; Animals; Anthelmintics; Cells, Cultured; Helminthiasis; Humans; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-5; Leukocytes, Mononuclear; Middle Aged; Mycobacterium bovis; Placebos; Transforming Growth Factor beta; Tuberculosis Vaccines

An effective host immune system prevents the growth of most cancer cells. However, as intestinal nematodes are able to induce both immunotolerance and immunosuppression in the host, it is possible that their presence could allow co-occurring cancer cells to proliferate and metastasize. Our findings indicate that previous, subsequent or concurrent intestinal nematode infection affects the formation of lung metastatic nodules in mice experimentally infected with Heligmosomoides polygyrus. In addition, pre-infection with nematodes renders mice resistant to metastasis development in lungs, with the inoculated EL4 cancer cells being located mainly in mesenteric lymph nodes. The present paper discusses the nematode-induced mechanisms which may influence the metastatic process.

Topics: Animals; Disease Models, Animal; Helminthiasis; Immunomodulation; Intestinal Diseases, Parasitic; Lung Neoplasms; Lymphoma; Male; Mice; Nematode Infections; Nematospiroides dubius; Neoplasm Metastasis; Transforming Growth Factor beta

In this study we investigated the mechanisms mediating T-cell hyporesponsiveness in chronically immune-activated individuals. We analyzed in healthy and persistently helminth-infected individuals the relationship between immune activation and general T-cell hyporesponsiveness, Th3/regulatory T-cell expression, transforming growth factor-beta (TGF-beta) secretion, CTL-associated antigen 4 (CTLA-4) levels, Casitas B-cell lymphoma-b (Cbl-b) (a negative regulator of T-cell activation) levels and phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK)-1 and -2. We found a very significant increase in plasma levels of TGF-beta and intracellular pools of CTLA-4 and Cbl-b in association with immune activation, which correlates with decreased T-cell responses to anti-CD3 stimulation. We demonstrate that the impaired activity of ERK of peripheral T cells in highly immune-activated individuals is associated with increased levels of CTLA-4 and Cbl-b. Interestingly, in some, but not in all, of these immune-activated individuals, induction of Cbl-b intracellular pools occurs by TGF-beta or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-beta, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation; Blotting, Western; CD3 Complex; Chronic Disease; CTLA-4 Antigen; Enzyme Activation; Ethiopia; Female; Helminthiasis; Humans; Immune Tolerance; Israel; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oncogene Protein v-cbl; T-Lymphocytes; Transforming Growth Factor beta