IL-4 Rezeptor α Polymorphismen und IL-4 sowie IFN-γ mRNA-Expression in MALT-Lymphomen des Magens

Lymphomas of the mucosa-associated lymphatic tissue (lymphomas of the MALT type) develop from secondary lymphatic tissue. This secondary MALT arises in the stomach as consequence of a chronic infection with Helicobacter pylori. MALT lymphomas of the stomach account for around 8 % of all Non-Hodgkins lymphoma. MALT lymphoma patients are infected with H. pylori in more than 90% of the cases and in many cases regression of the lymphoma can be achieved by eradication of H. pylori. Non-neoplastic tumour-infiltrating CD4 positive T-lymphocytes (T helper cells, Th cells) react specifically with the infecting H. pylori strain and support as a consequence the proliferation of the B cells of the MALT lymphoma. It is assumed on the basis of cell culture tests and cytokine expression examinations that the help of the tumour-infiltrating Th cells given to the MALT lymphoma cells occurs through the secretion of Th2 cytokines. Th cells can be differentiated into Th1 and Th2 cells according to their cytokine production profile, as marker interleukins are considered interferon-γ (IFN-γ) for Th1 cells and interleukin-4 (IL-4) for Th2 cells. Th1 and Th2 cells can be viewed as polarised forms of specific immune response; the clearest signs of Th1/Th2 dichotomy are found in chronic stages of disease. Diseases of the atopic syndrome, especially bronchial asthma, have been recognized as surely Th2-mediated. Many studies could prove an association between bronchial asthma and polymorphisms in the IL-4 receptor α (IL-4Rα). Because of this association and the fact that IL-4 develops its effect (including the Th2 cell response inducing effect) through the IL-4Rα, as well as indications of an increased signal transduction through the receptor in the presence of IL-4Rα polymorphisms, it has been postulated that (individual) IL-4Rα polymorphisms could have a favourable effect on a Th2 cell response. Under the assumption that the development of MALT lymphomas is connected with a local Th2 cell response and in view of the association of individual IL-4Rα polymorphisms with Th2-mediated diseases, 99 MALT lymphoma patients and 120 control persons were examined by means of an allele-specific polymerase chain reaction (PCR) for the presence of the seven known IL-4Rα polymorphisms. So far only a few data on the expression of interleukin profiles in MALT lymphomas are available. Therefore the mRNA expression of IFN-γ in 15 and of IL-4 in seven MALT lymphomas and H. pylori gastritis cases each was examined by means of a quantitative real-time PCR. The validation of the results of the allele-specific PCR was by means of sequencing and resulted in a 100% agreement, moreover the acquired allele frequencies of the control group correlate with the known allele frequencies in the normal population. The results of the real-time PCR were also reproducibly valid, as could be shown by reference to intraassays and interassays. No association of an IL-4Rα polymorphism with the presence of MALT lymphomas was shown. Should a Th2 cytokine profile be present in lymphomas of the MALT-type, mechanisms or predispositions other than IL-4Rα polymorphisms appear to cause this polarisation. The real-time PCR showed no difference with regard to the IFN-γ and IL-4 mRNA expression in MALT lymphomas and H. pylori gastritis: with lack of IL-4 evidence IFN-γ was detected constantly. Since H. pylori gastritis is considered to be a Th1-associated disease and IL-4 could not be detected in the MALT lymphomas, the data submitted here speak for the presence of a Th1 cytokine profile in lymphomas of the MALT-type. This result stands in contradiction to cell culture studies and theoretic considerations that suggest a Th2 immune response in MALT lymphomas, but fits well in a number of studies that with regard to the direct cytokine evidence in MALT lymphomas also point to an IFN-γ/(Th1) dominance. Currently it cannot be assessed finally whether lymphomas of the MALT-type belong to the diseases associated with a polarised Th immune response. However, it remains undisputed that MALT lymphoma B cells rely on a form of T cell help by the tumour-infiltrating Th cells. The more current research results indicate that this phenomenon is relevant primarily in early stages of MALT lymphoma and loses significance with the appearance of genetic aberrations such as translocation (1;18).