| Adaptive immune system consists of T cells and B cells. Dysfunction of either T cells or B cells can be very pathogenic. For example, reactivity of BCR to non-pathogenic environmental antigens causes allergy (anaphylaxis as a very severe condition). Malignant mutations in T cells causes accumulation of immature T cells in the periphery and lead to lymphomas. Here, we studied the mechanism of allergic response caused by pathogenic IgE antibody-producing B cells, and the mechanism of T cell acute lymphoblastic leukemia (T-ALL) of a transgenic mouse line (Tg8).;In the former, we demonstrated that there are two distinct pathways to generate high and low affinity IgE. High affinity IgE is generated through sequential class switching (μ→γ→ϵ) in which an intermediary IgG phase is necessary for the affinity maturation of the IgE response, where the IgE inherits somatic hypermutations and high affinity from the IgG1 phase. In contrast, low affinity IgE is generated through direct class switching (μ→ϵ) and is much less mutated. Mice deficient in IgG1 production cannot produce high affinity IgE, even after repeated immunizations. We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fcϵ Receptors and prevents anaphylaxis, and is thus beneficial.;In the latter, we found that ectopic expression of Notch ligand Dll4 on T cells alone was sufficient in inducing T-ALL. Furthermore, we discovered that spleen generated and exported CD4+CD8+ double-positive (DP) T cells. On the other hand, thymus, which is the major site of DP cell production and T cell development, didn't allow DP cell egress. Lin-Sca1+Kithigh (LSK) multi-potent progenitors and early T cell progenitors (ETP) were observed only in the spleen of Tg8 but not in the other organs of Tg8 or in WT. Splenectomy surgery rescued the mice from developing T-ALL. Secondary mutations are required for a swift malignancy transformation of DP cells. Similar over-expression of DLL4 was found in human pediatric T-ALL samples. |
