Immune response maturation

CpG-ODN Synthetic oKgodeoxynucelotides (ODN) containing CpG motifs stimulate cells via TLR9. The stimulatory effect is due to mimicking bacterial DNA which is rich in unmethylated CpG sequences, while in mammahan DNA these sequences are rare and methylated. In man, TLR9 is expressed on plas-macytoid DC and B cells, while in mice it is also expressed on myeloid DC and monocytes. CpG-ODN activate both innate and adaptive immune responses, stimulate Thl-type immune responses, mature DC, and induce CTL responses. They promote IFN-a and TNF-a production. In melanoma patients, enhanced CDS -b T cell responses were observed in vaccine -I- CpG-ODN recipients, but the outcome was not affected. Interestingly, CpG-ODN can protect immime cells from the damaging effects of chemo- and radiotherapy. 

Several cytokines are in clinical use that support immune responses, such as IL-2, DFNs, or colony-stimulating factors. IL-2 supports the proliferation and effector ftmction of T-lymphocytes in immune compromised patients such as after prolonged dialysis or HIV infection. IFNs support antiviral responses or antitumoral activities of phagocytes, NK cells, and cytotoxic T-lymphocytes. Colony-stimulatory factors enforce the formation of mature blood cells from progenitor cells, e.g., after chemo- or radiotherapy (G-CSF to generate neutrophils, TPO to generate platelets, EPO to generate erythrocytes). 

The key end result of TLR signalling is the induction of cytokines. Cytokines are proteins produced during an immune response that allow the maturation, activation and differentiation of effector cells in the immune system. The activation of NFkB and AP-1 by the MyD88 and the TREF dependent pathways leads to the production of proinflammatory cytokines such as IL-6, TNF-a and various chemokines. This pathway can also activate IRF-7 via TLR-7and TLR-9 allowing Type-I interferons to be produced. 

B cells play a large role in the humoral immune response. In humans, B cells are produced and mature in the bone marrow. However, the abbreviation B does not stand for bone marrow. It stands for the bursa of Fabricius, an organ unique to birds, where B cells originally were discovered to mature. 

IFN-y also directly modulates the immune response by affecting growth, differentiation and function of both T- and B-lymphocytes. These effects are quite complex and are often influenced by additional cytokines. IFN-y acts as a growth factor in an autocrine manner for some T cell sub-populations, and it is capable of suppressing growth of other T cell types. It appears to have an inhibitory effect on development of immature B-lymphocyte populations, but it may support mature B cell survival. It can both up-regulate and down-regulate antibody production under various circumstances. 

Babe A, Harcus Y, Holland MJ, Maizels RM Selective maturation of dendritic cells by Nippostrongylus brasiliensis secreted proteins drives T-helper type 2 immune responses. Eur J Immunol 2004 34 3047-3059. 

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