Other novel Th1 specific hits identified by the LIGAP include two cytoskel eton associated protein coding genes dystrophin and palladin. DMD encodes actin binding cyto skeletal structure molecule, which has been mostly studied in patients with Duchennes muscular dystrophy. These patients develop dystrophin specific autoreactive T cells, however, the biological role for dystrophin or palladin in differentiating Th cells is not known. Other genes novel in this context and putatively important for Th1 cell differentiation and or function include METRNL, asso ciated with rare cases of Mild ring 17 syndrome, GLUL encoding a glutamine synthetase, and associated Inhibitors,Modulators,Libraries with neuronal disorders and atherosclerotic carotid pla ques, MCTP2, BBS12, STAG3, a meiotic gene, as well as PGAP1.

NAPSB coding for aspartic protease Napsin B is known to be expressed in human spleen and peripheral blood leucocytes, how ever, it is estimated to be only a transcribed pseudogene. Similarly, Inhibitors,Modulators,Libraries MIAT is a non protein coding gene, and the rele vance of these transcripts in T cell differentiation is not understood, yet. The top LIGAP hits of Th2 specific genes included several genes with very high probability values and include a vast num ber of genes that are both specifically up regulated and down regulated in Th2 conditions compared to other Th subsets. Therefore, the list of Th2 specific genes with highest probability is consistent with the previously pub lished results obtained with other computational methods. Importantly, GATA3, the well characterized master transcription regulator of Th2 polarization was iden tified among the top Th2 hits.

The transcrip tional expression profile of GATA3 was observed to be Carfilzomib highly up regulated at all time points among the cells cultured in Th2 polarizing conditions, whereas the ex pression profiles in Th0 and Th1 cells exhibited down regulation. In addition to well known subset signature molecules, the analysis Inhibitors,Modulators,Libraries identified also a number of poorly characterized molecules in relation to their func tion in polarized Th cells. Among the highly expressed top 50 Th2 hits, the specificity of these transcripts relative to Th0, but not to Th1, has already been identified at dif ferent time points with the standard LIMMA methods in the past. One of these Th2 specific top hits was MAOA, a gene encoding monoamine oxidase A, whose expression was increasingly up regulated during the time course.

This enzyme degra des amine neurotransmitters, and was previously found to Inhibitors,Modulators,Libraries be up regulated in human peripheral blood monocytes after IL 4 and IL 13 stimulation as well as in Th2 cells derived from cord blood na ve CD4 T cells and, im portantly, being indirectly controlled by STAT6. It has been hypothesized that MAOA may act as an anti inflammatory mediator by degrading serotonin which inhibits generation of TNF from macrophages and up regulates phagocytosis.