Discussion

Immunotherapy is a method of treating autoimmune diseases which recently has assumed importance. Two main molecules have been utilized in confronting autoimmune diseases: CTLA-4 and PD-1. PD-1 is a type I membrane protein composed of 288 amino acids. It is a member of the CD28/CTLA-4 family of T cell regulators. Programmed Cell Death 1 construction contains an extracellular IgV domain, a transmembrane region, and an intracellular tail. It is mainly found on B cells, T cells, macrophages, and some types of Dendritic cells. Programmed Cell Death-1 hinders T cell responses by activating PPA2 (inhibitory phosphatase 2) which culminates in an augmented migration of T cells from tissues. The two ligands of Programmed Cell Death 1 are PD-L1 and PD-L2. PD1/ PD-L1 interaction leads to the secretion of IL-10 and the subsequent decrease in T cell multiplying. This pathway plays an important role in tolerating and abolishing self-AG-specific cells. One of the principal mechanisms by which PD-1 induces tolerance is the promotion of Foxp3+ Treg cells, which depends on the engagement of PDL-1-expressing APCs. The strength of the TCR signal is a major factor in the extent of PD1-mediated inhibition. The lower levels of TCR stimulation are, the more PD1-mediated inhibition occurs. It has been approved that PD1 is of vitality in control of Type 1 diabetes since it blocks Ab treatment and leads to rapid precipitation of the disease. PDL1 blockade triggers diabetes by a straight impact on pathogenic T cells owing to the assumption that the PD-L1 pathway blocks the responses of CD4+ and CD8+ T cells. CD4+ and CD8+ are vital throughout the late phases of diabetogenesis. In lupus erythematosus, B cells expand. This puts forward the theory that B-cell PD-1 is not sufficiently expressed or ligate in SLE. Moreover, PD-1+Tfh cells have a direct relation with the severity of the disease. Although expression of PDL1 is unregulated on SLE patients peripheral blood neutrophils, it dwindles on DCs and monocytes. These alterations are explicable solely based on a shortage in C3 and C1 q complement proteins. Standing on the other side of the continuum, Rheumatoid arthritis is another autoimmune disease that is mainly induced by Collagen II (CII). Indeed, owing to the impact of grown T-cell proliferation and increased emission of IFN-c and IL-17, the severity and incidence of RA increase. However, IL-10 and Anti-CII IgG do not undergo any significant alterations. Hence, it has been shown that RA PD1 has a more considerable impact on the Th1/ Th12 pathway in preference to Th2 or humoral responses. Therefore, it is deduced that by blocking PD-1 pathways, SLE can be treated. Additionally, blockage of Th1 CD4+T cell responses, which is a definite result of PD-1 emission, leads to a subsequent reduction in the severity of rheumatoid arthritis. Treatment of diverse cancers is facilitated by the intervention of Anti-CTLA-4 and anti-PD-1 antibodies. Nevertheless, these drugs have distinct mechanisms to place their effect. CTLA-4 blockade confronts the co-stimulation required to reactivate the T cells. On the other hand, PD-1 blockade obstructs the signaling from the TCR complex abundant on T cells. The TCR complex is a very elaborate set of proteins that cooperates with antigens emitted by APCs, such as MHC molecules expressed on APCs. Subsequently, T cells are allowed to accomplish their functions owing to the downstream signaling brought about by the cooperation of TCR and APCs antigens. Modifications in the TCR signaling cascade lays the fundamentals of interrupted T cell performance. Since the PD1 blockade switches the downstream signaling from the TCR and interrupts signals of T cell inhibition, T cells are left free to stay activated; and therefore, distinguish and destroy tumor cells. In other words, the anti-PD1 ought to maintain T cells active whereas CTLA-4 tries to reactivate them. Concerning the fact that each molecule has its mechanisms in treatment, a combination of both would be a worthwhile therapy method to achieve the maximum anti-autoimmune effects. Taking all of the above-mentioned into consideration, it is still necessary to remember manipulation of PD-1 may bring about indelible damages. Still much is unclear about the Programmed cell death-1. However, evidence is that its pathways have the potential to be utilized in novel treatments of autoimmune disease.