**6. Rheumathoid Arthritis (RA)**

212 Immunodeficiency

[38].

**5.2. miR125a, 126, 21 and 148a** 

progression of the disease.

inducible genes. Finally, IFN pathway could be downregulated when overexpression of miR146a was attained in PBMCs taken from normal donors and SLE patients. The same group [36] has identified a genetic variant of the miR146a promoter region, that confers reduced binding affinity to the transcription factor ETS1, thus leading to reduced levels of miR146a and increased susceptibility to SLE. These data have been further confirmed by a genomic analysis, where a SLE associated polymorphic SNP variant, rs2431697, was found to be related to low expression levels of miR146a gene [37]. Overall, these findings

Autoimmune disorders are often characterized by disregulated expression of proinflammatory chemokines and its receptor that drive and sustain unchecked immune responses, favoring autoimmunity. This is the case for RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), also known as CCL5, whose elevated levels are observed in the context of chronic systemic inflammations such as arthritis and nephritis. Renal damage is initiated by RANTES over-expression in mouse models of SLE

Zhao et al. [39] have shown that miR125a levels are underexpressed in T cells of SLE patients, while its predicted target KLF13 (Kruppel like factor 13) was upregulated. KLF13 directly controls the expression of RANTES in T cells. Interestingly, prolonged mitogenic stimuli evoke miR125a upregulation in normal T cells, providing a negative feedback loop that controls chemokine expression and helps to turn off inflammatory responses. The deficiency of this mechanism in SLE patients provide further insights on the onset and

DNA methylation is a relevant mechanism to regulate gene transcription in eukaryotic cells [40] and any perturbation of these pathways can have crucial impact in health and disease. T cells from SLE patients suffer of a global hypomethylation [41], which is related to disease activity. The reduction of DNA methylation depends upon the reduced levels of Dnmt1 (Dna methyl transferase-1), the key enzyme that transfers methyl groups to CpG islands. The paired analysis of CD4 T cells from normal donors and SLE patients revealed the presence of an upregulated miRNA in SLE-T cells, miR126, that was independent from costimulatory signals [42]. miR126 targets Dnmt1 and reduces its levels in SLE- CD4 T cells. miR126 downstream effects include hypomethylation of critical genes in autoimmune pathogenesis such as TNSFS7 and ITGAL, that encode CD70 and CD11a [43], respectively. Indeed, CD70 [44] is the cellular ligand for the tumor necrosis factor receptor family member CD27,and is required on activated T cells and B cells to stimulate the synthesis of IgG. CD11a, also known as lymphocyte function–associated antigen 1, belongs to the integrin family of cell surface receptors and can strengthen the adhesion of T lymphocytes to other immune cells. These events could be reverted by miR126

suggest a pivotal role of miR146a in SLE susceptibility and development.

RA is a systemic inflammatory disorder, primary involving synovial joints. The inflammatory milieu is the base for disease onset and progression. Several groups reported an increase of miR155 and 146a in synovial fibroblasts and PBMCs from RA patients [46, 47]. Interestingly, these miRNAs can be stimulated by inflammatory stimuli, though promoting opposite effects. miR155 sustains inflammation, while miR146a attenuates through TNFα suppression. In this setting, miR146a seems not able to promote its action. A possible explanation is that both miRNAs are elicited by the pro-inflammatory environment of RA, with miR155 enforcing inflammation, while miR146a should shut off it, but it is unable to exert its activity.
