X Monosomy in Female Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, predominantly occurring in women of childbearing age. SLE, like several other autoimmune diseases, is characterized by a striking female predominance and, although sex hormone influences have been suggested as an explanation for this phenomenon, definitive data are still unavailable. Our group recently reported an increased X monosomy in lymphocytes of women, affected with primary biliary cirrhosis (PBC), systemic sclerosis (SSc), and autoimmune thyroiditis (AITD) in comparison to healthy women, thus suggesting the involvement of this chromosome in female predominance and in the deregulation of the immune system that characterizes autoimmunity. We have now evaluated X monosomy rates in SLE using fluorescence in situ hybridization (FISH) on peripheral mononuclear white blood cells (PBMCs) from female patients compared to healthy age-matched controls. In addition, because of a previous finding of microchimerism as a pathogenetic cause of a number of autoimmune diseases, we investigated the presence of cells carrying the Y chromosome. We did not identify an increased X monosomy in women with SLE compared to controls (P = 0.3960, SLE vs. HCs, Student's t-test), thus suggesting that a different mechanism of immune deregulation might be predominant in the female population of patients with SLE.

The X chromosome and immune associated genes

“…Nevertheless, it is possible that this is not true for any AID as we failed to confirm the finding in women suffering for SLE [43,44]. In one of this AID, PBC, we have also demonstrated that X chromosome is preferentially lost, thus ruling out the possibility that a specific haplotype on X chromosome could trigger AID in a predisposed subject.…”

“…In one of this AID, PBC, we have also demonstrated that X chromosome is preferentially lost, thus ruling out the possibility that a specific haplotype on X chromosome could trigger AID in a predisposed subject. At this point, we still need to determine the parental origin of the remaining chromosome mainly because the disease is characterized by a relatively old mean age at diagnosis with consequent difficulty in obtaining DNA from parents [43]. We believe that the progressively acquired haploinsufficiency for genes on X chromosome in immune-related cells is a mechanism for immunosenescence, the state of altered immune function of the elderly known to concur to the increased susceptibility to infection, cancer, and the onset of AID [33,45].…”

Autoimmune disease and gender: Plausible mechanisms for the female predominance of autoimmunity

“…It is also notable that increased X monosomy rates have been found more frequently in peripheral T and B lymphocytes than in other blood cell populations without evidence of microchimerism that would explain the existence of the monosomic cells [100e105]. However, these findings could not be duplicated in a study of female patients with SLE, in which the authors proposed that the methylation pattern rather than the monosomy of the X chromosome, along with other hypotheses, might have a more preponderant role in female biased autoimmunity, but this needs further research [104]. Invernizzi et al offers an explanation of how X monosomy might be associated with autoimmunity by hypothesizing that X chromosome monosomy may cause a haploinsufficiency in X-linked genes that escape X chromosome inactivation and, as a consequence, autoreactive T cells are not exposed to self-antigens encoded by one of the two X chromosomes.…”

Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis

“…Our group has mostly focused on the latter, identifying peculiar patterns of X chromosome loss in peripheral cells of individuals affected by several autoimmune diseases [11e13], including autoimmune thyroiditis (AIT). Nonetheless, some other conditions, such as systemic lupus erythematosus (SLE) did not display haploinsufficiency at increased rates compared to the general population [14] but, on the contrary, an increased dose of X chromosomes [15].…”