Background: CD4⁺CD25⁺regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females.Results: To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4⁺CD25⁺CD45RO⁺T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161,P< 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121,P< 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction ofbona fideFOXP3⁺CD4⁺CD25⁺Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants ofCTLA4andTGFβwere associated with the decreased frequency of Treg in PBMC, whileFOXP3gene variants were associated with affection status, but not with Treg frequency.Conclusion: SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3⁺CD25^-into FOXP3⁺CD25⁺T cells. Treg frequency is highly heritable within SLE families, with specific variants of theCTLA4andTGFβgenes contributing to this trait, whileFOXP3contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8)(q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C>T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S Kv7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with Kv7.5 but not with Kv7.2 or Kv7.4. The nucleotide change did not affect trafficking of heteromeric mutant Kv7.3/2, Kv7.3/4 or Kv7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric Kv7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders (ASD), epilepsy and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.