Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Secretion of tumor necrosis factor-alpha (TNF-alpha) by macrophages plays a predominant role in the development and progression of rheumatoid arthritis. We demonstrate that knockdown of TNF-alpha expression in systemic macrophages by intraperitoneal (i.p.) administration of chitosan/small interfering RNA (siRNA) nanoparticles in mice downregulates systemic and local inflammation. Chitosan nanoparticles containing an unmodified anti-TNF-alpha Dicer-substrate siRNA (DsiRNA) mediated TNF-alpha knockdown (approximately 66%) in primary peritoneal macrophages in vitro. The presence of Cy3-labeled nanoparticles within peritoneal macrophages and specific TNF-alpha knockdown (approximately 44%) with TNF-alpha siRNA after i.p. injection supports our therapeutic approach. Downregulation of TNF-alpha-induced inflammatory responses arrested joint swelling in collagen-induced arthritic (CIA) mice dosed i.p. with anti-TNF-alpha DsiRNA nanoparticles. The use of 2'-O-Me-modified DsiRNA resulted in the lowest arthritic scores and correlated with reduced type I interferon (IFN) activation in macrophages in vivo compared with unmodified DsiRNA. Histological analysis of joints revealed minimal cartilage destruction and inflammatory cell infiltration in anti-TNF-alpha-treated mice. The onset of arthritis could be delayed using a prophylactic dosing regime. This work demonstrates nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages as a method to reduce both local and systemic inflammation, thereby presenting a novel strategy for arthritis treatment.

Atopic dermatitis (AD) is a common skin disease associated with a T(H)2 response and increased levels of T(H)2-associated cytokines and IgE. The mechanisms resulting in skewing the immune response in a T(H)2 direction in AD are not fully elucidated. However, such skewing has recently been associated with IL-25 in a murine model for allergic airway disease. The aim of this study was to investigate whether IL-25 may have a role in AD. We have identified IL-25-producing cells within the dermis of AD patients and propose that these cells are dendritic cells (DCs). This is supported by in vitro experiments that indicate that monocyte-derived DCs are capable of producing IL-25. As null mutations of filaggrin are associated with the development of an impaired skin barrier in AD, we investigated whether IL-25 affects filaggrin synthesis by keratinocytes. Using mRNA analysis, we have shown that IL-25 stimulation does indeed decrease filaggrin synthesis in cultured keratinocytes. These results suggest that IL-25 produced by DCs could have a dual role as both an inducer of the T(H)2 response and as an inhibitor of filaggrin synthesis, thereby directly affecting skin barrier function in AD patients.