Immune recognition of self nucleic acids driven by endogenous antimicrobial peptides: role in autoimmunity

Innate immune recognition of extracellular host-derived self-DNA and self-RNA is prevented by endosomal seclusion of the Toll-like receptors (TLRs) in the dendritic cells (DCs). However, in psoriasis plasmacytoid dendritic cells have been found to be able to sense self-DNA molecules in complex with the endogenous cationic antimicrobial peptide LL37, which are internalized into the endosomal compartments and thus can access TLR9. We investigated whether this endogenous peptide can also interact with extracellular self-RNA and lead to DC activation. We found that LL37 binds self-RNA as well as self-DNA going into an electrostatic interaction; forms micro-aggregates of nano-scale particles protected from enzymatic degradation and transport it into the endosomal compartments of both plasmacytoid and myeloid dendritic cells. In the plasmacytoid DCs, the self-RNA-LL37 complexes activate TLR7 and like the self-DNA-LL37 complexes, trigger the production of IFN-α in the absence of induction of maturation or production of IL-6 and TNF-α. In contrast to the self-DNA-LL37 complexes, the self-RNA-LL37 complexes are also internalized into the endosomal compartments of myeloid dendritic cells and trigger activation through TLR8, leading to the production of TNF-α and IL-6, and the maturation of the myeloid DCs. Furthermore, we found that these self nucleic acid-LL37 complexes can be found in vivo in the skin lesions of the cutaneous autoimmune disease psoriasis, where they are associated with mature mDCs in situ. On the other hand, in the systemic autoimmune disease systemic lupus erythematosus, self-DNA-LL37 complexes were found to be a constituent of the circulating immune complexes isolated from patient sera. This interaction between the endogenous peptide with the self nucleic acid molecules present in the immune complexes was found to be electrostatic and it confers resistance to enzymatic degradation of the nucleic acid molecules in the immune complexes. Moreover, autoantibodies to these endogenous peptides were found to trigger neutrophil activation and release of neutrophil extracellular traps composed of DNA, which are potential sources of the self nucleic acid-LL37 complexes present in SLE immune complexes. Our results demonstrate that the cationic antimicrobial peptide LL37 drives the innate immune recognition of self nucleic acid molecules through toll-like receptors in human dendritic cells, thus elucidating a pathway for innate sensing of host cell death. This pathway of autoreactivity was found to be pathologically relevant in human autoimmune diseases psoriasis and SLE, and thus this study provides new insights into the mechanisms autoimmune diseases.

An Examination of Treatment Fidelity in an Intensive Family Preservation Program

Most models of intensive family preservation services are based on providing flexible services to reduce risk and keep families together. This study examined 40 cases served by a public agency Family Preservation Unit in 1992-1993, in order to assess the provision of hard, soft and enabling services in the program and whether their provision matched the program model. The relationships of these services to program outcomes, in terms of child removal, new reports of abuse or neglect, and family gains in resources and strengths, are also assessed.

Towards a Prosperous Future for our Children and Nation

Invited Commentary on "A Multidisciplinary Team Experience with Food Insecurity and Failure to Thrive" by Drs. Kersten and Bennett.

The assessment of standardized training programs in public health preparedness

The Texas Bioterrorism Continuing Education Consortium (BCE) provided National Disaster Life Support (NDLS) training courses throughout the state of Texas in 2005, to help improve knowledge and skills pertaining to bioterrorism and other public health emergencies. The NDLS training courses include curriculum in Basic Disaster Life Support (BDLS) and Core Disaster Life Support (CDLS). A course evaluation which included items assessing ability and willingness of training participants, role of responders, and other variables was mailed to all NDLS participants who provided contact information. An analysis was conducted to determine whether the survey respondents participated in the Hurricanes Katrina and/or Rita relief efforts, as well as to evaluate the impact of the NDLS training courses on the participant's ability and willingness to respond during a disaster. The study population (n = 2150) consisted mostly of nurses (50%) (n=1074). A chi-square test of analysis indicated the following results. Among the survey respondents who took the CDLS course, there was no statically significant difference by occupation pertaining to ability or willingness to respond (x2 [df = 5] = 4.02, p= 0.546); (x2 [df = 5] = 2.45, p = .783). However, there was a statistically significant difference among those respondents who took the BDLS course with respect to ability, and a slightly significant difference with respect to willingness (x2 [df = 5] = 13.35, p = .020 and (x2 = [df = 5] = 10.299, p = .067). These findings are similar to previous studies assessing willingness to respond to a disaster.^ A second analysis was conducted with these survey data to evaluate the implications for disaster response training for the NDLS courses. Results indicated that the majority of disaster responders served in the role for which they were professionally trained (Physicians=68%; Nurses = 50.4%). Nurses, EMT, and Fire professionals served in multiple roles. These results suggest the importance of developing training programs that will prepare professionals to serve in multiple roles. The development of standardized evaluation methods would fill an important gap in assessing impact of national training programs. ^