Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses.

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22-/- T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Low bone mineral density measurements in care home residents--a treatable cause of fractures.

PURPOSE: to assess predictors of fracture risk and treatment for osteoporosis among elderly care home residents. DESIGN: cross-sectional survey; SETTING: residents of care homes in Newcastle upon Tyne, UK; PARTICIPANTS: representative sample from residential care (87), nursing homes (105) and specialist homes for elderly people with dementia [elderly mentally infirm (EMI)]: residential (124) and nursing (76); MAIN OUTCOME MEASURES: dual-energy X-ray absorptiometry bone mineral density (BMD) at calcaneum; functional assessments, including cognition, using Mini-Mental State Examination (MMSE), Clifton Assessment Procedure for the Elderly-Behaviour Rating Score (CAPE-BRS) and Functional Assessment Staging Test (FAST) scores; current drug prescription. RESULTS: MMSE, CAPE, FAST (all ANOVA P < 0.001) and weight (ANOVA P < 0.02) were lower in EMI homes. Drugs with sedative effects (chi-square, P < 0.0001) were more likely and calcium and vitamin D (CaD) supplementation (chi-square, P < 0.02) less likely in EMI care. For residential care, the odds ratio (OR) for sedative drugs in EMI was 2.13 (95% CI 1.11-4.06) with no significant difference between nursing homes. For CaD supplementation, the OR for EMI nursing homes was 0.19 (95% CI 0.05-0.72) and for EMI residential homes 0.38 (NS to 95% CI 0.12-1.27). BMD was low: mean T-score was -2.29 (95% CI -2-48 to -2.09) and Z-score -0.96 (95% CI -1.16 to -0.76) with a prevalence of osteoporosis (T-score < -1.6) of 69.2%. MMSE and FAST scores did not predict BMD. In EMI residential care, a decrease of CAPE score by 5 points was associated with a decrease in T-score by 0.6 (95% CI 0.15-1.1). CONCLUSIONS: of the tools used to assess function, only CAPE predicted low BMD in EMI residential care. Rates of CaD supplementation are particularly low in EMI care, where risk factors for fracture were the greatest. We conclude that fracture risk is neglected in these homes, and targeted education and treatment are warranted.