Divergent Effects of T Cell Costimulation and Inflammatory Cytokine Production on Autoimmune Peripheral Neuropathy Provoked by Aire Deficiency

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) results from autoimmune destruction of the peripheral nervous system (PNS) and is a component of the multi-organ autoimmunity syndrome which results from Autoimmune Regulator (Aire) gene mutations in humans. In parallel, PNS autoimmunity resembling CIDP develops spontaneously in NOD mice with a partial loss of Aire function (NOD.AireGW/+ mice), and is a T cell-mediated disease. In this study, we analyze how key aspects of T cell activation and function modulate disease development in Aire-deficient mice. We show here that genetic ablation of the Th1 cytokine IFNγ completely prevents clinical and electrophysiological evidence of neuropathy in NOD.AireGW/+ mice. IFNγ deficiency is associated with absence of immune infiltration and decreased expression of the T cell chemoattractant IP-10 in sciatic nerves. Thus, IFNγ is absolutely required for the development of autoimmune peripheral neuropathy in NOD.AireGW/+ mice. Because IFNγ secretion is enhanced by B7-CD28 costimulation of T cells, we sought to determine the effects of these costimulatory molecules on neuropathy development. Surprisingly, B7-2 deficiency accelerated neuropathy development in NOD.AireGW/+ mice, and antibody blockade of both B7-1 and B7-2 resulted in fulminant, early-onset neuropathy. Thus, in contrast to IFNγ, B7-2 alone and B7-1/B7-2 in combination function to ameliorate neuropathy development in NOD.AireGW/+ mice. Together, these findings reveal distinct and opposing effects of T cell costimulatory pathways and IFNγ production on the pathogenesis of autoimmune peripheral neuropathy

Adherence to Oral Chemotherapy in Acute Lymphoblastic Leukemia during Maintenance Therapy in Children, Adolescents, and Young Adults: A Systematic Review

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. Treatment is long and involves 2–3 years of a prolonged maintenance phase composed of oral chemotherapies. Adherence to these medications is critical to achieving good outcomes. However, adherence is difficult to determine, as there is currently no consensus on measures of adherence or criteria to determine nonadherence. Furthermore, there have been few studies in pediatric B-ALL describing factors associated with nonadherence. Thus, we performed a systematic review of literature on oral chemotherapy adherence during maintenance therapy in ALL following PRISMA guidelines. Published studies demonstrated various objective and subjective methods of assessing adherence without generalizable definitions of nonadherence. However, the results of these studies suggested that nonadherence to oral maintenance chemotherapy was associated with increased risk of relapse. Future studies of B-ALL therapy should utilize a uniform assessment of adherence and definitions of nonadherence to better determine the impact of nonadherence on B-ALL outcomes and identify predictors of nonadherence that could yield targets for adherence improving interventions

Schwann cell-derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment

Chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS) are inflammatory neuropathies that affect humans and are characterized by peripheral nerve myelin destruction and macrophage-containing immune infiltrates. In contrast to the traditional view that the peripheral nerve is simply the target of autoimmunity, we report here that peripheral nerve Schwann cells exacerbate the autoimmune process through extracellular matrix (ECM) protein induction. In a spontaneous autoimmune peripheral polyneuropathy (SAPP) mouse model of inflammatory neuropathy and CIDP nerve biopsies, the ECM protein periostin (POSTN) was upregulated in affected sciatic nerves and was primarily expressed by Schwann cells. Postn deficiency delayed the onset and reduced the extent of neuropathy, as well as decreased the number of macrophages infiltrating the sciatic nerve. In an in vitro assay, POSTN promoted macrophage chemotaxis in an integrin-AM (ITGAM) and ITGAV-dependent manner. The PNS-infiltrating macrophages in SAPP-affected nerves were pathogenic, since depletion of macrophages protected against the development of neuropathy. Our findings show that Schwann cells promote macrophage infiltration by upregulating Postn and suggest that POSTN is a novel target for the treatment of macrophage-associated inflammatory neuropathies