The autoimmune regulator Aire is a key mediator of central tolerance for peripherally restricted antigens. Its absence in human patients results in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. The cellular signals that regulate Aire expression are undefined. We show here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes. The failure of Aire induction in the thymi of lymphotoxin-deficient and lymphotoxin-beta receptor-deficient mice contributes to overt autoimmunity against self antigens normally protected by Aire. Conversely, stimulation of lymphotoxin-beta receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line. These findings define the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.

The development of spontaneous insulin-dependent diabetes mellitus is preceded by the organization of tertiary lymphoid organ (TLO) in situ, but its role in the development of tissue destruction and the cytokines that control such structures have not been fully defined. We have now observed that TNF superfamily 14 (TNFSF14) is upregulated in aged nonobese diabetic (NOD) pancreas with the appearance of TLO. Blockade of TNFSF14 signaling caused a substantial reduction in the expression of lymphotoxin beta receptor (LTbetaR)-controlled migration factors within the islets and disrupts organization of tertiary structures, leading to prevention of diabetes. Consistently, enhancing LTbetaR signaling by transgenic expression of TNFSF14 in the islets of NOD mice rapidly promoted de novo formation of local TLO, resulting in diabetes, even in the absence of draining lymph nodes (LN). Thus, the TNFSF14-LTbetaR pathway appears to be critical in the development and maintenance of TLO for the onset of diabetes.

NF-κB2-deficient mice have impaired T and B cell responses. We found, however, that in these mice there was severe infiltration of lymphocytes into multiple organs and increased activity of autoantibodies to peripheral tissue antigens in a manner similar to that of autoimmune regulator-deficient (Aire-deficient) mice. We further demonstrated that NF-κB2 was required for thymic Aire gene transcriptional regulation. The Nfkb2 -/-thymus had distinct cortical and medullar structures, but reduced Aire and target gene expression of peripheral tissue antigens. Engraftment of Nfkb2 -/-thymic stroma to nude mice recapitulated the autoimmune phenotype of the native Nfkb2 -/-mice, confirming a key defect in central tolerance. Lymphotoxin β receptor (LTβR) ligation-induced Aire gene expression was also largely abolished in the absence of NF-κB2. Thus NF-κB2 downstream of LTβR plays an important role in the regulation of central tolerance in an Aire-dependent manner.

In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-κB pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-κB target Gadd45b in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b -/-mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b -/-mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b -/-mice. Interestingly, Gadd45β ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45β as a potential therapeutic target in liver diseases.

Background & Aims-The ability of the liver to regenerate hepatic mass is essential to withstanding liver injury. The process of liver regeneration is tightly regulated by distinct signaling cascades involving components of the innate immune system, cytokines, and growth factors. However, the role of the adaptive immune system in regulation of liver regeneration is not well-defined. The role of adaptive immune system in liver regeneration was investigated in lymphocyte-deficient mice and in conditional lymphotoxin-deficient mice.

Ectopic expression of peripherally restricted Ags by medullary thymic epithelial cells (mTECs) is associated with negative selection. Autoimmune regulator (AIRE) is considered to be the master regulator of these Ags. We show in this study that the ectopic expression of type II collagen (CII) in mTECs and the corresponding central tolerance to CII are AIRE independent but lymphotoxin dependent. The failure to properly express CII in mTECs of Lta−/− and Ltbr−/− mice leads to overt autoimmunity to CII and exquisite susceptibility to arthritis. These findings define the existence of additional pathways of ectopic peripheral Ag expression, parallel to and independent of AIRE, which may cover an extended spectrum of peripheral Ags in the thymus.

BACKGROUND The “kickstand rod technique” has been recently described for achieving and maintaining coronal correction in adult spinal deformity (ASD). Kickstand rods span scoliotic lumbar spine from the thoracolumbar junction proximally to a “kickstand iliac screw” distally. Using the iliac wing as a base, kickstand distraction produces powerful corrective forces. Limited literature exists for this technique, and its associated outcomes and complications are unknown. OBJECTIVE To assess alignment changes, early outcomes, and complications associated with kickstand rod distraction for ASD. METHODS Consecutive ASD patients treated with kickstand distraction at our institution were retrospectively analyzed. RESULTS The cohort comprised 19 patients (mean age: 67 yr; 79% women; 63% prior fusion) with mean follow-up 21 wk (range: 2-72 wk). All patients had posterior-only approach surgery with tri-iliac fixation (third iliac screw for the kickstand) for mean fusion length 12 levels. Three-column osteotomy and lumbar transforaminal lumbar interbody fusion were performed in 5 (26%) and 15 (79%) patients, respectively. Postoperative alignment improved significantly (coronal balance: 8 to 1 cm [P < .001]; major curve: 37° to 12° [P < .001]; fractional curve: 20° to 10° [P < .001]; sagittal balance: 11 to 4 cm [P < .001]; pelvic incidence to lumbar lordosis mismatch: 38° to 9° [P < .001]). Pain Numerical Rating Scale scores improved significantly (back: 7.2 to 4.2 [P = .001]; leg: 5.9 to 1.7 [P = .001]). No instrumentation complications occurred. Motor weakness persisted in 1 patient. There were 3 reoperations (1-PJK, 1-wound dehiscence, and 1-overcorrection). CONCLUSION Among 19 ASD patients treated with kickstand rod distraction, alignment, and back/leg pain improved significantly following surgery. Complication rates were reasonable.

Synchronous CRC and GIST has been more frequently reported. Because of the limited number of cases, we cannot exclude an incidental relationship. The genetic pathways of tumorigenesis appear different for the two neoplasms. Further studies are needed to clarify a possible role of c-Kit in the development of colonic adenocarcinomas.