In rheumatoid arthritis, peripheral blood T cells have age-inappropriate telomeric erosion. We examined whether HLA-DRB1*04 alleles, the major susceptibility genes for this disease, confer risk for T cell senescence. In healthy individuals, HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4 ؉ T cells. Accelerated telomeric erosion occurred during the first two decades of life and was followed by reduced homeostatic T cell proliferation during adulthood. Premature telomeric loss also affected granulocytes, suggesting that the hematopoietic stem cell is the primary target. Telomeric repair mechanisms were intact in HLA-DRB1*04 ؉ donors. We propose that HLA-DRB1*04 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in rheumatoid arthritis.

IntroductionDe novo T-cell generation requires a functional thymus. 1 The current paradigm is that the human T-cell repertoire is established during late fetal development and that, by the time of birth, thymectomy does not cause immediate immunodeficiency. 2,3 Thymic epithelial space-the component of the thymus relevant for T-cell production and selectioninvolutes rapidly after birth. Thymic involution starts at the age of 1 year and continues with a yearly loss of 3%. 4,5 The peripheral T-cell compartment is under homeostatic control 6 ; with the reduction in thymopoietic capacity, alternative mechanisms of T-cell generation are necessary to prevent lymphopenia. Autoproliferation of postthymic T cells, particularly those in the memory compartment, is now accepted as a mechanism of T-cell production. 7,8 With advancing age, a shift occurs from efficient thymic lymphopoiesis to T-cell generation through peripheral replication; however, both mechanisms likely coexist during adult life. Age-related loss of thymic function is not the only condition that necessitates alternative means of repopulating the T-cell compartment. A number of clinical conditions, including chemotherapy, bone marrow transplantation, and infection with human immunodeficiency virus, are associated with T-cell depletion and the subsequent need to regenerate T cells despite limited thymopoietic capability. Evidence shows that recovery of peripheral T-cell numbers after chemotherapy is from thymic sources in children younger than 18 years of age. 7 In adults, thymopoiesis may still contribute to some degree, but replication of peripheral T cells becomes the dominant mechanism of filling the pool. It is obvious that the proliferation of postthymic T cells, especially when not entirely random, can have profound consequences on the composition of the T-cell repertoire. 9,10 What precisely these consequences are for immunocompetence is not understood.Functionality of the immune system is tightly linked to the receptor diversity of the T-cell pool. 11,12 Obviously, a large spectrum of T-cell receptors (TCRs) increases the chances of recognizing invading microorganisms. Thymopoiesis, the single mechanism of creating novel T cells, should be the key factor in determining immunocompetence. Young adults carry approximately 2 ϫ 10 11 CD4 ϩ T cells and approximately 1 ϫ 10 11 CD8 ϩ T cells. 13,14 The highest degree of diversity would be obtained if each naive T cell in the pool had a unique TCR. However, such a high degree of diversity might not be advantageous because it would decrease the probability of antigen recognition at a given tissue site. Instead, a minimal clonal size for each naive T-cell specificity is required to increase the chance for a T cell to encounter antigen and to mount a defensive response. Generation of a minimal clonal size requires that T cells selected in the thymus undergo intrathymic or postthymic proliferation.Arstila et al 15 have estimated the clonal size of naive T cells in adult humans. They measured an average diversity ...

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5W414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

Nearly 15 % of all patients operated with TAPT for HD continue to experience persistent bowel symptoms with constipation as the main problem. Further studies on the long-term outcome of children operated with this technique for HD are necessary to evaluate stooling patterns, urinary and sexual function as well as general quality of life during adolescence and adulthood.

Including a full range of articles reflecting the heterogeneity of EA, mortality rate significantly decreased during the course of 80 years. Along with the decrease in mortality, there is a shift to the importance of major postoperative complications and long-term morbidity regardless of surgical technique.

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This meta-analysis shows that nearly one-third of the patients continue to have long-term bowel problems, such as constipation, soiling and recurrent enterocolitis following LAPT. Many patients treated by LAPT require secondary surgery. Large randomized studies with long-term follow-up are necessary to determine the difference in outcome between LAPT and completely transanal pull-through operation.

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