Seronegative Myasthenia Gravis, as a Rare Autoimmune Condition in Turner Syndrome

Girls with Turner syndrome (TS), especially with isochromosome 46,X,i(X)(q10), are prone to develop autoimmunity. Associations of several autoimmune conditions with TS have been frequently described in the past. However, the unique combination of TS and myasthenia gravis (MG) has been reported only once before in a girl with mosaic monosomy 45,X/46,XX. Here, we present the second case of a girl affected with seronegative MG but with mosaic isochromosome TS. This is a child with developmental delay presented with muscle weakness, frequent fall, and bilateral ptosis. Diagnosis of MG was made based on positive Tensilon and electromyography tests and excellent response to intravenous immunoglobulin. At the age of 11 years due to short stature and developmental delay, a karyotype was done and revealed the mosaic isochromosome 45,X/46,X,i(X)(q10). Overall, clinicians should be aware of the vulnerability of girls with TS to autoimmunity, especially if the isochromosome 46,X,i(X)(q10) karyotype is identified. Furthermore, if a child with TS develops muscle weakness, ptosis, or ophthalmoplegia, MG should also be included in the differential diagnosis, particularly if other concurrent autoimmune conditions are present

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

3 páginas, 1 figura con 8 paneles.Supported by grants (MICINN, P.I3, SAF2006-12863, SAS/PI-024/2007, and SAS/PI-0236/2009, to Dr. Cuesta-Muñoz) from the Junta de Andalucía, and a grant (to Dr. Glaser) from the Russell Berrie Foundation and D-Cure, Diabetes Care in Israel.Peer reviewe

The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease

IRAK-4-and MyD88-Dependent Pathways Are Essential for the Removal of Developing Autoreactive B Cells in Humans

Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for interleukin-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 (MyD88), and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal, and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive mature naive B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans