Genetic polymorphisms in the IL-2Rα chain (CD25) locus are associated with several human autoimmune diseases, including multiple sclerosis (MS). Blockade of CD25 by the humanized monoclonal antibody (Ab) daclizumab decreases MS-associated inflammation, but has surprisingly limited direct inhibitory effects on activated T cells. The present study describes unexpected effects of daclizumab therapy on innate lymphoid cells (ILCs). The number of circulating RORγt+ ILCs, which include lymphoid tissue inducer (LTi) cells, was found to be elevated in untreated MS patients compared to healthy subjects. Daclizumab therapy not only decreased numbers of ILCs, but also modified their phenotype away from LTi cells and toward a natural killer (NK) cell lineage. Mechanistic studies indicated that daclizumab inhibited differentiation of LTi cells from CD34+ hematopoietic progenitor cells or c-kit+ ILCs indirectly, steering their differentiation towards immunoregulatory CD56bright NK cells through enhanced intermediate affinity IL-2 signaling. Because adult LTi cells may retain lymphoid tissue inducing capacity or stimulate adaptive immune responses, we indirectly measured intrathecal inflammation in daclizumab-treated MS patients by quantifying the cerebrospinal fluid CXCL13 and immunoglobulin G (IgG) index. Both of these inflammatory biomarkers were inhibited by daclizumab treatment. Our study indicates that innate lymphoid cells are involved in the regulation of adaptive immune responses, and their role in human autoimmunity should be investigated further, including their potential as therapeutic targets.
Background-Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI.
Objectives:We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon- and that this response correlated with expansion of CD56 bright NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. Methods:Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. Results:The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56 bright NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Conclusions: Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMSand immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. Classification of evidence:The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period. Neurology ® 2011;77:1877-1886 GLOSSARY Ab ϭ antibodies; BFV ϭ brain fractional volume; CEL ϭ contrast-enhancing lesion; EDSS ϭ Expanded Disability Status Scale; FLAIR ϭ fluid-attenuation inversion recovery; FSE ϭ fast spin echo; IFN- ϭ interferon-; IL ϭ interleukin; mAb ϭ monoclonal antibody; MOA ϭ mechanism of action; MFI ϭ mean fluorescence intensity; MS ϭ multiple sclerosis; MSFC ϭ Multiple Sclerosis Functional Composite; MTR ϭ magnetization transfer ratio; NRS ϭ Neurological Rating Scale; RRMS ϭ relapsing-remitting multiple sclerosis; T2LV ϭ T2 lesion volume; TNF␣ ϭ tumor necrosis factor ␣.We previously reported that patients with persistent MS disease activity on interferon- (IFN-) therapy were successfully treated by the addition of daclizumab, a humanized monoclonal antibody (mAb) against the ␣-chain of the interleukin (IL)-2 receptor (CD25). 1-3 The efficacy of therapeutic response correlated with the expansion of immunoregulatory CD56 bright NK cells,4 suggesting that this measurement may become a useful biomarker in therapeutic development of daclizumab.2 All of these observations have now been reproduced in an independent, multicenter, placebo-controlled clinical trial of daclizumab in MS (CHOI...
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the US. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African-Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; twenty (17%) nonsense; nine (8%) deletion; eight (7%) splice-site and seven (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34 % (147/435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36/115) of all mutations and 41% (29/71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35/71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C> T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum, summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5′ methylated CpG dinucleotides. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations.
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