No abstract

Background: The integrin α4β7 is highly expressed on activated T cells and is thought to direct homing of lymphocytes to the intestine. Since ulcerative colitis (UC) and Crohn's disease (CD) are characterized by mucosal oligoclonal T cells' expansion, we aimed to assess whether similar repertoire features are identified in circulating gut-specific memory T cells. Methods: Memory CD3 + T cells were isolated from blood samples of control subjects and patients with active UC or CD and then FACS-sorted into α4β7 + and α4β7 − populations. DNA was extracted from each subset and subjected to next-generation sequencing of the TCRβ. Different repertoire characteristics were compared between α4β7 + and α4β7 − subsets for each subject, and between groups. Results: The percentages of memory T cells and α4β7 + cells were comparable between groups. α4β7 + memory T cells displayed a polyclonal distribution, in control subjects and in UC or CD patients, with similar indices of diversity. Strikingly, the clonal overlap between α4β7 + and α4β7 − T cells for each subject in all three groups was high, ranging between 20%-50%. We were unable to identify shared T cell clones that were specific to one of the groups. Conclusion: α4β7 + memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active inflammatory bowel disease, with high rates of overlap with α4β7 − memory T cells. Our study, along with additional recent reports, may suggest that the suppression of intestinal inflammation by vedolizumab is independent of the drug's effect on T cell migration to the gut.

Introduction: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies and Hirschsprung disease. Objective: To provide clinical and immunological insights obtained from two unrelated patients who displayed clinical characteristics of CHH. Methods: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency, underwent immunological and genetic work-up using flow cytometry, immune repertoire next-generation sequencing (NGS), and Sanger sequencing to identify the underlying defects. Results: P1 presented with low birth weight and skeletal dysplasia. Newborn screening (NBS) was suggestive of T cell immunodeficiency as T cell receptor excision circle (TREC) levels were undetectable. Both T cell receptor (TCR) - Vβ and T-cell receptor gamma (TRG) repertoire were restricted with evidence of clonal expansion. Genetic analysis identified compound heterozygous variants inherited from both parents in RMRP. P2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive and hepatomegaly. TCRβ repertoire revealed a normal polyclonal pattern with only slight overexpression of TCR-βV20 and several restricted expression of Vβs. TRG expressed a normal diverse repertoire, similar to the healthy control sample. Genetic analysis identified bi-allelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. Conclusion: Our findings demonstrate how immunological work-up, supported by genetic findings can dramatically change the suggestive treatment and future outcome in patients with the same clinical syndrome.