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The immunological events leading to type 1 diabetes (T1D) are complex and heterogeneous, underscoring the necessity to study rare cases to improve our understanding. Here, we report the case of a 16-year-old patient who showed glycosuria during a regular checkup. Upon further evaluation, stage 2 T1D, autoimmune thrombocytopenic purpura (AITP), and common variable immunodeficiency (CVID) were diagnosed. The patient underwent low carb diet, losing > 8 kg, and was placed on Ig replacement therapy. Anti-CD20 monoclonal antibody (Rituximab, RTX) was administered 2 years after diagnosis to treat peripheral polyneuropathy, whereas an atypical mycobacteriosis manifested 4 years after diagnosis and was managed with prolonged antibiotic treatment. In the fifth year of monitoring, the patient progressed to insulin dependency despite ZnT8A autoantibody resolution and IA-2A and GADA autoantibody decline. The patient had low T1D genetic risk score (GRS = 0.22817) and absence of human leukocyte antigen (HLA) DR3/DR4-DQ8. Genetic analysis identified the monoallelic mutation H159Y in TNFRSF13C, a gene encoding B-cell activating factor receptor (BAFFR). Significant reduced blood B-cell numbers and BAFFR levels were observed in line with a dysregulation in BAFF–BAFFR signaling. The elevated frequency of PD-1+ dysfunctional Tfh cells composed predominantly by Th1 phenotype was observed at disease onset and during follow-up. This case report describes a patient progressing to T1D on a BAFFR-mediated immunodysregulatory background, suggesting a role of BAFF–BAFFR signaling in islet-specific tolerance and T1D progression.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS, as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID. This article is protected by copyright. All rights reserved.

Patients with Down syndrome (DS) are characterized by increased susceptibility to autoimmunity and respiratory tract infections that are suggestive of humoral immunity impairment. Here, we sought to determine the follicular helper (Tfh) and follicular regulatory (Tfr) T cell profile in the blood of children with DS. Blood was collected from 24 children with DS, nine of which had autoimmune diseases. Children with DS showed skewed Tfh differentiation towards the CXCR3+ phenotype: Tfh1 and Tfh1/17 subsets were increased, while Tfh2 and Tfh17 subsets were reduced. While no differences in the percentage of Tfr cells were seen, the ratio of Tfh1 and CXCR3+PD-1+ subsets to Tfr cells was significantly increased in the affected children. The excessive polarization towards a CXCR3+ phenotype in children with DS suggests that re-calibration of Tfh subset skewing could potentially offer new therapeutic opportunities for these patients. Patients with Down syndrome (DS) are characterized by increased susceptibility to autoimmunity and respiratory tract infections that are suggestive of humoral immunity impairment. Here, we sought to determine the follicular helper (Tfh) and follicular regulatory (Tfr) T cell profile in the blood of children with DS. Blood was collected from 24 children with DS, nine of which had autoimmune diseases. Children with DS showed skewed Tfh differentiation towards the CXCR3+ phenotype: Tfh1 and Tfh1/17 subsets were increased, while Tfh2 and Tfh17 subsets were reduced. While no differences in the percentage of Tfr cells were seen, the ratio of Tfh1 and CXCR3+PD-1+ subsets to Tfr cells was significantly increased in the affected children. The excessive polarization towards a CXCR3+ phenotype in children with DS suggests that re-calibration of Tfh subset skewing could potentially offer new therapeutic opportunities for these patients.

Background:Clinical improvement after B-cell depletion with rituxmab suggests a prominent pathogenic role of B-lymphcytes in IgG4-related disease (IgG4-RD). IgG4-RD, however, relapses in most cases together with re-expansion of clonally divergent plasmablasts indicating that treatment with rituximab does not completely abrogates T follicular helper (Tfh)-cells dependent germinal center reactions leading to de-novo plasmablast differentiation.Objectives:In the present work we aim to study the effects of B-cell depletion therapy with rituximab on circulating Tfh cells and on the levels of CXCL13 - a chemotactic factor for B-lymphocytes produced by Tfh cells - in patients with IgG4-RD.Methods:Thirty patients with IgG4-RD, diagnosed according to the “Consensus Statement on the Pathology of IgG4-RD” and fulfilling the “2019 ACR/EULAR Classification Criteria” were included in the present study. Ten patients with relapsing disease were treated with the anti-CD20 monoclonal antibody rituximab (two 1g infuxions 15 days apart). Peripheral blood mononuclear cells and serum were collected before rituximab and three months after infusion. Tfh cells subsets in the peripheral blood were measured by flow cytometry and CXCL13 plasma levels were measured by ELISA assay.Results:No changes in total Tfh cells and Tfh cells subsets were observed three months after rituximab neither in absolute counts nor in percentage of CD4+ T cells. In particular, no difference in Tfh1, Tfh2, Tfh17, T follicular regulatory and highly functional Tfh cells counts was observed before and after treatment. The serum level of CXCL13 was significantly higher in active untreated IgG4-RD patients compared to healthy controls (151.94 pg/ml vs 66.98 pg/ml, p value = 0.0026), but was not affected by rituximab treatment (p value = 0.41).Conclusion:In relapsing patients with IgG4-RD rituximab does not affect circulating Tfh cells numbers and serum levels of CXCL13. Persistence of Tfh cells after rituximab and reconstitution of germinal center reactions likely drives IgG4-RD flare.References:[1]Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067. doi: 10.1136/bmj.m1067. PMID: 32546500.[2]Lanzillotta M, Della-Torre E, Stone JH. Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes. Curr Top Microbiol Immunol. 2017;401:85-92. doi: 10.1007/82_2016_58. PMID: 28091934.[3]Campochiaro C, Ramirez GA, Bozzolo EP, Lanzillotta M, Berti A, Baldissera E, Dagna L, Praderio L, Scotti R, Tresoldi M, Roveri L, Mariani A, Balzano G, Castoldi R, Doglioni C, Sabbadini MG, Della-Torre E. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45. doi: 10.3109/03009742.2015.1055796. Epub 2015 Sep 23. PMID: 26398142.[4]Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, Deshpande V, Stone JH, Pillai S. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014 Sep;134(3):679-87. doi: 10.1016/j.jaci.2014.03.034. Epub 2014 May 6. PMID: 24815737; PMCID: PMC4149918.Disclosure of Interests:None declared

Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA, or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency. These findings offer useful insight for human Tfh biology, with potential implications for understanding the molecular basis of HIGM syndrome caused by mutations in CD40.