Autoimmunity in Hyper-IgM Syndrome

Jesus, Adriana A.; Duarte, Alberto J. S.; Oliveira, João Bosco

doi:10.1007/s10875-008-9171-x

Cited by 89 publications

(60 citation statements)

References 29 publications

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“…48 Strengthening this possibility, defective CD40-CD40L signaling leads to autoimmunity in both humans and mice. [46][47][48] In this scenario, we propose that recognition of self-peptide-major histocompatibility complexes by high-affinity TCRs expressed on positively selected DP thymocytes may be the mechanism that triggers CD40L expression on nTreg progenitors and leads to feedback maturation of thymic pDCs in vivo, thereby facilitating a functional cross-talk between pDCs and developing thymocytes, resulting in terminal nTreg differentiation. Still, further in vivo studies are required to establish the physiologic relevance of CD40-CD40L in such cross-talk.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Martín‐Gayo

Sierra‐Filardi

Corbí

et al. 2010

Blood

175

142

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The generation of natural regulatory T cells (nTregs) is crucial for the establishment of immunologic self-tolerance and the prevention of autoimmunity. Still, the origin of nTregs and the mechanisms governing their differentiation within the thymus are poorly understood, particularly in humans. It was recently shown that conventional dendritic cells (cDCs) in human thymus were capable of inducing nTreg differentiation. However, the function of plasmacytoid DCs (pDCs), the other major subset of thymic DCs, remains unknown. Here we report that pDCs resident in the human thymus, when activated with CD40 ligand (CD40L) plus interleukin-3, efficiently promoted the generation of CD4 ؉ CD25 ؉ Foxp3 ؉ nTregs from autologous thymocytes. The progenitors of these nTregs were selectively found within CD4 ؉ CD8 ؉ thymocytes that had accomplished positive selection, as judged by their CD69 hi TCR hi phenotype. Supporting the involvement of the CD40-CD40L pathway in pDC-induced nTreg generation, we show that positively selected CD4 ؉ CD8 ؉ progenitors specifically transcribed CD40L in vivo and upregulated CD40L expression on T-cell receptor engagement, thereby promoting the activation of pDCs. Finally, evidence is provided that nTregs primed by pDCs displayed reciprocal interleukin-10/transforming growth factor-␤ cytokine expression profiles compared with nTregs primed by cDCs. This functional diversity further supports a nonredundant tolerogenic role for thymic pDCs in the human thymus. (Blood. 2010;115(26):5366-5375) IntroductionDendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) that are crucial in the regulation of innate and adaptive immunity. DCs respond to danger signals by antigen uptake, maturation, and induction of antigen-specific immune responses in secondary lymphoid organs. 1,2 In addition, tissue DCs are able to present antigen in a tolerogenic fashion, leading to anergy or deletion of potentially self-reactive T cells, or inducing the generation of regulatory T cells (Tregs). [3][4][5][6] Tregs play a key role in the control of immune homeostasis and immunologic tolerance and are crucial to protect against fatal autoimmunity throughout life. Tregs also regulate or suppress other classes of immune responses, such as allograft rejection, allergy, tumor immunity, and responses to microbes. 7,8 Thus, there is great interest in understanding how do Tregs develop.During thymopoiesis, nearly all positively selected CD4 ϩ CD8 ϩ double-positive (DP) thymocytes carrying high-affinity T-cell receptors (TCRs) for self-peptide-major histocompatibility complexes are eliminated by a mechanism of clonal deletion that ensures central tolerance. 6 Self-reactive thymocytes that escape clonal deletion undergo an alternative process of nondeletional tolerance that involves their positive selection and further differentiation into immunosuppressive CD4 ϩ T cells, termed natural Tregs (nTregs). [8][9][10][11] In addition, Tregs can be induced in the periphery (iTregs) from CD4 ϩ T lymphocytes. 4 Generation o...

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Section: Discussionmentioning

confidence: 99%

Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Martín‐Gayo

Sierra‐Filardi

Corbí

et al. 2010

Blood

175

142

View full text Add to dashboard Cite

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“…Consistent with this idea, many patients have poor responses to pneumococcal vaccines following BM transplant, despite having reconstituted normal B cell numbers, and T cell targeting to mitigate graft-versus-host disease further exaggerates this defect (53). In addition, the altered BCR repertoire generated in the absence of CD40 signals may promote autoimmunity because hyper-IgM patients lacking CD40L suffer from various autoimmune symptoms (54). These collective impacts of the CD40 pathway should be taken into account when considering treatments that suppress T cells or CD40 signals because these manipulations are likely to have previously unappreciated effects on the B cell repertoire.…”

Section: /2mentioning

confidence: 97%

CD4+ T Cells and CD40 Participate in Selection and Homeostasis of Peripheral B Cells

Schwartz

Kolhatkar

Thouvenel

et al. 2014

The Journal of Immunology

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Control of peripheral B cell development and homeostasis depends critically on coordinate signals received through the BAFFRs and BCRs. The extent to which other signals contribute to this process, however, remains undefined. We present data indicating that CD4+ T cells directly influence naive B cell development via CD40 signaling. Loss of CD4+ T cells or CD40–CD40L interaction leads to reduced B cell homeostatic proliferation and hindered B cell reconstitution posttransplantation. Furthermore, we demonstrate that in the absence of CD40 signals, these events are modulated by BCR self-reactivity. Strikingly, murine models lacking CD40 reveal a broadly altered BCR specificity and limited diversity by both single-cell cloning and high-throughput sequencing techniques. Collectively, our results imply that any setting of T cell lymphopenia or reduced CD40 function, including B cell recovery following transplantation, will impact the naive B cell repertoire.

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“…In addition to the susceptibility to recurrent and opportunistic infections, these patients are also prone to autoimmune complications, especially hematologic abnormalities, autoimmune thyroid disease, nephritis, IBD, and RA. Moreover, organ-specific autoantibodies are commonly found in hyper-IgM patients [88,89,90]. Autoimmune complications mostly occur in patients with activation-induced cytidine deaminase (AID; 25%), NF-κB essential modulator (NEMO; 23%), and CD40 ligand (CD40L; 20%) defects [72].…”

Section: Autoimmunity In Padsmentioning

confidence: 99%

Autoimmunity in Primary Antibody Deficiencies

Azizi¹,

Ahmadi²,

Abolhassani³

et al. 2016

Int Arch Allergy Immunol

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Primary antibody deficiencies (PADs) are the most common inherited primary immunodeficiencies in humans, characterized by hypogammaglobulinemia, an inability to produce specific antibodies, and recurrent infections mainly caused by encapsulated bacteria. However, it has been shown that inflammatory disorders, granulomatous lesions, lymphoproliferative diseases, cancer, and autoimmunity are associated with the various types of PAD. Both systemic and organ-specific autoimmune diseases could be attributed to B-cell defects in PAD patients. Immune thrombocytopenic purpura and autoimmune hemolytic anemia are the most common autoimmune disorders in this group of patients. The aim of this review is to describe the proposed mechanisms for autoimmunity and to review the literature with respect to the reported autoimmune disorders in each type of PAD.

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Autoimmunity in Hyper-IgM Syndrome

Cited by 89 publications

References 29 publications

Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

CD4+ T Cells and CD40 Participate in Selection and Homeostasis of Peripheral B Cells

Autoimmunity in Primary Antibody Deficiencies

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