Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity

Sogkas, Georgios; Atschekzei, Faranaz; Adriawan, Ignatius Ryan; Dubrowinskaja, Natalia; Witte, Torsten; Schmidt, Reinhold

doi:10.1038/s41423-020-00626-z

Cited by 55 publications

(44 citation statements)

References 269 publications

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“…Lymphadenopathy and splenomegaly, seen frequently in patients with CVID, are rare amongst GS patients. The contrasting features of these two predominantly antibody deficiencies are shown in Table 1 and may provide more insight on the intersection of genetics, autoimmunity, and inborn errors of immunity ( 41 , 42 ).…”

Section: Controversies Regarding Underlying Immune Pathologymentioning

confidence: 99%

Good’s Syndrome: Time to Move on From Reviewing the Past

2022

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For seven decades, the pathophysiology of Good’s syndrome (GS) has remained a mystery, with few attempts to solve it. Initially described as an association between hypogammaglobulinemia and thymoma, controversy exists whether this is a unique disease, or a subgroup of Common Variable Immune Deficiency (CVID). Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history. In this mini review, we discuss current state of the art data and identify research gaps. In order to resolve controversies and fill in knowledge gaps, we propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease. We hope this novel approach sets a clear direction to solve the current controversies.

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Section: Controversies Regarding Underlying Immune Pathologymentioning

confidence: 99%

Good’s Syndrome: Time to Move on From Reviewing the Past

2022

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“…Aberrations in TCR may result in altered TCR signalling and may also impair the central tolerance through an altered negative selection of autoreactive TCRs. These autoreactive TCRs may give rise to immune dysregulations that may present as autoimmune and inflammatory complications [58,59].…”

Section: T Cell Receptor (Tcr) Structure In Patients With Xlamentioning

confidence: 99%

T Cell Abnormalities in X-Linked Agammaglobulinaemia: an Updated Review

Chawla

Jindal

Arora

et al. 2022

Clinic Rev Allerg Immunol

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X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency (PID) resulting from a defect in the B cell development. It has conventionally been thought that T cells play a major role in the development and function of the B cell compartment. However, it has also been shown that B cells and T cells undergo bidirectional interactions and B cells also influence the structure and function of the T cell compartment. Patients with XLA offer a unique opportunity to understand the effect of absent B cells on the T cell compartment. In this review, we provide an update on abnormalities in the T cell compartment in patients with XLA. Studies have shown impaired memory T cells, follicular helper T cells, T regulatory cells and T helper 17 in patients with XLA. In addition, these patients have also been reported to have abnormal delayed cell-mediated immune responses and vaccine-specific T cell-mediated immune responses; defective T helper cell polarization and impaired T cell receptor diversity. At present, the clinical significance of these T cell abnormalities has not been studied in detail. However, these abnormalities may result in an increased risk of viral infections, autoimmunity, autoinflammation and possibly chronic lung disease. Abnormal response to SARS-Cov2 vaccine in patients with XLA and prolonged persistence of SARS-Cov2 virus in the respiratory tract of these patients may be related to abnormalities in the T cell compartment. Keywords X-linked agammaglobulinaemia (XLA) • Primary Immunodeficiency (PID) • Severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) • Bruton tyrosine kinase (BTK) • T cell receptor (TCR) • T follicular helper cells (TFH)Abbreviations XLA X-linked agammaglobulinaemia PID Primary immunodeficiency BTK Bruton tyrosine kinase BCR B cell receptor GC Germinal centre APC Antigen-presenting cells TCR T cell receptor MHC Major histocompatibility complex FDCs Follicular dendritic cells CVID Common variable Immunodeficiency ELISPOT Enzyme-linked immunospot CTL Cytotoxic T lymphocytes Tfh T follicular helper cells Tregs Regulatory T cells Th17 T helper 17 cells RTE Recent thymic emigrants DCs Dendritic cells CDR3 Complementarity determining region 3 GvHD Graft versus host disease EBV Epstein-Barr virus CMV Cytomegalovirus

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“…Next-generation sequencing (NGS) has considerably advanced our understanding of the genetic background of primary immunodeficiency disorders (PIDs) and led to the identification of an increasing number of monogenic forms of CVID ( 7 ). Furthermore, genetic studies provided new insights into the pathogenesis of PID-associated manifestations, such as autoimmunity and polyclonal lymphoproliferation ( 8 ). The same holds true for PID-associated cancers, where PID-associated genetic variants can either directly confer susceptibility to cancer or indirectly support carcinogenesis by causing genetic instability, persistent lymphoproliferation, and/or oncogenic infections ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

et al. 2022

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ObjectiveThe aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID).MethodsIn this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients’ family history and WES data were evaluated for genetic predisposition to cancer.ResultsA total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome.ConclusionsGastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

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Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity

Cited by 55 publications

References 269 publications

Good’s Syndrome: Time to Move on From Reviewing the Past

Good’s Syndrome: Time to Move on From Reviewing the Past

T Cell Abnormalities in X-Linked Agammaglobulinaemia: an Updated Review

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

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