The Autoimmunity-Associated Gene CLEC16A Modulates Thymic Epithelial Cell Autophagy and Alters T Cell Selection

Schuster, Cornelia; Gerold, Kay D.; Schober, Kilian; Probst, Lilli; Boerner, Kevin; Kim, Mi-Jeong; Ruckdeschel, Anna; Serwold, Thomas; Kissler, Stephan

doi:10.1016/j.immuni.2015.04.011

Cited by 94 publications

(87 citation statements)

References 44 publications

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“…Autophagy itself is also an important process in central selection as thymic epithelia utilize this process in effectively presenting to and negatively selecting T cells [48,49]. Thus it is possible that the aberrant autophagy in Copa syndrome itself may be promoting autoreactivity in the T cell compartment – perhaps directly explaining pathological autoantibody production.…”

Section: Pathogenesismentioning

confidence: 99%

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

et al. 2016

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Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: “Copa syndrome”. Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1β and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.

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Section: Pathogenesismentioning

confidence: 99%

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

et al. 2016

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“…Clec16a knockdown mice show reduced numbers of B cells,29 and are protected from autoimmunity 30. Further work is required to determine whether CLEC16A or DEXI is the relevant gene in this interval.…”

mentioning

confidence: 99%

Common variants at PVT1, ATG13–AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency

Bronson¹,

Chang²,

Bhangale³

et al. 2016

Nat Genet

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Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our GWAS meta-analysis of 1,635 IgAD patients and 4,852 controls identified four new significant (P < 5x10 −8 ) loci and association with a rare IFIH1 variant (Ile923Val). Peak novel variants (PVT1 P = 4.3x10 −11 , ATG13-AMBRA1 P = 6.7x10 −10 , AHI1 P = 8.4x10 −10 and CLEC16A P = 1.4x10 −9 ) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including eQTLs for AHI1 and DEXI and DNase hypersensitivity in FOXP3+ T regulatory cells. A pathway analysis of the meta-analysis results showed a striking association with the KEGG pathway for IgA production (pathway P < 0.0001): where 22 of 30 annotated pathway genes contained at least one variant with a P-value ≤0.05 in the IgAD metaanalysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contribute to IgAD.IgAD is the most common primary immunodeficiency and is defined by serum IgA level <0.07 g/L.1 The prevalence in Europeans is 1:600.1 Secretory IgA (sIgA) is important for mucosal immunity and gut commensalism2,3, and clinical features of IgAD include recurrent mucosal infections. In IgAD, B cells fail to terminally differentiate into IgA+ plasma cells, however IL-21 can restore B cell IgA production in vitro4,5. IgAD is strongly associated with HLA6 and aggregates in families with autoimmunity.7 The prevalence of Celiac disease is 35 times higher in IgAD patients whereas the prevalence of systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) is 10 times higher.8Ferreira et al.6 previously imputed HLA-B, HLA-DRB1 and HLA-DQB1 in IgAD cases and controls (>2,700 individuals).9 The primary signal mapped to HLA-DQB1*02 (OR = 2.8, P = 7.7x10 −57 ), due to combined independent effects of the HLA-B*08:01-DRB1*03:01-DQB1*02 and HLA-DRB1*07:01-DQB1*02 haplotypes.9 There was a secondary signal at HLA-DRB1*01:02 (OR = 4.28, P = 5.86x10 −17 ) and a protective effect for HLA-DRB1*15:01 (OR = 0.13, P = 2.24x10 −35 ).9 HLA-DQB1*02:01 is protective for IgA nephropathy (OR = 0.71, P = 2.61x10 −13 ). 10 None of the non-MHC IgAD loci overlapped with IgA nephropathy.10 A previous GWAS identified the common allele IFIH1 Thr946Ala (OR = 0.62, control allele frequency = 0.39) as the first and, to date, only non-HLA genome-wide significant IgAD To expand our understanding of IgAD risk, we studied four new IgAD cohorts, and performed a GWAS meta-analysis of ~9.5M SNPs in 1,635 cases and 4,852 controls (Table 1). Genotypes for untyped markers were imputed for each cohort separately (1000 Genomes Project) and genotypes for variants fully typed in the entire cohort. Up to four controls per new case were iteratively selected based on ancestry eigenvectors14 to minimize population substructure (Online Methods). Genomic inflation factor values were minimal ( Table 1), indicating that population substructure was adequately addressed. Association analyses were c...

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“…One possible explanation for the discrepancy between results from Atg5 versus Atg7 deficient mice is that autophagy associated antigen presentation may utilize different components than the autophagy pathway itself (71, 75–77). Interestingly, a recent report suggested that knockdown of Clec16a, an autophagy/mitophagy-associated protein (78, 79), is protective in the Non-obese diabetes (NOD) model of type 1 diabetes (80). They proposed that this was due to alterations in the generation and presentation of ligands by mTECs responsible for selecting diabetogenic T cells, rather than tolerance to islet associated antigens.…”

Section: Role Of Mtecs and Bm Apcs In Self-tolerancementioning

confidence: 99%

Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen

Perry

Hsieh

2016

Immunological Reviews

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The development of T cell self-tolerance in the thymus is important for establishing immune homeostasis and preventing autoimmunity. Here, we review the components of T cell tolerance, which includes TCR self-reactivity, costimulation, cytokines, and antigen presentation by a variety of APCs subsets. We discuss the current evidence on the process of regulatory T (Treg) cell and negative selection and the importance of TCR signaling. We then examine recent evidence showing unique roles for bone marrow (BM)-derived APCs and medullary thymic epithelial cells (mTECs) on the conventional and Treg TCR repertoire, as well as emerging data on the role of B cells in tolerance. Finally, we review the accumulating data that suggest that cooperative antigen presentation is a prominent component of T cell tolerance. With the development of tools to interrogate the function of individual APC subsets in the medulla, we have gained greater understanding of the complex cellular and molecular events that determine T cell tolerance.

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The Autoimmunity-Associated Gene CLEC16A Modulates Thymic Epithelial Cell Autophagy and Alters T Cell Selection

Cited by 94 publications

References 44 publications

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

Common variants at PVT1, ATG13–AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency

Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen

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