Genetic basis of autoimmunity

Marson, Alexander; Housley, William; Hafler, David A.

doi:10.1172/jci78086

Cited by 100 publications

(86 citation statements)

References 120 publications

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“…In contrast to UC and CD, SNPs identified for RA and T1D were enriched in Th1–Th17 SEs. Many genes linked to these SNP-containing SEs have been implicated in RA or T1D, including IL2RA/B , CTLA4 , and CSF2 (Marson et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Koues

Collins

Cella

et al. 2016

Cell

145

150

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SUMMARY Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been studied extensively in model organisms, little is known about these “first responders” in humans, especially their lineage and functional kinships to cytokine-secreting T helper (Th) cell counterparts. Here, we report gene regulatory circuitries for four human ILC–Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells, but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell identity genes in each lineage, uncovering new modes of regulation for signature cytokines, new molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC–Th subsets.

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Section: Resultsmentioning

confidence: 99%

Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Koues

Collins

Cella

et al. 2016

Cell

145

150

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“…Disease-relevant polymorphisms are predominantly located in regulatory regions of genes associated with the immune response and only the accumulation of multiple variations contributes significantly to pathogenesis in single patients [5,6]. However, some genes like the human leukocyte antigen (HLA) alleles show strong association and have been known for long time [7].…”

Section: Autoimmunity-immune System Out Of Balancementioning

confidence: 99%

Follicular Helper T Cells in Autoimmunity

2016

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The development of multiple disease-relevant autoantibodies is a hallmark of autoimmune diseases. In autoimmune type 1 diabetes (T1D), a variable time frame of autoimmunity precedes the clinically overt disease. The relevance of T follicular helper (TFH) cells for the immune system is increasingly recognized. Their pivotal contribution to antibody production by providing help to germinal center (GC) B cells facilitates the development of a long-lived humoral immunity. Their complex differentiation process, involving various stages and factors like B cell lymphoma 6 (Bcl6), is strictly controlled, as anomalous regulation of TFH cells is connected with immunopathologies. While the adverse effects of a TFH cell-related insufficient humoral immunity are obvious, the role of increased TFH frequencies in autoimmune diseases like T1D is currently highlighted. High levels of autoantigen trigger an excessive induction of TFH cells, consequently resulting in the production of autoantibodies. Therefore, TFH cells might provide promising approaches for novel therapeutic strategies.

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“…Genome wide association studies (GWAS) have been instrumental in advancing our understanding of the genetic architecture of autoimmune diseases and demonstrate that most result from a number of complex interactions between polygenetic factors and environmental triggers [2]. GWAS has identified hundreds of common (i.e.…”

Section: Introductionmentioning

confidence: 99%

Rare variants, autoimmune disease, and arthritis

Chung

Shum²

2016

Current Opinion in Rheumatology

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Purpose of review We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. Recent findings Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the COPA syndrome due to rare mutations in COPA and Haploinsufficiency of A20 (HA20) resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus. Summary Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases.

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Genetic basis of autoimmunity

Abstract: R e v i e w S e R i e S : A u t o i m m u n i t y2 2 3 5

Cited by 100 publications

References 120 publications

Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Follicular Helper T Cells in Autoimmunity

Rare variants, autoimmune disease, and arthritis

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