How to Build a Fire: The Genetics of Autoinflammatory Diseases

Zhang, Jiahui; Lee, Pui Y.; Aksentijevich, Ivona; Zhou, Qing

doi:10.1146/annurev-genet-030123-084224

Cited by 10 publications

(2 citation statements)

References 195 publications

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“…Systemic autoinflammatory diseases (SAIDs) are a group of disorders induced by overactivation of innate immune system characterized by recurrent fever and multi-organ inflammation, but typically without high-titer antibodies or antigen-specific T cells. Distinct from autoimmune diseases defined by dysregulation of the adaptive immune system, SAIDs are believed to be mostly driven by the malfunction of innate immune cells such as monocytes and neutrophils 1,2 . Therefore, the contribution of adaptive immune cells in triggering activation of myeloid cells has not been appreciated in the pathogenesis of SAIDs.…”

Section: Introductionmentioning

confidence: 99%

RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

Dai,

Jin,

et al. 2024

Preprint

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Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of cell fate decision between pro-survival signaling and programmed cell death. The activation of RIPK1 is extensively modulated by posttranslational modification, such as ubiquitination. RIPK1 overactivation mediates autoinflammatory diseases in humans. However, the role of RIPK1 ubiquitination in human autoinflammatory diseases has not been reported, and the mechanism mediating the interaction of cell death and autoinflammation is largely unknown. Here, we report two patients carrying compound heterozygous RIPK1 variants K377E/R390G with recurrent fevers, lymphadenopathy and skin rashes. Mechanistically, K377E and R390G mutations impaired ubiquitination of RIPK1, which suppresses the formation of TNFR1 signaling complex (TNF-RSC) and NF-κB activation, resulting in the loss of CD8+ T cells mediated by RIPK1 activation-induced cell death in the patients. We reveal that the death of CD8+ T cells promotes the secretion of TNF and IFNγ to activate monocytes and macrophages, which triggers further production of proinflammatory cytokines to amplify autoinflammation. Disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFNγ attenuated proinflammatory cytokine production in macrophages. Collectively, our results demonstrate a crucial role of RIPK1 ubiquitination in regulating CD8+ T cell death and restraining autoinflammation. Our study demonstrates the mechanism for a group of autoinflammatory diseases mediated by RIPK1 activation-induced cell death, and highlights an important role of CD8+ T cells in driving autoinflammation.

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Section: Introductionmentioning

confidence: 99%

RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

Dai,

Jin,

et al. 2024

Preprint

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“…The most studied monogenic RDs are systemic autoinflammatory diseases (SAIDs) and early‐onset lupus. SAIDs comprise a group of over 40 diseases caused by dysregulation of the innate immune system 3,4 . These diseases typically present in infancy or early childhood and last throughout a patient's lifetime.…”

Section: Introductionmentioning

confidence: 99%

Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

Rowczenio,

Aksentijevich

2024

Arthritis & Rheumatology

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Rare and complex rheumatic diseases (RDs) present with immense clinical variability inherent to all immunological diseases. In addition to systemic and organ‐specific inflammation, patients may display features of immunodeficiency or allergy, and as such, they may represent major diagnostic and therapeutic challenges. The person's genetic architecture has been a well‐established risk factor for RDs, albeit to variable degrees. Patients with early‐onset diseases and/or positive family history have a strong genetic component, while patients with late‐onset RDs demonstrate a more complex interplay of genetic and environmental risk factors. Overall, the genetic studies in RDs have been instrumental to our understanding of innate and adaptive immunity in human health and disease. The elucidation of the molecular causes underlying rare diseases has played a major role in the identification of genes that are critical in the regulation of inflammatory responses. In addition, studies of patients with rare disorders may help determine the mechanisms of more complex autoimmune diseases by identifying variants with small effect sizes in the same genes. In contrast, studies of common RDs are carried out in cohorts of patients with well‐established phenotypes and ancestry‐matched controls, and they aim to discover disease‐related pathways that can inform the development of novel targeted therapies. Knowing the genetic cause of a disease has helped patients and families understand the disease progression and outcome. Here, we discuss the current understanding of genetic heritability and challenges in the diagnosis of RDs and how this field may develop in the future.image

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Curating Genetic Associations With Rheumatologic Autoimmune Diseases to Improve Patient Outcomes

Bridges,

Shapira,

Aksentijevich

et al. 2024

Arthritis & Rheumatology

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How to Build a Fire: The Genetics of Autoinflammatory Diseases

Cited by 10 publications

References 195 publications

RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

Curating Genetic Associations With Rheumatologic Autoimmune Diseases to Improve Patient Outcomes

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