Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

Pathway paradigms revealed from the genetics of inflammatory bowel disease.

CARD protein–BCL-10–MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system. CARD protein–BCL-10–MALT1 (CBM) signalosomes are key regulators of innate and adaptive immunity and inflammation. This Review summarizes the regulation and function of CBM signalling for host defence and tissue homeostasis and the pathophysiological consequences of genetic CBM alterations in human disease.

CARD-BCL-10-MALT1 signalling in protective and pathological immunity.

CARD9 is a signaling adaptor protein that is involved in the transduction of signals from a variety of innate pattern recognition receptors, including the C-type lectin receptors and intracellular NOD receptors and nucleic acid sensors. As a result, CARD9 has been shown in animal models to be an important regulator of immunity to bacteria, fungi, and viruses. Studies in humans with autosomal recessive CARD9 deficiency have indicated a highly specific role for this molecule in the activation of antifungal immune responses in the central nervous system, the oral mucosa, and the skin. Moreover, CARD9-dependent functions have recently been indicated to modulate the development of autoimmunity, inflammatory bowel diseases, and cancer. In this mini-review, we highlight the recent studies that have identified several novel functions of CARD9 in various disease contexts, and we summarize the contemporary understanding of the genetics and immunology of human CARD9 deficiency.

/pdf/human-card9-a-critical-molecule-of-fungal-immune-2quqa644o5.pdf

Human CARD9: A Critical Molecule of Fungal Immune Surveillance.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology. 

/pdf/large-scale-sequencing-identifies-multiple-genes-and-rare-45u1rduz.pdf

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB–mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9–TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics.

https://www.pnas.org/content/pnas/114/43/11392.full.pdf

Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease

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Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease