Human type I interferonopathies

Transcription

1 Human type I interferonopathies Yanick Crow Institut Imagine, Paris University of Manchester Human type I interferonopathies 1

2 Inborn errors of enhanced type I interferon signaling Type I interferons 2

3 Type I interferons Primary antiviral cytokines 3

4 Probably all nucleated cells can produce IFN in response to virus infec7on, which reflects the importance of type I IFN in cell defense. Ini7a7on of the type I IFN an7viral state can be summarized by the following: 1. Recogni7on of viral pathogen- associated molecular paderns (PAMPS; i.e., conserved microbial mo7fs) by germline- encoded padern recogni7on receptors (PRR; i.e., cellular sensors) 2. S7mula7on of intracellular transduc7on pathways leading from PRR engagement to de novo IFN transcrip7on 3. Secre7on of IFNs that act in both an autocrine and paracrine manner through binding to a single heterodimeric type I IFN receptor composed of IFNAR1 and IFNAR2 4. Receptor binding that leads to intracellular signaling via the JAK STAT pathway and the induc7on of hundreds of IFN- s7mulated genes (ISGs), the majority of which have unknown func7ons 4

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8 Virus DNA ssrna dsrna TLR9 TLR7(8) TLR3 RIG-I cgas MDA5 Type I IFN induced antiviral state Intrinsic immunity proteins eif2α, 2-5 OAS, ADAR1, Mx, APOBEC, Fv, TRIM etc Adaptive immune system B T 8

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15 Loss of AGS- related protein ac7vity Nucleic acid accumula7on Nucleic acid sensing Triggered immune response AGS Human type I interferonopathies 15

16 Monogenic disorders in which an upregulation of a type I interferon response may be directly relevant to disease pathogenesis Inappropriate stimulation of the type I interferon machinery Abnormal accumulation of an endogenous nucleic acid ligand Change in the composition of an endogenous nucleic acid ligand Enhanced sensitivity or ligand-independent (constitutive) activation of a nucleic acid receptor Enhanced sensitivity or ligand-independent (constitutive) activation of a non-nucleic acid receptor (e.g. an adaptor molecule) Defective negative regulation of a nucleic-acid dependent type I interferon response Mutations in genes involved in non-nucleic acid related stimulation / regulation of the type I interferon pathway (including components of the adaptive immune response) 16

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19 Aicardi-Goutières syndrome (AGS) is a paradigm type I (monogenic) interferonopathy Do other type I interferonopathies exist? 19

20 How to identify type I interferonopathies? 20

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23 PAXgene tube 2.5ml Stable at room temperature (for at least 72 hours) Result within 5 working days 23

24 The phenotypic extent of the type I interferonopathies is likely not yet fully defined 24

25 Because There is no routine clinical test in use for detecting dysregulated type I interferon signalling 25

26 Male (32 years of age) has cerebral palsy, diagnosed in very early childhood significant spasticity. Condition very slowly progressive. Recent brain and spine MRI normal. His daughter has neurologically similar disease from early infancy - increased tone and reflexes in lower limbs, some dystonic hand movements. Considering family history, thought must just be dominant HSP. Child then became unwell (before age 2 years) with irritability / crying episodes and white matter changes on MRI, and reddening of her hands. Child has developed lupus and now on immunosuppresion. 26

27 Severe developmental delay Presented age 29 months with a 4 week history of recurring fevers, irritability, weight loss and diarrhea Florid ulcera7ve photosensi7ve vasculi7c rash Hepatosplenomegaly, generalized lymphadenopathy, arthri7s Serosi7s with pericardial effusion Raised ESR and CRP Haemoly7c anaemia Markedly abnormal autoan7body profile (ANA >1:640, dsdna 1200 IU/ml, raised an7- cardiolipin Abs, low complement, and strongly posi7ve panca) 27

28 Male. Development normal un7l the age of 15 months, at which 7me he was riding a push car and had 6-10 words Acer this point he developed intermident posturing and rigidity of his legs, and then of the upper extremi7es with a relentless loss of motor and intellectual skills, so that by age 24 months he was unable to sit unsupported and had lost the ability to swallow Now, at the age of 12 years, he has no useful hand func7on, cannot sit independently and has limited words, although his understanding is somewhat beder 28

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32 Inappropriate stimulation of the type I interferon machinery Abnormal accumulation of an endogenous nucleic acid ligand Change in the composition of an endogenous nucleic acid ligand Enhanced sensitivity or ligand-independent (constitutive) activation of a nucleic acid receptor Enhanced sensitivity or ligand-independent (constitutive) activation of a non-nucleic acid receptor (e.g. an adaptor molecule) Defective negative regulation of a nucleic-acid dependent type I interferon response Mutations in genes involved in non-nucleic acid related stimulation / regulation of the type I interferon pathway (including components of the adaptive immune response) 32

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37 Inappropriate stimulation of the type I interferon machinery Abnormal accumulation of an endogenous nucleic acid ligand Change in the composition of an endogenous nucleic acid ligand Enhanced sensitivity or ligand-independent (constitutive) activation of a nucleic acid receptor Enhanced sensitivity or ligand-independent (constitutive) activation of a non-nucleic acid receptor (e.g. an adaptor molecule) Defective negative regulation of a nucleic-acid dependent type I interferon response Mutations in genes involved in non-nucleic acid related stimulation / regulation of the type I interferon pathway (including components of the adaptive immune response) 37

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42 NG 2007;39: Autosomal dominant Familial chilblain lupus VI at 8 years Lee- Kirsch et al AJHG Direct IF showing deposi?on of C3 on BM. Similar staining was seen for IgA and IgM 42

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50 25/01/16 SPENCD: Immuno-osseus dysplasia Lupus, Sjögren s, Polymyositis, Scleroderma, Hypothyroidism 50

51 Autoimmune phenotype Antinuclear antibodies Anti-dsDNA antibodies Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Pt 8 Pt 9 Pt 10 1:1280 1:640 No 1:640 No >1:320 Yes 1:1280 1:1600 1:640 No 1:320 No Yes No 1:1280 Yes Yes Yes Yes Thrombocytopenia No Yes Yes No No No Yes Yes Yes No Autoimmune haemolytic anaemia No No No No No Yes No No Yes No Lupus nephritis No Yes No No No No Yes No Yes No Non-erosive arthropathy (>2 joints) ACR diagnosis of lupus Treated Hypothyroidism Raynaud s / Vasculitis No No No No No No No Yes No No No Yes No No No No Yes Yes Yes No Yes Yes No No No No No Yes No No Yes No No Yes Yes No No No No No Sjögren s syndrome Yes No No No No No No No No No Myositis Yes No No No No No No No No No 51

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55 HUMAN GENOME Genes Junk 40% of human genome derived from fragments of ancestral viral sequence 55

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