ImmunoGenetics Presentation PDF

The genetics of inflammatory disease Deborah Cunninghame Graham  Learning Objectives Understand that there is a spectrum of inflammatory/autoimmune disorders Overview of disease progress: IBD, psoriasis, SLE with differences/commonality between them Summary of gen...

The genetics of inflammatory disease Deborah Cunninghame Graham  Learning Objectives Understand that there is a spectrum of inflammatory/autoimmune disorders Overview of disease progress: IBD, psoriasis, SLE with differences/commonality between them Summary of genetic risk factors Relevance of GWAS to therapy and drug discovery in AID Inflammatory/Autoimmune Diseases McGonagle and McDermott, PLoS Medicine 2019 Inflammatory/Autoimmune Diseases IBD: Crohn’s/UC McGonagle and McDermott, PLoS Medicine 2019 Inflammatory/Autoimmune Diseases IBD: Crohn’s/UC Psoriasis/ psoriatic arthritis McGonagle and McDermott, PLoS Medicine 2019 Inflammatory/Autoimmune Diseases IBD: Crohn’s/UC Psoriasis/ psoriatic arthritis Systemic Lupus Erythematosus McGonagle and McDermott, PLoS Medicine 2019 What is Inflammatory bowel disease (IBD)? Inflammation/ulcers Inflammation of all layers only in the mucosa of of the GI tract the colon Ileitis Ileocolitis Colitis Joints – arthritis; Skin – erythema nodosum; pyoderma gangrenosum; Eye – iridocyclitis; Liver – cholostatic liver diseases (primary sclerosing cholangitis)  Two types of IBD Ulcerative Colitis Crohn’s Disease – Continuous inflammation – Patchy inflammation – Colon only – Mouth to anus involvement – Superficial inflammation – Full-thickness inflammation – Variable extent – Fistulas and strictures – Risk of cancer – Risk of cancer – Extra-intestinal – Extra-intestinal manifestations manifestations Four Etiologic Hypotheses ETIOLOGIC HYPOTHESES for IBD Four Adapted from Terez-Shea Donohue, University of Maryland Four Etiologic Hypotheses ETIOLOGIC HYPOTHESES for IBD Four Adapted from Terez-Shea Donohue, University of Maryland  What is Psoriasis? A common, life-long, genetic, autoimmune skin disease Characterized by well circumscribed areas of thick, red, scaly skin From the Greek “psoros” meaning “rough, scabby”  Clinical features of psoriasis Itchiness Cracked skin Pain Pitted nails Arthritis (10-20%) Social isolation  Clinical features of Psoriasis Type Characteristics Plaque psoriasis Dry scaling patches (AKA common psoriasis) 75% Guttate psoriasis Drop-like dots, occurs after strep or viral infection 12% Erythrodermic Exfoliation of fine scales (total body “dandruff”), widespread, psoriasis often accompanied by severe itching and pain 7% Pustular psoriasis Pus-like blisters, noninfectious, fluid incl white blood cells 2% Seen on toenails and fingernails, starts as numerous pits, at Nail psoriasis times progresses to yellowing, crumbly, and thickened nail; nails may slough Erythema, thickening and peeling of the skin, blistering is often Palmar/Plantar present. Can lead to disability. Psoriasis Inflammation, swelling, and joint destruction Psoriatic arthritis Plaque-type lesion Scalp psoriasis  Triggers for Psoriasis Infections (e.g. streptococcal, viral) Skin trauma (Koebner phenomenon) Psychological stress Drugs (e.g. lithium, beta blockers) Sunburn Metabolic factors (e.g. calcium deficiency) Hormonal factors (e.g. pregnancy) u/k skin antigens stimulate immune response – Antigen-specific memory T-cells are primary mediators Leads to impaired differentiation and hyperproliferation of keratinocytes  Triggers for Psoriasis Infections (e.g. streptococcal, viral) Skin trauma (Koebner phenomenon) Psychological stress Drugs (e.g. lithium, beta blockers) Sunburn Metabolic factors (e.g. calcium deficiency) Hormonal factors (e.g. pregnancy) Unkown skin antigens stimulate immune response – Antigen-specific memory T-cells are primary mediators Leads to impaired differentiation and hyperproliferation of keratinocytes  Skin Changes in Psoriasis Normal skin Psoriatic skin stratum corneum disorganised neutrophil accumulation stratum granulosum stratum immaturity spinosum proliferation stratum basale dermis What is Systemic Lupus Erythematosus (SLE)? Autoimmune disease with unknown aetiology: – Chronic, inflammatory, multi-system disease – Skin, joints, kidneys, CNS involvement What is Systemic Lupus Erythematosus (SLE)? collapsing femur discoid lupus vasculitis joint disease butterfly rash kidney failure What is Systemic Lupus Erythematosus (SLE)? Autoimmune disease with unknown aetiology: – Chronic, inflammatory, multi-system disease – Skin, joints, kidneys, CNS involvement 3–4 fold less common in white Eur populations Frequency betw. 150 per 105 to 500 per 105 ~ 10:1 ratio females : males affected More common in females of child-bearing years What is Systemic Lupus Erythematosus (SLE)? Autoimmune disease with unknown aetiology: – Chronic, inflammatory, multi-system disease – Skin, joints, kidneys, CNS involvement 3–4 fold less common in white Eur populations Frequency betw. 150 per 105 to 500 per 105 ~ 10:1 ratio females : males affected More common in females of child-bearing years Auto-antibody production Nuclear antigens eg) dsDNA, Ro & La Cellular antigens eg) heat-shock proteins Cell surface antigens eg) anti-platelet, ACL Serum components eg) C1q 1982 ACR (rev. 1997) SLE Classification Criteria 1. Malar (butterfly) rash 2. Discoid lesions 3. Photosensitivity 4. Oral ulcers 5. Non-deforming arthritis (non-erosive for the most part) 6. Serositis: pleuropericarditis, aseptic peritonitis 7. Renal: persistent proteinuria › 0.5 g/d or ›3+ or cellular casts 8. Neurologic disorders: seizures, psychosis 9. Heme: hemolytic anemia; leukopenia, thrombocytopenia 10. Immune: anti-DNA, or anti-Sm, or APS (ACA IgG, IgM), or lupus anticoagulant (standard) or false + RPR 11. Positive FANA (fluorescent antinuclear antibody)  Comparison of SLE, IBD and Psoriasis SLE Crohn’s Disease Ulcerative colitis Psoriasis Prevalence 1:4000 5-10:100,000 10-20:100,000 15,000:100,000 Sex bias (M:F) 1:10 1.2:1 1:1.2 ~ 1.1 Ethnic bias Less common More common More common More common Europeans Europeans Europeans Europeans Age of onset Women childbearing Mean age = 26 Mean age = 34 15-40 years; esp. in 30s years Aetiology Complex trait Complex trait Complex trait Complex trait 10x inc risk MZ vs DZ High concor MZ; 50% High concor MZ; 50% 65–72%, versus 15– DZ DZ 30% in dizygotic twins. Relapsing remitting Relapsing remitting Relapsing remitting Relapsing remitting Sib risk ratio = 15 10% patients – family 10% patients – family > 50% of patients have history, sib risk = 30- history, sib risk = 10-20 positive family history; 40 sib risk = 10 Risk factors Oestrogen, 3x more common in non-/ex-smokers, Infection, stress pregnancy, smokers, low fibre, appendicectomy (physical/emotional), infections, UV light, high refined sugar protects, bacterial smoking, drugs (anti- stress, drug-induced diet, bacterial trigger trigger malarials, beta blockers, lithium Major Autoimmune Disease Loci Selected Major Association Signals in Autoimmune Diseases. Cho JH, Gregersen PK. N Engl J Med 2011;365:1612- 1623. Design of a GWAS EBI training online 2019 Typical GWAS study NHGRI-EBI GWAS catalogue  IBD Genetics studies 71 confirmed Crohn’s disease loci from a meta-analysis of 6 separate GWA studies from adult and early-onset cohorts from USA, UK, France/Belgium, and Germany (a total of 6,333 patients with Crohn's disease; 15,056 healthy controls). 47 confirmed UC loci from a meta-analysis of. 6 GWA studies were included from USA, UK, Germany and Sweden (a total of 6,782 patients with UC and 20,099 healthy controls). 163 total loci from ImmunoChip study – The CD cohorts contained a total of 6299 cases and 15148 controls, and the UC cohorts contained a total of 7211 cases and 20783 controls detailed study of genes implicated from immune-related diseases Jostins et al. Nature 2012  Psoriasis genetics studies Multiple association studies, including 7 GWAS – 60 risk loci (47 in Europeans)  SLE genetics studies GWAS studies: 7 EUR 6 Asian 1 Amerindian 84 loci Trans-ancestral ImmunoChip study AA: 2,970 cases 2,452 controls EA: 6,748 cases 11,516 controls HA: 1,872 cases 2,016 controls Chen et al. Curr. Opinion. Rheumatol. 2017  IBD susceptibility loci Lees C W et al. Gut 2011;60:1739-1753 Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.  Function of SLE loci 2 1 6 3 4 5 Geurra et al. Arth, Res. & Ther 2012 Gene Disease Function of Psoriasis Loci LCE Ps PsA IL12B Ps PsA IL13 Ps PsA IL23A Ps PsA IL23R Ps PsA ZNF313 Ps PsA IL2/IL21 PsA NFKB1A Ps TYK2 Ps TNFAIP3 Ps PsA TNIP1 Ps PsA TRAF3IP2 Ps PsA ERAP1 Ps HLA-C Ps PsA IFIH1 Ps IL28RA Ps  Disease overlap with IBD Lees C W et al. Gut 2011;60:1739-1753 Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.  Therapies for autoimmune diseases Largely non-specific treatments Historically treatments have limited clinical efficacy - based on – non-selective immunosuppression – cytotoxic drugs Biologicals have higher efficacy/faster onset of action – expensive – some patients do not respond adequately – can cause severe side effects Evidence from genetics (and immunological) studies may: – indicate specific drug targets – likely responders Companies market one drug over multiple diseases to recoup development costs  Genomic Medicine GWAS today, so new drug tomorrow? No. There are many steps between GWAS and improved health... From GWAS to Drug Discovery - I From GWAS to Drug Discovery - II From GWAS to Drug Discovery - III  GWAS Prevention, Dx, and Rx GWAS Replicate/validate Identify gene(s)/gene product(s) Develop Dx test Define function Devise prevention/ Identify drug target non-drug Show analytic therapeutic validity, clinical Design strategies validity and utility candidate drug Validate Clinical trials Obtain NHS usage via or third party payer outcome coverage Obtain FDA approval studies  Summary Large number of autoimmune/inflammatory disorders Three representative diseases: IBD, psoriasis, SLE Compare and contrast disease pathogenesis Overview of disease progress Genetic risk factors important in AID and pathways implicated Relevance of GWAS to therapy and drug discovery for AID  References Harden JL et al The immunogenetics of Psoriasis: A comprehensive review Journal of Autoimmunity 2015 (64) 66-73 Lees CW et al. New IBD genetics: common pathways with other diseases. J. Gut. 2011 Dec;60(12):1739-53. Epub 2011 Feb 7 Bentham J and Morris DL et al Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015 Dec;47(12):1457-64. Personalised Medicine 8-guttmacher.ppt http://www.nejm.org/doi/pdf/10.1056/NEJMp1006304 Hebert et al. Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy (British Journal of Dermatology) 2011 166: 474-482.