Multiple Facets of Systemic Lupus Erythematosus (SLE)

©2020 AstraZeneca. All rights reserved. US-44966 Last Updated 09/20

Multiple Facets of Systemic Lupus

Erythematosus (SLE)

Complexity of SLE Pathogenesis

The Role of Type 1 Interferon (IFN)

©2020 AstraZeneca. All rights reserved.US-44966 Last Updated 09/20

THE ROLE OF TYPE 1 IFNPREVIOUS COMPLEXITY OF

SLE PATHOGENESIS NEXT

Complexity of SLE Pathogenesis




Reprinted by permission from Springer Nature: Nature Medicine. Liu Z et al. Nat Med. 2012;18(6):871-882. Copyright 2012.1

IL = interleukin; UV = ultraviolet.

References: 1. Liu Z, Davidson A. Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18(6):871-882. 2. Rönnblom L, Eloranta M-L, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):408-420. 3. Bertsias G, Cervera R, Boumpas DT. Systemic lupus erythematosus: pathogenesis and clinical features. In: Bijlsma J, Hachulla E, eds. EULAR Textbook on Rheumatic Diseases. BMJ Group; 2012:476-505. 4. Lichtman EI, Helfgott SM, Kriegel MA. Emerging therapies for systemic lupus erythematosus: focus on targeting interferon-alpha. Clin Immunol. 2012;143(3):210-221. 5. Marian V, Anolik JH. Treatment targets in systemic lupus erythematosus: biology and clinical perspective. Arthritis Res Ther. 2012;14(suppl 4):S3. 6. Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11(12):890-897. 7. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013;382(9894):819-831. 8. Zharkova O, Celhar T, Cravens PD, Satterthwaite AB, Fairhurst AM, Davis LS. Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology (Oxford). 2017;56(suppl 1):i55-i66. 9. Dennis GJ. Belimumab: a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. Clin Pharmacol Ther. 2012;91(1):143-149.

Pathogenesis of SLE Involves Genetic, Environmental, and Immunologic Factors1

Environmental triggers (such as viral infections or UV light exposure) can generate apoptotic and necrotic material, leading to immune dysregulation in a genetically susceptible individual, resulting in loss of tolerance to self-antigens.1-5




Reprinted by permission from Springer Nature: Nature Medicine. Liu Z et al. Nat Med. 2012;18(6):871-882. Copyright 2012.

IL = interleukin; UV = ultraviolet.

References: 1. Liu Z, Davidson A. Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18(6):871-882. 2. Rönnblom L, Eloranta M-L, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):408-420. 3. Bertsias G, Cervera R, Boumpas DT. Systemic lupus erythematosus: pathogenesis and clinical features. In: Bijlsma J, Hachulla E, eds. EULAR Textbook on Rheumatic Diseases. BMJ Group; 2012:476-505. 4. Lichtman EI, Helfgott SM, Kriegel MA. Emerging therapies for systemic lupus erythematosus: focus on targeting interferon-alpha. Clin Immunol. 2012;143(3):210-221. 5. Marian V, Anolik JH. Treatment targets in systemic lupus erythematosus: biology and clinical perspective. Arthritis Res Ther. 2012;14(suppl 4):S3. 6. Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11(12):890-897. 7. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013;382(9894):819-831. 8. Zharkova O, Celhar T, Cravens PD, Satterthwaite AB, Fairhurst AM, Davis LS. Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology (Oxford). 2017;56(suppl 1):i55-i66. 9. Dennis GJ. Belimumab: a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. Clin Pharmacol Ther. 2012;91(1):143-149.

Pathogenesis of SLE Involves Genetic, Environmental, and Immunologic Factors1

Cellular material, including nucleic acids, can activate the innate immune system and serve as autoantigens for humoral- and cell-mediated immunity.3,6

Disturbances in innate and adaptive immunity are amplified by cytokines (eg, type 1 IFN, IL-6) and immune complexes creating positive feedback loops.7,8

Deposition of immune complexes in tissue and inflammation triggered by circulating inflammatory mediators can lead to irreversible tissue and organ damage.1,4,5,9




Crosstalk Between Adaptive and Innate Systems1,2

Tap the sign for more information

BAFF = B-cell activating factor; LT-α = lymphotoxin-alpha; mDC = myeloid dendritic cell; MHC = major histocompatibility complex; NK cell = natural killer cell; pDC = plasmacytoid dendritic cell; TGF-β = transforming growth factor beta; TNF = tumor necrosis factor.

References: 1. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013;382(9894):819-831. 2. Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11(12):890-897. 3. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1. 4. Choi J, Kim ST, Craft J. The pathogenesis of systemic lupus erythematosus-an update. Curr Opin Immunol. 2012;24(6):651-657. 5. Dema B, Charles N. Advances in mechanisms of systemic lupus erythematosus. Discov Med. 2014;17(95):247-255. 6. Kim JM, Park SH, Kim HY, Kwok SK. A plasmacytoid dendritic cells-type 1 interferon axis is critically implicated in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2015;16(6):14158-14170. 7. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36-49. 8. Ma F, Li B, Yu Y, Iyer SS, Sun M, Cheng G. Positive feedback regulation of type I interferon by the interferon-stimulated gene STING. EMBO Rep. 2015;16(2):202-212.




TC cell = T cytotoxic cell; TH cell = T helper cell; TREG cell = T regulatory cell.

References: 1. Rönnblom L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci. 2011;116(4):227-237. 2. Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11(12):890-897. 3. Rönnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6(6):339-347. 4. Rönnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med. 2019;6(1):e000270. doi:10.1136/lupus-2018-000270. 5. Bezalel S, Guri KM, Elbirt D, Asher I, Sthoeger ZM. Type 1 interferon signature in systemic lupus erythematosus. Isr Med Assoc J. 2014;16(4):246-249. 6. Kim JM, Park SH, Kim HY, Kwok SK. A plasmacytoid dendritic cells-type 1 interferon axis is critically implicated in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2015;16(6):14158-14170. 7. Lichtman EI, Helfgott SM, Kriegel MA. Emerging therapies for systemic lupus erythematosus—focus on targeting interferon-alpha. Clin Immunol. 2012;143(3):210-221. 8. Liu Z, Davidson A. Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18(6):871-882.

Type 1 IFN Plays a Central Role in SLE Pathogenesis1,2

Tap the for information on the effects of type 1 IFN on each type of cell




Type 1 IFN Plays a Central Role in

SLE Pathogenesis

Ro, U1, RNP,and Sm

antibodiesESR

Albumin24-hour

urineprotein

Hemoglobin

dsDNA antibodies

Skindisease

Disease activity

Renaldisease

SDI

C3 and C4

ALC

BIOLOGIC1,5,6 CLINICAL1,4-6




ALC = absolute lymphocyte count; C = complement; dsDNA = double-stranded DNA; ESR = erythrocyte sedimentation rate; RNP = ribonucleic protein; Sm = Smith.

References: 1. Lauwerys BR, Hachulla E, Spertini F, et al. Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon α-kinoid. Arthritis Rheum. 2013;65(2):447-456. 2. Yao Y, Higgs BW, Richman L, White B, Jallal B. Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus. Arthritis Res Ther. 2010;12(suppl 1):S6. 3. Hoffman RW, Merrill JT, Alarcón-Riquelme MM, et al. Gene expression and pharmacodynamic changes in 1,760 systemic lupus erythematosus patients from two phase III trials of BAFF blockade with tabalumab. Arthritis Rheumatol. 2017;69(3):643-654. 4. Kennedy WP, Maciuca R, Wolslegel K, et al. Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE. Lupus Sci Med. 2015;2(1):e000080. 5. Kirou KA, Lee C, George S, Louca K, Peterson MGE, Crow MK. Activation of the interferon-α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 2005;52(5):1491-1503. 6. Tang J, Gu Y, Zhang M, et al. Increased expression of the type I interferon-inducible gene, lymphocyte antigen 6 complex locus E, in peripheral blood cells is predictive of lupus activity in a large cohort of Chinese lupus patients. Lupus. 2008;17(9):805-813.

Type 1 IFN: Correlation With SLE Manifestations1,2

• Increased type 1 IFN levels were reported during periods of increased SLE disease activity1,2

• It is estimated that 60%-80% of patients with SLE display an elevated IFN gene signature2-4

• In patients with SLE, levels of IFN-induced genes have been demonstrated to correlate with clinical and biologic disease indexes1,4-6




References: 1. Rönnblom L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci. 2011;116(4):227-237. 2. Chan VS-F, Nie Y-J, Shen N, Yan S, Mok M-Y, Lau C-S. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11(12):890-897. 3. Liu Z, Davidson A. Taming lupus: a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18(6):871-882. 4. Lichtman EI, Helfgott SM, Kriegel MA. Emerging therapies for systemic lupus erythematosus: focus on targeting interferon-alpha. Clin Immunol. 2012;143(3):210-221. 5. Marian V, Anolik JH. Treatment targets in systemic lupus erythematosus: biology and clinical perspective. Arthritis Res Ther. 2012;14(suppl 4):S3. 6. Bertsias G, Cervera R, Boumpas DT. Systemic lupus erythematosus: pathogenesis and clinical features. In: Bijlsma J, Hachulla E, eds. EULAR Textbook on Rheumatic Diseases. BMJ Group; 2012:476-505. 7. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36-49. 8. Bezalel S, Guri KM, Elbirt D, Asher I, Sthoeger ZM. Type 1 interferon signature in systemic lupus erythematosus. Isr Med Assoc J. 2014;16(4):246-249. 9. Rönnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med. 2019;6(1):e000270. doi:10.1136/lupus-2018-000270. 10. Ma F, Li B, Yu Y, Iyer SS, Sun M, Cheng G. Positive feedback regulation of type I interferon by the interferon-stimulated gene STING. EMBO Rep. 2015;16(2):202-212.


Adaptive Immune System

• Autoreactive B cells produce autoantibodies to self-antigens1,2

• Autoantibodies bind to circulating nuclear antigens forming an autoantibody-antigen complex1,2

• Complement binds to the autoantibody-antigen complex forming an immune complex1,2

• Immune complexes deposit on tissues, which can lead to inflammation and organ and tissue damage3-5






Cellular Damage

• Exposure to environmental triggers, such as UV light or infections, can generate apoptotic and necrotic material6

• Cellular material, including nucleic acids, can activate the innate immune system and serve as autoantigens for B and T cells in genetically predisposed individuals2,6






Innate Immune System

• Immune complexes can activate pDCs leading to the release of cytokines, particularly type 1 IFN2,7,8

• Type 1 IFN promotes B- and T-cell functions, including autoantibody and cytokine production2,3,9

• In addition, type 1 IFN can act to perpetuate the pathogenic feedback loop indicative of SLE7,8,10



SLE PATHOGENESIS

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Multiple Facets of Systemic Lupus Erythematosus (SLE)

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