Systemic Lupus Erythematosus

Ryan Douglas TurnewitschBrandon Joseph Stewart

December 2, 2014Biology 430

SLE – What is it?

Systemic lupus erythematosus (SLE) is a chronic

autoimmune disease characterized by the production of

autoantibodies resulting from the dysfunction of T cells,

B cells, and dendritic cells. These antibodies are

principally anti-nuclear and induce an inflammatory

response throughout the body.

- Sang et al. 2013; Perl A. 2009; Dorner et al. 2011

SLE Around the World 5 million people with SLE

o 40-80 of every 100,000 o 1.5 million Americans o 16,000 new US cases annually

90% of cases occur in womeno 10X more susceptible

Contributions from ethnicity o Incidence compared to Caucasians

• 3X higher for Asians• 4X higher for African Americans (women)

o Mortality compared to Caucasians• 2X higher for Asians • 3X higher for African Americans (women)

Survival Rateso ~90-95% in Western world

(Lau et al. 2006; Ahmadpoor et al. 2014; “What is Lupus?”)

General Symptoms

Wide range of symptoms o Affects many systems o Symptoms wax and wane

Most common symptoms o Mouth Soreso Hair Losso Chest Paino Extreme Fatigueo General Discomfort

o Fever o Sunlight Sensitivityo Difficulty Breathingo Swollen Lymph Nodeso Skin Rashes (Butterfly

Rash)

(Bartels et al. 2014; “What is Lupus?”; Shiel et al. 2014)(http://www.lupusimages.com/browser/detail/129/mucocutaneous-sle-malar-

rash)

System Specific Symptoms

Nervous Systemo Headaches, numbness, tingling, seizures, psychosis

Digestive Systemo Nausea, vomiting, dyspepsia

Cardiovascular Systemo Arrhythmias, pericarditis, myocarditis

Respiratory Systemo Pleurisy, pleural effusion, pneumonitis, pulmonary

hypertension Integumentary system

o Raynaud’s phenomenon, malar rash Excretory system

o Edema, weight gain, acute renal failure(Bartels et al. 2014)

Genetic Predispositions

HLA genes most studiedo HLA Class II gene polymorphismso HLA DR2 and DR3

Associated with autoantibodies:o Anti-Sm, anti-Ro, anti-La, anti-nRNP, anti-dsDNA, anti-PL

Other Associated Genes o BANK1, BLK, IL-21-R, CD40, Lyn, PTPN22, TNFAIP3, FcγRs,

Blimp-1

Klinefelter Syndromeo Contributes to female susceptibility o Hypogonadotrophic hypogonadism

(Dorner et al. 2011; Mok and Lau. 2003; Hu and Deng 2014)

Immunological Mechanisms

Two Stage Disease o Loss of self-tolerance/Auto-Abs generationo Immune complex formation, causes

inflammation/disease

Stage One: Loss of Self-toleranceo Involves self-antigen presentation by DCs

Role of Apoptosis o Impaired clearance of apoptotic cellso Results from defective complement system

• C2, C4, C1q defects • Reduced CR1 receptors

o Cells serve as immunogenso Induce auto-reactive T/B cells

(Ahmadpoor et al. 2014; Dorner et al. 2011; Mok and Lau. 2003)

Immunological Mechanisms

Aberrant DC activity o DC’s present self antigens from apoptotic cells

• Mostly nucleosomes, apoptotic blebs o DCs present to CD4 cells

Aberrant Lymphocyte Activityo Unregulated T-cell dependent B-cell activation

Aberrant Germinal Center Activity o Ligation between certain CD pairingso Somatic Hypermutation

Autoantibody Production o 95% are antinuclear Abs (anti-Sm, Anti-DNA)

(Ahmadpoor et al. 2014; Dorner et al. 2011; Mok and Lau. 2003)

Immunological Mechanisms

(Dorner et al. 2011)

Immunological Mechanisms

Stage Two: Immune Complex Formationo Auto-Abs bind to:

• Pieces of DNA• Nucleosomes• Proteoglycans

o Immune complex formation • Accumulate in organ basement membranes

Results of Immune Complexeso Local inflammationo Local complement activation o Local apoptosiso Positive feedback loop (Ahmadpoor et al. 2014;

Dorner et al. 2011; Mok and Lau. 2003)

Treatments No permanent cure for SLE: treatment relieves symptoms

NSAIDs (nonsteroidal anti-inflammatory drugs)o Aspirin (Bayer), ibuprofen (Advil, Motrin), naproxen (Aleve)o Reduce inflammation and pain

Corticosteroidso Reduce inflammationo Used after significant organ damage

Antimalarial Drugs o Hydroxychloroquine (Plaquenil), chloroquinone (Aralen)o Reduces inflammation, protects against organ damage o Used for skin symptoms, joint pain

DMARDs (disease-modifying antirhematic drugs)o Belimumab (Benlysta), rituximab (Rituxan)o Suppress B cell development, block B cell stimulation (Bartels et al. 2014; Schur et al. 2014; Shiel et al.

2014)

Literature References Ahmadpoor P, Dalili N, Rostami M. 2014. An update on pathogenesis of systemic lupus erythematosus. Iranian

Journal of Kidney Diseases. 8(3): 171-184.

Bartels CM, Muller D, Diamond HS, Farina GA, Goldberg E, Hildebrant J, Krause RS, Lakdawala VS, Leber MJ, Lozada CJ, Talavera F. 2014. Systemic Lupus Erythematosus (SLE). “Practice Essentials.” Medscape. Web.

<http://emedicine.medscape.com/article/332244-overview>.

Dorner T, Giesecke C, Lipsky PE. 2011. Mechanisms of B cell autoimmunity in SLE. Arthritis Research and Therapy. 13(243): 1-12.

Hu, ZD, Deng AM. 2014. Autoantibodies in pre-clinical autoimmune disease. Clinical Chimica Acta. 435: 14-18.

Lau CS, Yin G, Mok MY. 2006. Ethnic and geographical differences in systemic lupus erthematosus: an overview. Lupus. 15: 715-719.

Mok CC, Lau CS. 2003. Pathogenesis of systemic lupus erythematosus. Journal of Clinical Pathology. 56(7): 481-490.

Perl A. 2009. Overview of signal processing by the immune system in systemic lupus erythmatosus. Autoimmunity Reviews. 8:177-178.

Sang A, Zheng YY, Morel L. 2014. Contributions of B cells to lupus pathogenesis. Molecular Immunology. 62: 329-338.

Schur P, Shmerling R, Ramirez M. 2014. "Patient Information: Systemic Lupus Erythematosus (SLE) (Beyond the Basics)." Systemic Lupus Erythematosus (SLE). UpToDate Health. Web.

<http://www.uptodate.com/contents/systemic-lupus-erythematosus-sle-beyond-the-basics?view=print>.

Shiel W, Stoppler MC, Driver CB. 2014. "Lupus Symptoms, Causes, Treatment - What Is the Treatment for Systemic Lupus?" MedicineNet. Web.

<http://www.medicinenet.com/systemic_lupus/page5.htm#what_is_the_treatment_for_systemic_lupus_erythematosus>.

"What Is Lupus?" 2014. Lupus.org. Lupus Foundation of America, Web.. <http://www.lupus.org/answers/entry/what-is-lupus>.

SLE Study QuestionsMultiple Choice Questions:

1) What immunological aberration is the principle cause for SLE?o Overproduction of T-helper cells o Inhibition of complement activityo Production of self-reactive antibodieso Stimulation of perforin and granzyme activity in facial tissue

2) What are the two stages of SLE pathogenesis?o Loss of immune-tolerance and degradation of secondary lymphoid

organso Overabundance of immune-tolerance and generation of immune

complexes causing inflammation o Overabundance of immune-tolerance and manifestation of SLE causing

bacteriao Loss of immune-tolerance and generation of immune

complexes causing inflammation

SLE Study QuestionsMultiple Choice Questions Continued:

3) What type of immune of cells are least effected by SLE?o Neutrophilso T cellso B cellso Dendritic cells

4) What reason listed below accounts for impaired clearance of immune complexes in SLE?

o Insufficient CTL activity o Serum viscosity is too high for complexes to fall out of solution o Insufficient quantities of macrophages to snarf up complexes o Defective complement system

SLE Study Questions Essay Response:

Explain how a self antigen found in an apoptotic bleb can cause inflammation in the nephron (nephritis). In your explanation of this process, be sure to describe the roles the following cells:

o Dendritic cells o CD4 cellso B cells

SLE Study Questions Study Questions Answers

o 1: C 2: D 3: A 4: D

Essay Response

o Key points to mention:

o Clearance of apoptotic cells/cell fragments is impaired because of defective complement system.

o DC cells encounter and present portions, particularly nuclear portions, of apoptotic cells as self-antigens to CD4 cells.

o T cell dependent B cell activation is unregulated and B cells that have self-antigen specificity are not eliminated as they should be.

o B cells are activated into plasma cells. These cells secrete auto-reactive antibodies that can migrate anywhere in body. Some will migrate to kidney.

o In kidney, antibodies will encounter self antigens, bind, and form immune complexes. These immune complexes will lead to an inflammatory response by immune system. Inflammation is local and will occur in portions of the kidney, such as the nephron, causing nephritis.