December 2, 2014
Biology 430
Ryan Douglas Turnewitsch
Brandon Joseph Stewart
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
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 women
o 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 Rates
o ~90-95% in Western world
(Lau et al. 2006; Ahmadpoor
et al. 2014; “What is Lupus?”)
Wide range of symptoms
o Affects many systems
o Symptoms wax and wane
Most common symptoms
o Mouth Sores
o Fever
o Hair Loss
o Sunlight Sensitivity
o Chest Pain
o Difficulty Breathing
o Extreme Fatigue
o Swollen Lymph Nodes
o General Discomfort
o Skin Rashes (Butterfly Rash)
(Bartels et al. 2014; “What is Lupus?”; Shiel et al. 2014)
Nervous System
o Headaches, numbness, tingling, seizures, psychosis
Digestive System
o Nausea, vomiting, dyspepsia
Cardiovascular System
o Arrhythmias, pericarditis, myocarditis
Respiratory System
o 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)
HLA genes most studied
o HLA Class II gene polymorphisms
o 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 Syndrome
o Contributes to female susceptibility
o Hypogonadotrophic hypogonadism
(Dorner et al. 2011; Mok and
Lau. 2003; Hu and Deng 2014)
Two Stage Disease
o Loss of self-tolerance/Auto-Abs generation
o Immune complex formation, causes inflammation/disease
Stage One: Loss of Self-tolerance
o Involves self-antigen presentation by DCs
Role of Apoptosis
o Impaired clearance of apoptotic cells
o Results from defective complement system
• C2, C4, C1q defects
• Reduced CR1 receptors
o Cells serve as immunogens
o Induce auto-reactive T/B cells
(Ahmadpoor et al. 2014; Dorner
et al. 2011; Mok and Lau. 2003)
Aberrant DC activity
o DC’s present self antigens from apoptotic cells
• Mostly nucleosomes, apoptotic blebs
o DCs present to CD4 cells
Aberrant Lymphocyte Activity
o Unregulated T-cell dependent B-cell activation
Aberrant Germinal Center Activity
o Ligation between certain CD pairings
o 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)
(Dorner et al. 2011)
Stage Two: Immune Complex Formation
o Auto-Abs bind to:
• Pieces of DNA
• Nucleosomes
• Proteoglycans
o Immune complex formation
• Accumulate in organ basement membranes
Results of Immune Complexes
o Local inflammation
o Local complement activation
o Local apoptosis
o Positive feedback loop
(Ahmadpoor et al. 2014; Dorner
et al. 2011; Mok and Lau. 2003)
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
o Reduce inflammation
o 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)
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.
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.
Shiel W, Stoppler MC, Driver CB. 2014. "Lupus Symptoms, Causes, Treatment - What Is the Treatment for Systemic
Lupus?" MedicineNet. Web.
"What Is Lupus?" 2014. Lupus Foundation of America, Web.. <>.
Multiple Choice Questions:
1) What immunological aberration is the principle cause for SLE?
Overproduction of T-helper cells
Inhibition of complement activity
Production of self-reactive antibodies
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
o Overabundance of immune-tolerance and generation of immune
complexes causing inflammation
o Overabundance of immune-tolerance and manifestation of SLE causing
o Loss of immune-tolerance and generation of immune complexes
causing inflammation
Multiple Choice Questions Continued:
3) What type of immune of cells are least effected by SLE?
o Neutrophils
o T cells
o B cells
o 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
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 cells
o B cells
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.