A presentation detailing the symptoms, pathogenicity, factors affecting, diagnosis and treatment of the autoimmune disorder systemic lupus erythematosus

1. Systemic Lupus
Erythematosus
PURNIMA KARTHA. N

3. Systemic lupus erythematosus (SLE) is an
autoimmune disease in which organs, tissues, and
cells undergo damage mediated by tissue-binding
autoantibodies and immune complexes.
• The clinical course is variable and may be
characterized by periods of remissions and of
chronic or acute relapses.
• Around 90% are females, the peak age at onset is
bw 20-30 yrs.
• The incidence is approximately 5 in 10,000 in most
countries, with an especially high incidence of 8.7
in 100,000 in Brazil.

4. CLINICAL
HETEROGENEITY OF SLE
• The multifaceted nature of SLE is shown by
the number of different organ systems that
can be affected.
• In addition, each organ-specific complication
can manifest in different ways.
• Arthritis and Arthralgia are the most common
presenting feature.

5. SYMPTOMS
Most common symptoms:
• Mouth Sores
• Hair Loss
• Chest Pain
• Extreme Fatigue
• General Discomfort
• Fever
• Sunlight Sensitivity
• Difficulty Breathing
• Swollen Lymph Nodes
• Skin Rashes (Butterfly Rash)

6. Malar Rash
Arthritis
Discoid Rash
Oral Ulcers

7. SYSTEM SPECIFIC SYMPTOMS
Nervous System: Headaches, numbness, tingling, seizures, psychosis
Digestive System: Nausea, vomiting, dyspepsia
Cardiovascular System: Arrhythmias, pericarditis, myocarditis
Respiratory System: Pleurisy, pleural effusion, pneumonitis, pulmonary
hypertension
Integumentary system: Raynaud’s phenomenon, malar rash
Excretory system: Edema, weight gain, acute renal failure

8. CRITERIA FOR
DIAGNOSIS OF SLE
Internationally accepted criteria by
American College of Rheumatology.
Patient must have 4 or more criteria to
establish diagnosis of disease

9. FACTORS CAUSING SLE

10. GENETIC FACTORS
• The concordance rate for SLE in monozygotic twins is 25% but only 2% in dizygotic
twins, suggesting that genetic factors alone do not explain the phenotype of SLE.
• C1Q and C4 single-gene defects.
• Interferon (IFN) regulatory factor 5 (IRF5), mutations in which are associated with
increases in the levels of the type 1 IFN family of molecules.
• HLA DR and DQ alleles that are associated with the production of specific
autoantibodies.
• Complement deficiency states and certain Fc-γ receptor alleles predispose to SLE, and
affect clearance of immune complexes
• IL-21-R, CD40, PTPN22, TNFAIP3 etc.

11. ENVIRONMENTAL FACTORS
Ultraviolet radiation- Langerhans cells of the skin and keratinocytes
release significant amounts of interleukin-1 upon exposure to UV light.
Infection: The normal immune response to bacterial and viral infections
may spin-off into a state of B-cell hyperactivity, triggering a relapse.
Infection, through the so-called molecular mimicry, can initiate an
autoimmune response. Eg: Parvovirus, Epstein–Barr virus (EBV)
infection.

12. Drugs- Drugs with DNA binding ability, can cause a drug-induced lupus-like
syndrome.
• cause DNA hypomethylation and thus transcription of genes at higher
rates
• such as hydantoin, isoniazid, hydralazine, procainamide, minocycline, and
anti-tumor necrosis factor (TNF) biologics.
Hormones: Estrogen, DHEA.
Silica Exposure, Smoking.
ENVIRONMENTAL FACTORS

13. HORMONAL FACTORS
• Female predisposition suggest that endocrine factors are important.
• When patients with SLE are given oestrogen and progesterone
hormone- replacement therapy, their risk of SLE flare is 1.34 times that
of women given placebo.
• Low levels of dehydroepiandrosterone (DHEA) have been associated
with predisposition to SLE.

14. PATHOGENESIS
Extracellular double-stranded DNA occurs
mainly in the form of nucleosomes, which
are fragments of chromatin that cells
release when they undergo apoptosis.
Pathogenic anti-ds-DNA autoantibodies
bind to nucleosomes and gets deposit on
different sites and induce the
inflammatory reaction.

15. PATHOGENESIS

16. IMMUNE RESPONSE ABNORMALITIES
• SLE is caused by an autoimmune reaction in which the innate and adaptive
immune systems direct an inappropriate immune response to nucleic acid-
containing cellular particles.
B-Cell Abnormalities
Auto-Antibodies
T-Cell Abnormalities
Dendritic cell
Abnormalities
Antinuclear Antibodies
DNA Antibodies

17. INNATE IMMUNITY ACTIVATION
• Nucleic acid containing immune complexes and cytoplasmic DNA and
RNA are potential stimuli for activation of TLRs and other receptors,
leading to IFNα production.
• Interferon α induces maturation of dendritic cells and drives monocytes
to become more effective in stimulating allogeneic T cells.
• IFNα can regulate the production of cytokines such as IL-10 and IL-12 by
monocytes.

18. DENDRITIC CELL ABNORMALITIES
• Dendritic cells may present autoantigen to T and B-cells at increased
rates in patients with SLE.
• Interferonα and circulating immune complexes (acting through Fc
receptors and TLR9) stimulate dendritic cell function in SLE.

19. B CELL ABNORMALITIES
• B cell regulation is impaired in SLE, contributing to the production of
autoantibodies, cytokines and augmented presentation of antigen to T cells.
• Increased availability of T cell help for B cell differentiation as well as B cell
survival, proliferation and differentiation factors (including BAFF and IL-21)
and activation of TLRs all contribute to autoimmunity.
• SLE-associated genetic variants encoding several kinases, phosphatases and
adaptor molecules, contribute to altered counter-selection of self-reactive
B cells or antigen- mediated B cell activation.

20. • Feedback mechanisms in the down
regulation of B-cell responses appear to be
deficient in SLE. SLE memory B cells show
modest decreases in the expression of the
inhibitory Fc receptor FCGR2B.
• Long-lived plasma cells are maintained by
chemokines and stromal cell products in
protective bone marrow niches - proposed
sources of anti-Sm and anti-Ro
autoantibodies.
B CELL ABNORMALITIES

21. AUTO-ANTIBODIES
• An autoantibody is an antibody produced by the immune system that is
directed against one or more of the individual's self antigen(s).
• Self antigens may be found in all cell types (e.g. chromatin, centromeres) or be
highly specific for a specific cell type in one organ of the body (e.g.
thyroglobulin in cells of the thyroid gland).
• They may comprise proteins, nucleic acids, carbohydrates, lipids or various
combinations of these.
• Also referred to as natural antibodies.

22. • Autoantibodies are essential mediators of pathology in SLE, particularly when they
form immune complexes.
• Virtually all patients with SLE are positive for ANAs or other characteristic SLE
autoantibodies.
• Autoantibodies in SLE can be categorized in relation to their targets:
• DNA and DNA-binding proteins, which are typically aggregated with histones in
nucleosomes.
• RNA and RNA-associated proteins, which are aggregated in cytoplasmic or nuclear
ribonucleoprotein particles;
• β2-glycoprotein, in association with phospholipids; and
• cell membrane proteins, typically those expressed on blood cells.
AUTO-ANTIBODIES

23. • ANA, Anti dsDNA and anti-Sm are most specific for SLE.
• Anti-C1q antibodies, are associated with SLE activity and with proliferative lupus
nephritis and are thought to be pathogenetic.

24. • The pathogenic antibodies in SLE undergo immuno globulin class switching
driven by CD4+ T helper cells or TLR ligands together with IL-21 or BAFF.
• A shift from a predominant polyclonal IgM profile towards IgG occurs over
time in most patients with SLE and with disease progression and
development of tissue damage.
• Class-switched IgG antibodies are better able to access extravascular spaces
than IgM antibodies
• Some IgM natural antibodies react with apoptotic cells and inhibit their
activation through TLRs.
• Some antibodies unexpectedly bind to two distinct self-antigens.
• For eg, some anti-dsDNA antibodies also bind to a peptide that is a feature
of glutamate receptors on central nervous system neurons

25. T CELL ABNORMALITIES
• Deficiencies or alterations in T cell signalling, in the production of cytokines,
in proliferation and in regulatory functions have been documented in
patients with SLE.
• T cells derived from patients with SLE readily express CD40 ligand (CD40L)
after activation and maintain the expression of this important co-
stimulatory molecule longer than T cells derived from healthy controls.
• Substitution of the T cell receptor-ζ (TCRζ) chain with the common-γ chain
(TCRγ)- lead to augmented intra cellular calcium signalling and
hyperpolarization of mitochondria, which can sensitize T cells for necrosis.

26. • T cells derived from patients show hypomethylation of CG-rich DNA
sequences and promoters of IFN-regulated genes.
• The population of T follicular helper cells, which promote differentiation
of autoantibody-producing B cells, is expanded in SLE.
• Relative depletion in the number of Treg cells, increased numbers of TH17
cells and increased levels of IL-17 in SLE.
T CELL ABNORMALITIES

27. IMMUNE COMPLEXES
• IC are formed at increased rates in patients with SLE, the clearance rate of
circulating IC is decreased, as a consequence of several factors.
• IC are cleared by the Fc receptor bearing cells of the reticuloendothelial
system.
• Many patients with lupus have alleles of Fc receptors that bind IgG with
less avidity. This results in slower immune complex clearance.

30. DIAGNOSIS
The diagnosis of SLE is made based on clinical manifestations and laboratory
tests, including the detection of autoantibodies, functional tests and imaging.
Health care providers tend to use the revised American College of
Rheumatology (ACR) classification criteria for SLE. Proposed by the ACR in
1971, revised in 1982 and 1997
• Need 4 of 11 criteria for diagnosis of SLE
• Not perfect, but have over 90% sensitivity and specificity

31. TREATMENT
• Treatment is determined by organ involvement.
• Photosensitive rashes are treated by sun avoidance, sun block, and by
hydroxychloroquine, an antimalarial drug with an immunomodulating effect.
• Arthritis is managed with NSAIDs and with hydroxychloroquine; severe cases
may require immunosuppressive drugs, including methotrexate or
leflunomide.
• Mild serositis may be controlled with NSAIDs, whereas severe cases may
require initial high-dose corticosteroid therapy.

32. • Severe hemolytic anemia or thrombocytopenia is treated with
corticosteroids and/or intravenous immunoglobulin.
• Severe internal organ involvement will require immuno-suppressive
regimens.
• Rapidly progressive nephritis may require intravenous cyclophosphamide,
usually given monthly for six months as “induction therapy” followed by
maintenance regimen of mycophenolate mofetil, azathioprine, or
quarterly cyclophosphamide.
TREATMENT

33. • Seizures due to active lupus are treated with both corticosteroids and
anti-epileptics.
• Psychosis can be caused by both SLE and by high-dose corticosteroids.
• New approaches :
• Target B cells by rituximab and monoclonal antibodies directed
against the B lymphocyte stimulator protein.
• Anti-C5 antibody that disrupts complement activation
TREATMENT

34. REFERENCE
• Medical Immunology 6th Edition- Gabriel Virella
• Essentials of Clinical Immunology- Helen Chapel, Mansel Haeney
• Autoimmune Diseases- Noel R Rose, Ian R Mackay
• Systemic lupus erythematosus- Arvind Kaul, Caroline Gordon
• Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis-
Chandra Mohan and Chaim Putterman
• New insights into the immunopathogenesis of systemic lupus erythematosus- George
C. Tsokos, Mindy S. Lo