UNDERSTANDING

Systemic Lupus
THE BASIC
SCIENCE BEHIND
LUPUS
Erythematosus
(SLE)
PRESENTER : NUR KHAIRAH AMALINA ABDUL RAHMAN
Overview of SLE
• Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease
affecting multiple organ systems.
• In another literature, Systemic lupus erythematosus (SLE), canonically
defined as an autoimmune disorder, can be considered as a chronic
inflammatory illness with clinical manifestations encompassing various
organs such as the blood vessels, brain, lungs, skin, kidneys and joints due
to polymorphic biological alterations.
• The immune system mistakenly targets the body’s own cells, leading to
systemic inflammation.
• Disease flares and remissions are common, making management
challenging.
• Etiology: Multifactorial—genetic, environmental, and immune
dysregulation.
Immunopathogenesis of SLE
Loss of Immune Tolerance
• SLE is characterized by autoantibody production against self-antigens,
primarily nuclear components (e.g., anti-dsDNA, anti-Sm).
• Defective apoptosis: Increased apoptotic debris containing nuclear
material serves as an antigenic source.
• Impaired clearance of apoptotic cells: Leads to excessive exposure of
self-antigens to immune cells.
Autoantibody Production
• B cells produce antibodies against self-antigens (e.g. Anti-nuclear
antibodies (ANA), anti-dsDNA, anti-Sm).
Immunopathogenesis of SLE
Immune Complex Formation: These autoantibodies bind to nuclear
materials, forming immune complexes.
Tissue Deposition: The immune complexes deposit in various organs
(kidneys, skin, joints) triggering inflammation.
Cytokine Overproduction: Dendritic cells produce high levels of
interferon-alpha, amplifying the immune response.
Complement System Activation: Leads to inflammation and tissue
damage.
Key Immune Cells in SLE
• B Cells: Hyperactive, produce excessive autoantibodies.
• T Cells: Dysfunctional regulatory T cells (Tregs), increased Th17
response  leading to loss of immune tolerance.
• Dendritic Cells: Enhanced type I interferon signalling. Produce
interferon-alpha, driving inflammation.
• Macrophages & Neutrophils: Contribute to tissue damage by releasing
inflammatory mediators.
 Role of Type I Interferons
• Type I IFN Signature: Increased IFN-α and IFN-β contribute to
autoimmunity.
• Source: Plasmacytoid dendritic cells (pDCs).
• Type I IFNs are central to the activation of both the innate and the
adaptive immune systems.
• Specifically, by interacting with their receptors, type I IFNs induce
signaling through the JAK/STAT pathway followed by the transcription of
IFNs-responsive genes that encode the ‘IFN signature’ for activated
immune response.
Genetic and Environmental
Triggers
• Genetic Susceptibility: HLA associations, IRF5, STAT4, PTPN22 genes.
• Environmental Factors: UV light exposure, viral infections (EBV)
• Hormonal Influence:
• Estrogen promotes B-cell activation, explaining higher SLE prevalence in
females.
• Testosterone may have protective effects, leading to lower male SLE
incidence.
 Complement Cascade

3 main pathways of activation , all converge at cleavage C3, leading to common

terminal pathways results in cell lysis, inflammation and opsonization.
There are three mechanisms, so In the classical pathway, the
far elucidated, to activate the complement system is triggered
complement system, i.e., the by the binding of the antibody
classical, alternative, and lectin complexes to C1q of the C1
pathways. complex.

In the lectin pathway, the system

In the alternative path, the is stimulated via the binding of
complement system is activated foreign carbohydrate moieties to
via spontaneous hydrolysis of C3. mannose binding lectin (MBL) or
ficolin.

Perturbed activation or
All pathways converge to the
availability of any part of this
generation of C4b2a or C3bBb,
cascade may impair immune
the cleavage of C3, and the
homeostasis and lead to severe
amplification loop.
clinical syndromes
Diagnosis of SLE
• Four or more of the ACR 1997 revised classification criteria for SLE.
• Relapse was described as the recurrence of clinical disease and
exacerbation of laboratory profile (C3, C4, ANA, dsDNA, proteinuria,
and hematuria); as a consequence, relapse required physicians to
increase the dose of steroid therapy or add an immunosuppressive
drug to control the disease.
• The SLICC criteria for SLE classification requires: 1)
Fulfillment of at least four criteria, with at least one clinical
criterion AND one immunologic criterion OR 2) Lupus nephritis
as the sole clinical criterion in the presence of ANA or anti-
dsDNA antibodies.
Biomarkers and Diagnostic
Tools
• Serologic Markers: ANA, anti-dsDNA, anti-Sm, anti-Ro/La.
Antinuclear Antibodies (ANA)
• Sensitivity: >95% in SLE (almost always positive)
• Specificity: Low (can be seen in other autoimmune diseases)
Anti-dsDNA Antibodies
• Sensitivity: 60-80%
• Specificity: High (~95%) (strong association with SLE)
• Clinical Importance:
• Correlates with disease activity and lupus nephritis
• Rising titers may precede a disease flare
 Anti-Smith (Anti-Sm) Antibodies
• Sensitivity: 15-30%
• Specificity: High (~99%)
• Clinical Importance:
• Associated with more severe disease, nephritis, and CNS lupus
• Does NOT correlate with disease activity

Anti-Ro and Anti-La Antibodies

• Anti-Ro Sensitivity: 30-50%
• Anti-La Sensitivity: 15-25%
• Specificity: Low (also seen in Sjögren’s syndrome)
• Clinical Importance:
• Associated with photosensitivity, subacute cutaneous lupus, neonatal lupus
• Congenital heart block in neonates of affected mothers (Anti-Ro positive)
• Complement Levels: Decreased C3, C4.
• C3 is included in the common cascade after
the convergence of the three pathways. By
contrast, C4 is included in the classical and
lectin pathways. Therefore, low levels of both
proteins indicate the activation of these two
pathways, whereas low C3 and normal C4
indicate the activation of the alternative
pathway.
• Hypocomplementemia indicate active
disease (due to consumption by immune
complex formation)
• Emerging Biomarkers: IFN signature,
cytokine profiles.
AKI was observed in 12 patients (approximately 24.0%). In addition, 14
patients (27.5%) died because of disease progression and infection during
study period
Therapeutic Targets in SLE
• Current Treatments: Corticosteroids, hydroxychloroquine,
immunosuppressants.
• Biologic Therapies: Belimumab (anti-BAFF), anifrolumab (anti-IFN
receptor).
• Future Directions: Targeting T and B cell interactions, JAK inhibitors.
Immunosuppressive Drugs in SLE
Antimetabolites (Inhibit DNA synthesis and immune cell proliferation)

 Azathioprine (AZA)
•Used for mild to moderate SLE, particularly in maintaining remission.
•Often used as a steroid-sparing agent.
•Side effects: Bone marrow suppression, liver toxicity, increased
infection risk.

 Mycophenolate Mofetil (MMF)

•First-line treatment for lupus nephritis (especially Class III, IV, and V).
•More effective and safer than cyclophosphamide for some patients.
•Side effects: GI upset, infections, and bone marrow suppression.
Immunosuppressive Drugs in SLE
Alkylating Agents (Suppress immune cell production)

 Cyclophosphamide (CYC)
•Used for severe lupus nephritis and CNS lupus.
•Given via intravenous pulse therapy (Euro-Lupus or NIH protocol).
•Side effects: Infertility, bladder toxicity (hemorrhagic cystitis), infection risk.

Calcineurin Inhibitors (T-cell inhibition)

 Tacrolimus & Cyclosporine

•Alternative options for lupus nephritis.
•Preserve kidney function and help in refractory cases.
•Side effects: Hypertension, kidney toxicity, hirsutism, gingival hyperplasia.
Immunosuppressive Drugs in SLE
Biologic Agents (Target specific immune pathways)

 Rituximab (anti-CD20, B-cell depleting therapy)

•Used for refractory SLE, particularly in hematologic and CNS
involvement.
•Side effects: Infusion reactions, increased risk of infections.

 Belimumab (anti-BAFF, B-cell modulator)

•Approved for moderate SLE (non-renal).
•Helps reduce flares and steroid use.
•Side effects: Increased risk of infections.
 Prognostic Factors in SLE

Severity of Organ Response to Treatment Complications

Involvement
Lupus nephritis (kidney Early and aggressive treatment Increased risk of infections due
involvement) is a major can help control disease to immunosuppressive
determinant of long-term activity. medications.
outcomes. Immunosuppressive therapy Cardiovascular disease risk is
CNS lupus can lead to may be needed for severe higher due to chronic
neurological and cognitive cases. inflammation.
impairments. Growth and developmental
issues due to prolonged steroid
use.
Survival Rates & Long-Term Outlook
•5-year survival rate: Over 90% with proper treatment.
•10-year survival rate: Around 80–90%.
•Major causes of mortality: Infection, kidney failure, and cardiovascular
disease.

Management Strategies to Improve Prognosis

•Regular monitoring of kidney function, blood pressure, and disease activity.
•Early treatment of flares to prevent organ damage.
•Lifestyle modifications (balanced diet, exercise, sun protection).
•Psychosocial support to help with emotional well-being.
Conclusion
• Systemic lupus erythematosus (SLE) is a chronic inflammatory illness
with heterogeneous clinical manifestations covering multiple organs.
• SLE is driven by genetic predisposition, immune dysregulation,
autoantibody production, and environmental triggers.
• Key mechanisms include loss of self-tolerance, B-cell hyperactivity, T-
cell dysfunction, Type I interferon signaling, and immune complex
deposition, ultimately leading to chronic inflammation and tissue
damage.
• Diversified types of medications have been shown effective for
alleviating SLE syndromes, ranging from cytokines, antibodies,
hormones, molecular inhibitors or antagonists.
THANK YOU!