PATHOLOGY, SECOND MBBS, MEDICAL COUNCIL OF INDIA, COMPETENCY BASED UNDERGRADUATE CURRICULUM FOR THE INDIAN MEDICAL GRADUATE, 2018

1. PA9.5
DEFINE & DESCRIBE THE
PATHOGENESIS OF SLE
Dr IRA BHARADWAJ
MCI TEACHER ID: PAT 2300569
KUHS FACULTY ID: M21512

2. TEXT BOOK REFRENCES
• ROBBINS BASIC PATHOLOGY
• HARSH MOHAN TEXTBOOK OF PATHOLOGY
• DAVIDSON’S PRINCIPLES AND PRACTISE OF MEDICINE
• OTHER STANDARD REFRENCES

3. SLO
• DEFINITION OF SLE
• ETIOPATHOGENESIS OF SLE – GENETIC & ENVIORNMENTAL
FACTORS
• MORPHOLOGY OF SLE – KIDNEY & OTHER ORGANS
• CLINICAL FEATURES, PROGNOSIS & TREATMENT OF SLE
• QUESTIONS AT END OF SECTION 9.7

4. SYSTEMIC LUPUS ERYTHEMATOSUS
DEFINITION
• SLE IS A MULTISYSTEM
• AUTOIMMUNE DISEASE
• OF PROTEAN MANIFESTATIONS & VARIABLE CLINICAL BEHAVIOUR
• CHARACTERIZED BY PRESENCE OF LARGE NUMBER & TYPES OF
AUTOANTIBODIES, SPECIALLY ANTI NUCLEAR ANTIBODIES [ANA]
• THERE ARE TWO VARIANTS – SYSTEMIC [AFFECTING MULTIPLE ORGANS]
AND DISCOID AFFECTING SKIN ONLY

5. SYSTEMIC LUPUS ERYTHEMATOSUS
ETIOPATHOGENESIS
GENETIC FACTORS
• 9:1 (f:m)
• Black American [more common]
• Familial predisposition (20% unaffected relatives of patient
have ANA)
• HLA-DR2/DR3
• Genetic defect of classical complement pathway proteins
• Inadequate control of BL activation (inhibitory Fc receptor
defect)

6. SYSTEMIC LUPUS ERYTHEMATOSUS
ETIOPATHOGENESIS
ENVIRONMENTAL FACTORS
• UV exposure
• Smoking
• Sex hormones (10 X more in reproductive age)
• Drugs (procainamide & hydralazine) – affect demethylation of
DNA – altered expression of genes in immunity.

7. SLE
IMMUNOLOGICAL ABNORMALITIES
INNATE IMMUNITY
• Type I interferon (IFN a) secretion increased by dendritic cells
[IFR5 gene]
• Increase in TLRs – present on macrophages, NK, neutrophils,
mucosal cells (bind toll Ags on bacteria, induce infl’ via TNF,
IL-I, & other cytokines, & activate BL)
• Increased immunological reactivity to nucleoproteins
ADAPTIVE IMMUNITY
• Failure of B L tolerance

8. SLE
PATHOGENESIS OF IMMUNOLOGICAL ABNORMALITIES
INCREASED APOPTOSIS DUE TO ENVIRONMENTAL CAUSES,
FOLLOWED BY:
• Decreased clearance of apoptotic cells,
• Exposure of immune system to nuclear Ags,
• Development of autoantibodies [ANA] which lead to
• Inflammation & necrosis [type 2 & 3 hypersensitivity
reactions] again followed by
• Decreased clearance of necrotic cells & increase in nuclear
Ags and increase in ANAs [anti nuclear antibodies]

9. Ig G antibody to nuclear & other self proteins
Type 2 & 3 hypersensitivity reactions
Clinical manifestations.
Environmental triggers Nucleosome proteins &
UV, smoking, hormones, drugs other self antigens
Activation of helper T cells & increase in INF-a & TLR &
failure of BL self tolerance
Genetically susceptible individual
Genes involved:
F>M, family history
MHC class - II HLA DR 2&3
Complement defects
inhibitory function of BL defect

11. ANTIBODIES IN SLE
ANA [anti nuclear antibodies]
• anti-dsDNA [double strand DNA]
• anti-Sm (ribonuclear core protein, Sm ag),
• anti-RNP UI
• anti-histone,
• anti-SS-A, anti-SS-B (ribonucleoprotein)

12. ANTIBODIES IN SLE
OTHER Abs-
• Against RBC, platelets, lymphocytes
• APL (antiphospholipid antibody)
• These antibodies are detected by IFA, ELISA & flow cytometer
• False positive test is seen in other autoimmune diseases,
malignancy and chronic infections

13. SLE
MECHANISM OF TISSUE INJURY
TYPE II HYPERENSITIVITY REACTIONS
• Abs (IgG & IgM ) bind to Ags on cell surface ,
• This activates phagocytes, complement, ADCC ( Ab
dependent cellular cytotoxicity ) mediated by NK cells,
monocytes, neutrophils, eosinophils in fixed tissues and
• Cell death - lysis of RBS, WBC,& platelets in circulation

14. TYPE II- ANTIBODY MEDIATED HYPERSENSTIVITY
ROLE IN PATHOGENESIS OF SLE

15. SLE
MECHANISM OF TISSUE INJURY
ANTIPHOSPHOLIPID Ab COMBINE WITH PHOSPHOLIPIDS,
LEADING TO:
• Coagulation disorders, like increased thrombosis
• Abortions
• Reaction with CNS receptors, causing neuropsychiatric
symptoms

16. SLE
MECHANISM OF TISSUE INJURY
TYPE III HYPERSENSITIVITY REACTION
• ANA+EXPOSED NUCLEOPROTEIN form Ag-Ab complexes,
which are deposited in tissues, depending on several factors
• INFLAMMATION in tissues occurs due to
• Complement activation, which promotes inflammation &
necrosis
• Platelet activation & Hageman factor ( f xii) activation - micro
thrombi – ischemia- necrosis - inflammation

17. TYPE III IMMUNE COMPLEX DISEASE
ROLE IN PATHOGENESIS OF SLE

18. SLE
MORPHOLOGY
• Highly variable, depend on tissue involved & duration
• Acute necrotizing (fibrinoid necrosis) vasculitis, with fibrosis
& luminal narrowing is seen in all affected tissues
KIDNEY
• GLOMERULONEPHRITIS ( LUPUS NEPHRITIS )- deposit of
DNA- Anti-DNA & COMPLEMENT– EM, IFA, six classes (types)
• TUBULAR, INTERSTIAL lesions are also seen

19. LUPUS NEPHRITIS [LN]
• CLASS I – MINIMAL MESANGIAL LN shows IC [immune
complex] deposits on EM [electron microscopy] &
immunofluorescence [IF]. Light microscopic changes nil.
• CLASS II – MESANGIAL PROLIFERATIVE LN- mild to moderate
increase in mesangial matrix & cellularity
• CLASS III – FOCAL LN- < half glomeruli are affected by
swelling & proliferation of endothelial & mesangial cells,
neutrophilic infiltration, fibrinoid deposits & capillary
thrombi

20. LUPUS NEPHRITIS [LN]
• CLASS IV – DIFFUSE LN -> 50% GLOMERULI ARE INVOLVED,
proliferation of endothelial & mesangial cells – narrowing of
Bowman’s space, subendothelial deposit of immune
complexes – thickening of vessel wall (PAS stain)
• CLASS V – MEMBRANOUS LN – thickening of BM due to
deposition of IC & basement like material
• CLASS VI – ADVANCED SCLEROSING LN – complete sclerosis
(fibrosis) of glomeruli

21. SLE
MORPHOLOGY
SKIN: LESIONS ARE SEEN IN SLE AS WELL AS LOCALIZED FORM
KNOWN AS DISCOID LE [limited to skin only]
• Erythematous/maculopapular rash on malar eminences &
bridge of nose (butterfly rash, very characteristic of the
disease) & trunk and limbs
• Photosensitivity
• Dermo epidermal junction shows edema, lysis, inflammation,
immune complex [IC] deposits

22. SLE
MORPHOLOGY
JOINTS
• Nonspecific inflammation is present, no specific feature is
seen
CNS
• Micro vessel thrombosis
• Intimal proliferation
• Ischemia
• Premature atherosclerosis

23. SLE
MORPHOLOGY
HEART
• Pericarditis
• Myocarditis
• Endocarditis (Libman-sacks endocarditis)
• Atherosclerosis of coronary vessels

24. SLE
MORPHOLOGY
SPLEEN
• Follicular hyperplasia & infiltration by plasma cells
• Perivascular fibrosis (onion skin lesion)
SEROSAL SURFACES - shows features of
• Inflammation
• Effusion
• Fibrosis
OTHER ORGANS – show features of vasculitis

25. SLE
CLINICAL FEATURES
YOUNG, FEMALE, presents with NONSPECIFIC/CHANGING
SYMPTOMS, due to relapses & remissions
• SKIN – malar & discoid rash, photosensitivity
• ORAL CAVITY – painless ulcers
• KIDNEY- proteinuria, hematuria, casts, renal failure
• NEUROLOGICAL- deficits, seizures & psychosis

26. SLE
C/F
• ARTHRITIS- nonerosive, involving peripheral joints like hands,
wrist, knee, elbow, feet, ankles
• HEMATOLOGICAL- pancytopenia of varying intensity
• CARDIAC- all layers of heart are affected, ischemic heart
disease [IHD]
• SEROSITIS – pleuritis, pericarditis
• INCREASED incidence of INFECTIONS

27. SLE
LAB DIAGNOSIS
SPECIFIC
• Anti Nuclear Antibodies [ANA],
anti ds DNA [double stranded DNA antibody] is
most specific
• RENAL BIOPSY shows features as described, EM &
immunofluorescence are very specific
• NONSPECIFIC – anemia, pancytopenia, raised ESR

28. SLE
LE CELL
LE CELL IS OF HISTORICAL IMPORTANCE ONLY
IT IS NO LONGER USED AS A DIAGNOSTIC TEST
LE cell test: In vitro test
• Blood is traumatized to expose the nuclei of leucocytes to
ANAs in circulation by
• Mixing the blood with glass beads & agitating it every half an
hour for 2 -3 hours.

29. SLE
LE CELL
LE CELL IS OF HISTORICAL IMPORTANCE ONLY
• Then the blood is centrifuged (after removing the glass
beads) and
• Buffy coat smear is prepared and the slide stained with
Leishman’s stain.
• The ANA-coated denatured nucleus (LE body) is chemotactic
for phagocytic cells, and it is seen as acellular amorphous
eosinophilic mass in neutrophil / monocyte

30. SLE
LE CELL
Typical LE cells has rounded
mass of amorphous nuclear
material (LE body) which may
displace the lobes of neutrophil
to the rim of the cell.
LE cell test is positive in 70%
cases of SLE
Other conditions with positive
LE test are: Rheumatoid arthritis,
Lupoid hepatitis , Penicillin
sensitivity.

31. SLE
TREATMENT & PROGNOSIS
• STEROIDS are useful in controlling the inflammation
• SPECIFIC B L DELETION THERAPY
• COURSE OF DISEASE IS MARKED BY REMISSION &
EXACERBATION
• DEATH IS USUALLY DUE TO RENAL FAILURE, INFECTION &
CADRIOVASCULAR DISEASE
• COMPLICATIONS SEEN MOST FREQUENTLY ARE INFECTIONS
& LYMPHOMA