Lupus nephritis etiology & pathogenesis

1. LUPUS NEPHRITIS

2. HISTORY OF LUPUS
• Hippocrates (460-375 BC) was the first to describe
cutaneous ulcers under the heading of herpes
esthiomenos
• The term "lupus", derived from Latin for wolf

3. Associated systemic manifestations was described in
1872 and termed "disseminated lupus erythematosus".
A preference for "systemic" rather than "disseminated"
was suggested in 1904 but would not prevail until the
1960s.
Term "nephritis", denoting "inflammation of the
kidneys" dating to the 1580s, was first used to describe
the renal lesions of SLE in 1902.
Late 1950s after the introduction of kidney needle
biopsies
Lesions observed were classified by glomerular changes
in 1975 and refined in 2003

4. DEFINITION
• Lupus nephritis (LN), immune complex
glomerulonephritis (GN)
• Common and serious in patients with
systemic lupus erythematosus (SLE).
• SLE is defined by clinical and laboratory
features as outlined in
• The 1997 American College of
Rheumatology (ACR) criteria
• The Systemic Lupus International
Collaborating Clinics (SLICC) criteria
introduced in 2012

5. ACR Criteria
Presence (cumulative) of four or more of the following:
• Malar rash
• Discoid rash
• Photosensitivity
• Oral or nasopharyngeal ulcers
• Nonerosive arthritis (involving ≥2 joints, characterized by tenderness, swelling, or effusion)
• Pleuritis or pericarditis
• Renal disease (proteinuria >500 mg/day OR 3+ by dipstick OR cellular casts)
• Neurologic disorder
• Hematologic disorder
• Immunologic disorder (positive anti-dsDNA antibody OR positive anti-Sm antibody OR positive antiphospholipid antibody (includes pr
lupus anticoagulant, false-positive treponemal test, positive anticardiolipin antibody)
• Positive ANA

6. SLICC Criteria
Presence (cumulative) of four or more of the following (with at least 1 clinical and 1 immunologic criteria) OR biopsy-proven lupus nephritis
with positive ANA or anti-dsDNA
Clinical Criteria Immunologic Criteria
• Acute OR subacute cutaneous lupus • Positive ANA
• Chronic cutaneous lupus • Positive anti-dsDNA antibody
• Nonscarring alopecia • Positive anti-Sm antibody
• Oral OR nasal ulcers
• Positive antiphospholipid antibody (includes presence of a lupus
anticoagulant, false-positive RPR, anticardiolipin antibody or anti-
β2 glycoprotein antibody)
• Synovitis ≥2 joints (swelling or effusion) OR tenderness in 2 or more
joints and ≥30 min of morning stiffness
• Low complement (C3, C4, or CH50)
• Serositis • Direct Coombs test (in the absence of hemolytic anemia)
• Renal disease (red blood cell casts OR proteinuria ≥500 mg/day on 24-
hr urine collection OR spot ratio of urine protein to creatinine ratio ≥0.5)
• Neurologic disorder
• Hemolytic anemia
• Leukopenia OR lymphopenia

7. EPIDIMIOLOGY
• SLE is more prevalent in women
• Female-to-Male ratio is highest at
reproductive age
• Ranging between 8:1 and 15:1
• Lowest in prepubertal children at about
4:3
• Black and Hispanic SLE patients
develop LN earlier and high risk for
CKD/ESKD (APOL1 gene-black)

8. • LN is a major risk factor for morbidity
and mortality in SLE and 10% of
patients with LN will develop ESRD
• The risk of ESRD is higher in class 4 LN
the risk may be as high as 44% over 15
years
• Patients with LN also have a higher
standardized mortality ratio and die
earlier than SLE patients without LN
• 10-year survival improves from 46% to
95% if disease remission can be
achieved

9. PATHOGENESIS
A meta-analysis of HLA-DRB1 alleles
in SLE concluded that
• Carriers of HLA-DR4 and DR11 were
protected against LN
• Conversely HLA-DR3 and DR15 conferred
an increased risk of LN
Meta-analysis- Patients were
women of European descent found
• LN mapped to the PDGF receptor A gene
and the gene for the sodium-dependent
glucose cotransporter SLC5A11

10. • Cell proliferation,
• Matrix accumulation, and
• Intrarenal inflammation
PDGF may mediate kidney
• Decrease in serum and an increase in
urine myo-inositol, active role of SLC5A11
in proximal tubule inositol reabsorption
• Inositol regulation, SLC5A11 may mediate
apoptosis through the programmed cell
death and TNF-α pathways
SLC5A11 may mediate a

11. PATHOGENESIS
• Autoimmune response in SLE is seen
against chromatin (normally is shielded
from the immune system due to its
location in the nucleus)
• The presence of apoptotic material may
be the result of
• An aberrant process of apoptosis,
increased rate of apoptosis or
apoptosis at the wrong moment or
location
• Insufficient clearance of apoptotic
cells and debris

12. • The innate and adaptive immune system may thereby be
activated in several ways
• Apoptotic blebs and apoptotic chromatin, containing apoptosis-
induced modifications myeloid dendritic cells (mDCs) ligation
of toll-like receptors (TLRs) autoreactive T cells activate
autoreactive B cells specific for chromatin
• Particular RNA-containing immune complexes plasmacytoid
dendritic cells (pDCs) ligation of TLR7 production of type I
interferons like IFN-α.
• NETs (neutrophil extracellular traps) pDCs
• Autoreactive B cells may be directly activated by apoptotic
chromatin

13. APOPTOSIS AND
SURVIVAL DEFECTS
IN SYSTEMIC LUPUS
ERYTHEMATOSUS
• Fas receptor (CD95; FasR) and Fas ligand (CD95L;
FasL)
• FasL is only expressed on immune cells, whereas
FasR is expressed on non-immune cells as well
• juvenile onset of SLE an increased expression of
FasR on T cells has been detected
• Bcl-2 family
• either anti-apoptotic ( Bcl-2) or pro-apoptotic
(Bim )
• Integrin alpha-M, (ITGAM (CD11/CD18))
• Regulation of apoptosis in neutrophils, but also
in leucocyte adhesion and complement C3b
binding
• B-cell survival signals affected in SLE include the
cytokine B-cell activating factor (BAFF)

14. • Neutrophil extracellular traps in SLE (NETs)
• Neutrophils can spill so-called neutrophil
extracellular traps (NETs), which consist of
their total chromatin and associated pep-
tides with anti-microbial activity like LL37 and
HNP
• process of NET formation is called NETosis
• insufficient degradation of NETs is linked to
SLE and lupus nephritis
• anti-LL37 and anti-HNP antibodies, which
correlate with anti-DNA antibody titres
• NETs are able to activate plasmacytoid
dendritic cells

15. CLEARANCE
DEFECTS IN
SYSTEMIC LUPUS
ERYTHEMATOSUS
• Cells undergoing apoptosis display
• ‘come and get me’ signals, like the lipid
phosphatidylcholine (PC)
• ‘eat me’ signals, like the lipid
phosphatidylserine (PS)
• This signals attract phagocytes and facilitate
phagocytosis mediated by receptors on
phagocytes.
• Bridging molecules (opsonins)serve as an
additional link between the signals on the
surface of the apoptotic cell and the receptors
on the phagocyte.
• Deficiencies in these components can lead to
decreased clearance of apoptotic cells and to the
development of SLE

16. • PS is an important apoptotic cell signal for
clearance which is present at the outer cell
membrane
• PS is bound directly by receptors on the
phagocyte or indirectly via bridging molecules
or opsonins.
• The phagocytic cells express multiple receptors
including
• PS receptor
• Milk fat globule-EGF factor 8 protein
(MFGE8)
• Complement factor C1q receptor
• c-Mer proto-oncogene tyrosine kinase
(MERTK)
• ITGAM
• macrophage receptor with collagenous
structure (MARCO)

17. Bridging molecules and opsonins that play an
important role in the clearance of apoptotic cells
include
• Complement C1q,
• Pentraxins (PTX3),
• Mannan-binding lectin (MBL),
• C-reactive protein (CRP), and
• Serum amyloid P protein (SAP)
C1q is an opsonin and required for uptake of
degraded chromatin. C1q deficiency always is
associated with SLE.
DNase1 (major endonuclease)-deficiency leads to
the accumulation of non-fragmented apoptotic
chromatin

18. THE ROLE OF
MYELOID
DENDRITIC CELLS
• •Macrophages can ingest apoptotic cells, blebs,
and debris in an anti-inflammatory manner,
which is characterized by the production of TGF
beta and IL-10
• •Dendritic cells encountering autoantigens
without being activated will induce
immunological tolerance.
• •The balance between immunity and tolerance
apparently is skewed towards autoimmunity in
SLE.
• •mDCs can be activated by apoptotic blebs and
modified chromatin, and after ingestion mDCs
present the modified histone peptides in a pro-
inflammatory manner to T cells, thereby
initiating an autoimmune response

19. • Presentation by activated mDCs of the
ingested modified chromatin to autoreactive
T cells may be the first step in breaking the
immunological tolerance that may occur in
patients with SLE
• IL-6 concentrations, produced by activated
mDCs, are high in patients with SLE
• IL-6inhibit the development of regulatory T
cells (TREG) while it stimulates the
development of Th17 cells
• Th17 cells activates autoreactive B cells and
recruit inflammatory cells to specific organs

20. The role of
plasmacytoid
dendritic cells and
IFN-α
• Plasmacytoid DC express TLR7 and TLR9,
• pDCs are activated, thereby initiating the
production of type I IFNs with IFN-α as key
cytokine
• IFN-α has a broad range of effector
functions
• mDC maturation
• B-cell activation
• T-cell activation
• enhancing NETosis,
• NETs also trigger pDCs to produce IFN-α

22. VIRAL IMMUNITY –
AUTOIMMUNITY-
RELAPSING
AUTOIMMUNE
DISEASE
• CD8 T cells become “exhausted” in the
setting of persistent antigen exposure
and the absence of CD4 T cell
costimulation.
• These exhausted CD8 cells lose effector
function and express inhibitory
receptors at high levels.
• This leads to an inability to clear viral
infections, but can be protective against
relapsing autoimmune disease
• The upregulated genes are 4–1BB,
CTLA4, PDCD1, LILRB4, and KLG1.

23. RENAL BIOPSY
• The kidney biopsy has been the gold standard
for the diagnosis of lupus nephritis for over 50
years.
• Renal histology is required to accurately define
the kidney injury associated with lupus nephritis
• The histologic features of LN were first
characterized in the 1950s
• Based on these early descriptions of LN
histology, the World Health Organization (WHO)
introduced the first histologic classification of LN
in 1974.
• This classification underwent modifications in
1982 and again in 1995.
• In 2003, the International Society of Nephrology
and the Renal Pathology Society (ISN/RPS)
added further refinement to the classification of
LN.

24. ISN/RPS 2018

25. Class II

26. CLASS III

27. CLASS 4

28. CLASS 5

32. CHANGES IN
ISN/RPS 2018
• The minimum mesangial hypercellularity
required to make a diagnosis of class II
lupus nephritis is the presence of ‘four or
more nuclei fully surrounded by matrix in
mesangial area not including the hilar
region
• The designations ‘A, C, and
A/C,’ respectively, for ‘acute, chronic and
acute/chronic,’ have been replaced by a
formal scoring of the activity and
chronicity indices
• Endocapillary hypercellularity’ replaces
‘endocapillary proliferation’

33. • ‘Neutrophils/Karyorrhexis’ replaces ‘leukocyte
infiltrate.’ This is because karyorrhexis is typically
the result of neutrophil fragmentation and it is
logical to group both lesions together.
• ‘Fibrinoid necrosis’ is now a separate item to be
graded instead of being graded as ‘fibrinoid
necrosis/karyorrhexis.’
• ‘Cellular/fibrocellular crescents’ replaces ‘cellular
crescent.’ In other words, both cellular and
fibrocellular crescents are accepted as indicators
of acute inflammatory activity.
• ‘Interstitial inflammation’ replaces ‘mononuclear
cell infiltration.’ This change recognized the role of
neutrophils, eosinophils, and mast cells in the
pathogenesis of tissue injury.
• ‘Total glomerulosclerosis score’ includes both
globally and segmental sclerosis, since global
sclerosis only captures later stages of disease.

34. THANK U…