Pathogenesis of scleroderma

1. SCLERODERMA PATHO
RITASMAN

2. Background
• Involves triad of
• vascular damage ,
• innate and adaptive autoimmunity ,
• fibrosis .
• Some having predominant vascular complication , some having
predominant fibrotic complication .

4. Inflammation and immunity
• Auto-antibodies and inflammatory cells in affected organs support
presence of immunity in scleroderma
• Genetic polymorphism located in genes associated with immunity .
• Immune deregulation happens

5. Role of innate immunity
• TLR have roles by recognizing both PAMP , DAMPS
• Monocyte -macrophage activation in fibrosis – macrophage imp role as immune
effectors.
• Secrete profibrotic inflammatory mediators – PDGF , TGFbeta , IL13 , IL6 .
• Dermal macrophage show activated phenotypes with increased expression of type
1IFN , AIF1
• Alternative macrophage is profibrotic , releases TGF beta
• Monocyte from SSC-PAH show express genes with alternative macrophage
activation – MRC1

6. • Activation of TLR dependent innate immunity – secretion of IL6 , TNF alpha
• Internalization of ATA -nucleic acid -containing complex by dendritic cells
stimulate nucleic acid sensing TLR activation and IFN alpha production
• Normal components of ECM – can also act as ligand for TLR and elicit their
activation.
• DAMPs are upregulated in lesional tissues in scleroderma
• TLR4 induces myofibroblast trans-differentiation in lung and skin , secretes TGF ,
produce collagen .

7. Oxidative stress –
• Marker of oxidative stress is increased in SSC
• NOX4 is upregulated in scleroderma
• Therapeutic inhibition of NOX4 is intriguing

8. ER stress , autophagy , UPR
• ER associated protein degradation , autophagy, catabolism of
cytoplasmic contents are activated
• HLA B35 shows increased endothelial cell ER stress response and
progression of PAH

9. Inflammasome in SSC
• NALP3 activate caspase 1 which turn activates IL1b , IL18
• Dysregulation of inflammasome in fibrotic disorders of kidney , lung ,
liver
• Expression of genes associated with inflammasome activation is
elevated in SSc fibroblast – AIM2 , CARD6 , CASP1 , IL6

10. Humoral immunity
• Anti centromere ab – CENP-A, B ,C ( Lc SSc)
• ATA – ILD , cardiomyopathy , SRC , anti pol3 – SRC, severe skin disease
in dcSSC
• Anti U3 RNP – target snoRNPs and fibrillarin , responsible for rRNA
processing
• Anti U11/U12 RNP – Ab to U11/U12 RNP - minor component of
spliceosomes
• Anti Th/To – directed against Rpp40 , Rpp38 , hPop4

11. Neoantigens as autoimmune target in SSC –
• Recent study suggests nuclear protein can become auto-antigen targets because of exposure of
neo-epitopes
• Hypoxia in exposure of certain metal stimulates fragmentation of several auto-antigens targeted
in SScs
• Generation of SSC auto Abs by neo-epitopes which are triggered by hypoxia , mercury , somatic
mutation
• Anti pol3 -associated with cancer

12. • AutoAbs implicated in tissue damage in SSc –
• AECA could effectively link autoimmunity and vascular injury
• TLR activation and autoreactive B cells

13. Cellular immune response
• MCP1 /CCL2 over-expressed in both GVHD and SSC
• Type2 helper cells mediate pulmonary fibrosis
• SSC-ILD – Th2 phenotype
• SSC-PAH – TH1 phenotype

14. Vascular damage
• Endothelial cell injury and apoptosis-- Endothelial cell apoptosis is
implicated in the UCD 200/206 chicken model of scleroderma
• Increased circulating levels and skin expression of granzyme have
been reported in SSc.
• Cytotoxic T cells might mediate vascular injury via granzyme–perforin
or Fas–FasL activation.

15. • Vascular injury leads to vascular activation, injury, and apoptosis and
might result from transient or latent viral infection
• Transforming growth factor-β (TGF-β) or other factors might induce
endothelial cells to transform into mesenchymal cells.
• Loss of perivascular pericytes disrupts vascular integrity.

16. Vascular spasm, reactive oxygen species, and hypoxia

17. Intimal hyperplasia
• Hyperplasia of the intimal layer of small- to
medium-sized arteries is a distinguishing
pathologic hallmark of SSc.
• The cells responsible for intimal hyperplasia
might be of endothelial, smooth muscle cells,
or pericyte origin
• myofibroblasts are implicated as the cells
making up the hyperplastic neointima

18. Other vascular injury
• Endothelial–mesenchymal transformation
• Circulating endothelial cells are increased in SSc, consistent with the
known vascular injury
• Circulating endothelial progenitor cells in SSc have yielded conflicting
results, with both increased and decreased numbers reported.

19. Platelet activation and coagulation
• Platelet activation and abnormalities in the coagulation and fibrinolytic systems are prominent in
SSc
• Platelet activation in SSc might occur secondary to endothelial dysfunction and contribute to the
occlusive arterial disease by release of PDGF, TGF-β, TSLP, and serotonin, which also have an
impact on fibrosis.
• Defects in endothelial cell regulation of thrombosis and fibrin deposition may thus contribute to
intimal hyperplasia and vasculopathy in SSc.

20. • excessive tissue accumulation of type I collagen and other fibrillar
collagens,
• along with ECM components fibronectin; elastin; cartilage oligomeric
protein (COMP); periostin and osteopontin; and
• proteoglycans such as decorin, fibromodulin, and lumican,
• as well as matricellular molecules, such as SPARC and tenascin-C.

21. Cellular determinants of fibrosis
• Fibroblasts - versatile tissue-resident mesenchymal cells that lack unique distinguishing surface markers
, pathologic fibrosis is characterized by unopposed fibroblast activation.
• Pericytes- normally reside in the walls of microvessels,, detachment of perivascular pericytes from the
vessel wall results in loss of pericyte coverage of endothelial cells, which leaves an unstable
endothelium prone to rarefaction, linking microvascular injury and fibrosis
• Bone marrow–derived progenitor cells, called fibrocytes, were described and implicated in wound
healing.

22. Myofibroblasts
• Pathologic matrix accumulation in SSc lesional tissues ,
• Specialized α-smooth muscle actin-positive cells that are seen in a wide variety of fibrotic
diseases
• Pathologic fibrogenesis is characterized by the persistence of myofibroblasts in lesional tissue,
which results in an excessively contracted tissue
• In SSc, the extent of myofibroblast accumulation within the dermis correlates with the extent
of clinical skin involvement as assessed by the MRSS

23. Epithelial–mesenchymal transition (EMT).
• epithelial cells lose cell–cell adhesion and apical polarity
• acquire mesenchymal features of motility, invasiveness, heightened resistance to
apoptosis, and synthesis of ECM molecules
• EMT can readily be induced by hypoxia, ROS, Wnt ligands, and TGF-β.
• Recent studies suggest that adipocytic mesenchymal progenitor cells residing within
specialized niches in the dermis also differentiate into myofibroblasts through a
process designated “adipocyte–mesenchymal transition” (AMT).

24. Molecular determinants of fibrosis
FIBROGENIC GROWTH
FACTORS AND
CHEMOKINES
Transforming growth
factor-β is a master
regulator of connective
tissue remodeling

25. TGF-beta pathway – canonical & non-canonical

26. Other molecular determinants
• Connective tissue growth factor or CCN2 - markedly elevated in SSc, and serum levels correlate
with the extent of skin and lung involvement in SSc
• Platelet-derived growth factors- Expression of PDGF and its receptors is elevated in SSc skin and
bronchoalveolar lavage fluid
• Wnt–β-catenin signaling- deregulated Wnt signaling in both SSc and mouse models of disease.
• Paracrine mediators with antifibrotic activity- Fibroblasts from patients with SSc are relatively
resistant to these inhibitory effects of IFN-gamma

27. • Cultured systemic sclerosis fibroblasts show altered activation ex vivo
• constitutively increased collagen gene expression and enhanced ECM
synthesis, secretion of profibrotic cytokines and chemokines,
spontaneous production of cytosolic and mitochondrial ROS, and
increased expression of cell-surface receptors for TGF-β and PDGF.

29. Genetic
• The HLA-DQB1*0301 allele is associated with SSc in genera
• IFN-related genes such as IRF5 and IRF7 and IL-12–associated genes
such as IL12A, IL12RB1, IL12RB2, and STAT4.
• T , B ,TNF genes

30. Epigenetic
• In SSc fibroblasts- hypo methylation of ITGA9, ADAM12, COL23A1, COL4A2, MYO1E, RUNX1, RUNX2, and
RUNX3 genes is associated with their increased expression,
• Decreased expression of BMPR2 by SSc endothelial cells is associated with increased CG methylation
• Altered histone methylation in key target genes.
• Several HDACs have been shown to be upregulated in SSc fibroblasts, including HDAC1, HDAC5, and HDAC7.
• Endothelial cells from patients with SSc express increased levels of HDAC4, HDAC5, and decreased HDAC6.

31. Infectious
• SSc - antibodies directed against the UL83 and UL94 protein epitopes
of human cytomegalovirus (hCMV).
• ATA I - cross-react with hCMV-derived proteins- molecular mimicry
• parvovirus B19 infection
• Epstein-Barr virus in SSc- viral genes are expressed in SSc skin
samples and the virus is able to infect dermal fibroblasts

32. ENVIRONMENTAL EXPOSURE, DRUGS, AND RADIATION