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Systemic Sclerosis

  • dcSSc
  • lcSSc

Note: Scleroderma,  characterized by thick and endurated skin is a distinguishing hallmark of Six

Genetic factors: Loci similar to SLE, RA, Psoriasis suggesting common pathogenic pathways shared among these phenotypically dissimilar conditions.  

Envioronmental and occupational risk factors:  (Harrison's)
  • Viral infections: Parvo Virus B19, CMV, EBV
  • Similar skin induration but varying biopsy findings. Conditions include. 
    • Toxic oil syndrome (contamination  rapeseed oil for cooking)
    • Eosinophilia Mayalgia Syndrome (l-tryptophan supplementation)
    • Nephrogenic Systemic Fibrosis linked to gadolinium 
  • Cigarette : Not linked (unlike RA)

Pathogenesis:  (Harrison's)
  • Sustained Fibroblast activation (Amplifying and Maintenance mechanisms B and C below)  is the key often initiated by transient generation of ROS and immune damage to the endothelial cells (triggering : A )

As noted above, sustained activation of Fibroblast is the key. Picture below highlights the mechanism of activation of fibroblasts. 
3 main pathways
  • SMAD signaling 
  • Non-smad signaling 
  • RAS-ERK1 signaling 

  • 3 cardinal pathophysiological mechanism include (Harrisons)
    • (1) diffuse microangiopathy, 
    Paradoxically, the process of revascularization that normally reestablishes blood flow to ischemic tissue is defective in SSc despite elevated levels of other angiogenic factors. Moreover, bone marrow–derived circulating endothelial progenitor cells are reduced in number and impaired in function. Widespread capillary loss, obliterative vasculopathy of small and medium-sized arteries, and impaired ability to repair and replace damaged vessels are hallmarks of SSc.
    • (2) inflammation and autoimmunity, and 
    • (3) visceral and vascular fibrosis in multiple organs

    Immunopathogenesis: https://doi.org/10.1080/1744666X.2019.1614915

    Microvascular endothelial cell injury and apoptosis is a key first step in the SSc that drives the immunopathogenesis. 
    • highlighted in purple are processes involved in pathogenesis of SSc; added information in black is to show the comparison of SSc pathogenesis to the rest of the clinical immunology)
      • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
        • Innate Immune System
          • Physical Mucosal Barrier
          • Proteins
          • Cells like Granulocytes, NK Cells, Macrophages, Dendritic Cells
            • Plasmacytoid dendritic cells infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-. (IFN-.alpha) and small chemokine PF4, also known as CXCL4) which are both hallmarks of the disease.
          • Phagocytic defects
          • Cell Signalling including IFN Gamma: TLR activation from IFN produced by plasmacytoid dendritic cells 
            • Type 1 IFN INTERFERON SIGNATURE is noted in SSc
          • Complement (Alternate and Lectin Pathways)
        • Adaptive Immune System
          • T-Cell
            • T-Cell Development
            • T-Cell Maturation
            • T-Cell Activation and antigen presentation or Functioning 
                • T cells are also involved in SSc
              • Th1:
              • Th2 : SSc has TH2 cell activation 
                • CD4+ Interestingly, among T cells (T cells), the type 2 T helper (TH2) cells – characterized by secretion of IL-4 and IL-13 – are more expressed in SSc than TH1 cells, which primarily secreteanti-fibrotic IFN.
              • Th17: Also, implicated in SSC. T reg cells have been noted to transform into Th17 cells
          • B-Cell
            • Impaired Development
            • Impaired Functioning 
              • T-cell mediated
              • T-cel independent 
                • In diffuse cutaneous SSc (dcSSc) anti-topoisomerase AAbs

                  (ATA), formerly known as anti-Scl70 AAbs, are more prevalent,

                  whereas anticentromere AAbs (ACA) are more frequent

                  in limited cutaneous SSc (lcSSc).

                  A possible pathogenic role of ATA in SSc has been suggested

                  following its binding to fibroblasts and induced adhesion and

                  activation of cocultured monocytes [48]. This observation might

                  provide an explanation for the amplification of the fibrogenic

                  cascade in ATA-positive SSc patients.

        • Regulatory Immune System
          • Innate System Regulation
            • Regulatory cell dysfunction is noted in SSc. Decreased regulatory T cells in circulation is noted. Also, these regulatory Tcells can transform into pathogenic effector T Cell 
          • Adaptive System Regulation