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SLE Pathophysiology

SLE pathophysiology: Mary Krow - NY Presby

  • A combination of increased generation of nuclear material, perhaps modified by oxidative stress, and impaired clearance may be important mechanisms of lupus immunopathogenesis

SLE resembling syndromes
  • Gene mutation: 
    • AGS (Aicardi-Goutieres syndrome): Seen in young children (skin, CNS, ab) - active innate immune system
      • TREX gene mutation that encodes DNAase - eventually leads to Type1 IFN (IFN B)
      • RNASEH2 gene mutation leads to impaired clearance of ribonucleotides from RNA-DNA hybrid 
    • Vasculopathy similar to SLE or SSc in young children (skin, livido-reticularis, distal ext ulcer, ILD, markers of systemic inflammation, low ab)
      • Mutations on TMEM173 mutations encode STING (stimulator of IFN genes) - IFN gene - IFN B - JAK STAT1 
  • Large SNP has bene implicated in Type 1 IFN signature 
    • IRF5 : IFN regulatory factor 5 and IRF 7: DNA or RNA in cytoplasm binds to endosomal TLR and activates IRF5 or IRF 7, which then translocate to nucleous from cytoplams and acts as a transcription factor to IFN alpha
  • Increased availability of nuclear debries 
    • C1q, C2, C4 deficiency 
    • CRP 
  • the altered threshold for lymphocyte activation or efficiency of cell signaling 
    • T cell-dependent B cell activation 
  • Gene changes that define the target organ damage 
    • SNP in TNIP1 associated with LN 
    • MTMR3 mutation leads to LN 
  • Female predominance
    • estrogen can influence pDC and lymphocyte activation
    • increased prolactin level noted in lupus patients
    • higher incidence of men with SLE have Kleifelters syndrome 47XXY
    • TLR 7 gene is located in X chromosome - epigenetic changes - DNA methylation leads to TLR 7 activation leads to Type 1 IFN activation by pDC

Environment triggers (24-57% concordance rate in monozygotic twins)
  • Definite: UV
  • Probable: Estrogen, Prolactin, EBV, Medications (altered DNA methylation is the mechanism); Hydralazine - inhibits ERK pathway signaling to result in the decreased expression of DNA methylation genes) : Any agents that may affect ERK pathway can trigger Lupus 
  • Possible: 
Innate: Fig: 79 -2 is the key 
  • TLR dependent pathway 
    • Signaling: 
      • IFN regulator factor (IRF)
      • NFkB
      • Mitogen activated protein (MAP) kinase  family
    • TLR 9 may be protective to decreaseTLR 7 mediated RNA-binding protein ab
  • TLR independent pathway 
    • Signaling
      • RNA sensors: RIG-1 and MDA - 5 --- signal through Mitochondrial adaptor protein like MAVS - activates IKK and TBK1
      • DNA sensors: IFI16, DAI, cGAS --- generates cGMP -- binds to ER protein STING -- activates TBK1 (like after RNA sensor)
        • Both Kinases leads to activation of TF, IRF3 and NFkB -- IFN B  
  • How do these dying cell gain access to TLR or intracytoplasmic receptors or RNA or DNA sensors
    • By Associated Neutrophil derived proteins like HMGB1, and Cathelicidin protein LL37 helps gain immune complex into the cells 
    • NETs leads to release of HMGB1, LL37 and others into the cytoplasm 
      • NETs are induced. by neutrophil interaction with vascular endothelial cells, platelets or various cytokines. Also, RNA-ICs, Nucleosome induces NETs
    • Apoptotic bleps or microparticles are release from activated and dying cells 

  • T cells
    • Direct T cell actiation associated T cell proliferation is normal 
    • But self or allogenic non T cells or soluble ag associated T cell proliferation is impaired --- also such T cell produce less IL 2 necessary to T reg cells formation
  • B cells
    • T cell depnedent B cell actication (CD4 T cells)
    • T cell independent B cell activation - IL21, BLyS/ BAAF

How to know the mechanism of SLE?
  • RNA binding protein ab (Ro, La, Sm, RNP) if present may point towards endosomal RNA sensor activation of Innate system IFN pathway 
  • dsDNA present (endosomal sensing the DNA)
  • decreased CRP, C1q, C2, C4 deficiency: May be related to RNA or DNA binding mechanisms as apoptotic cells are not fully cleare

Anti-Sm antibody, and Anti-U1 RNP antibody 

Per uptodate 
Anti-Sm antibodies bind to one or more of a series of Sm proteins designated SmB, SmD1, SmD2, SmD3, SmE, SmF, and SmG. The Sm proteins comprise a heptameric ring that forms a complex with small, uridine (U)-rich nuclear ribonucleic acids (RNAs) designated U1, U2, U4, and U5. The Sm proteins bind the U RNAs in the cytoplasm and are critical for the import of snRNPs into the nucleus [33]. snRNPs have an important role in processing ("splicing") precursor messenger (m)RNAs into mature mRNAs [14].

Anti-U1 RNP antibodies — Anti-U1 RNP antibodies react with one or more of three proteins (70-kD, A, and C) that are specifically present in the U1 snRNP complex. Unlike the Sm antigens (which bind to U-rich RNAs U1, U2, U4, and U5), 70-kD, A, and C are only present in the U1 snRNP complex. Anti-U1 RNP antibodies are present in a subset of patients with SLE, and high titer anti-U1 RNP antibodies are present in all patients with mixed connective tissue disease, a disorder that is closely related to SLE. Anti-U1 RNP antibodies may also be present in lower titers in other autoimmune diseases, including rheumatoid arthritis, systemic sclerosis, Sjögren's syndrome, and polymyositis

The elevated IL-6 level has been observed in the preclinical stage of lupus concurrently or before first positive auto-antibody, suggesting a key role of IL-6 in initiating breaks in B or T cell tolerance. Established lupus patients also have higher IL-6 levels in healthy control [22]. Furthermore, active SLE patients have higher IL-6 levels than inactive SLE patients [22]In addition, studies looking into the individual lupus manifestations and cytokine profile have noted a higher level of serum IL-6 in NPSLE [25], cognitive fatigue [26], SLE-Sjogren syndrome [27], anemia [28], arthritis [29], cutaneous involvement [30], and in lupus patients with elevated cardiovascular risk factors [31].  [PM2] Likewise, urinary IL-6 level has been higher in patients with lupus nephritis [32] [33]. In addition, B cells form autoantibodies in lupus and Increased B cells response to the IL-6  has been reported in lupus patients[21]. IL-6 inhibition in established lupus patients helped restore these naïve B and naïve T cell balance suggesting such break in B or T cell tolerance is reversible using IL-6 inhibition [24].
However, there have been conflicting reports on whether IL-6 levels correlate with lupus disease activity [34] [35]. However, a recent meta-analysis compiled 1817 SLE patients and 874 healthy individuals and IL 6 level was higher in SLE than in healthy individuals and, using SLEDAI >4 as a definition of active Lupus, IL-6 level correlated with the disease activity in lupus. However, when using SLEDAI-2K > 4 to define the active disease, such association between IL-6 level and lupus activity was not seen [36].