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SLE Pathophysiology

SLE pathophysiology section of K and F is written by 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

Three critical processes are involved, perhaps in combination, to initiate the disease 
  1. Increased auto-antigen 
    1. Increased production
    2. Decreased clearance 
  2. Increased innate immune system response, including the one generating Type 1 IFN
    1. TLR dependent: The nuclear ab-ag immune complex can access endosomal TLR
    2. TLR independent: 
  3. Increased adaptive immune system response 
The organ damage is done by releasing reactive oxygen species from Neutrophils and Macrophages. Neutrophil and Macrophages activation is due to the effect of 
  1. Auto-ab
  2. Immune complex formation 
  3. Complement activation
  4. Pro-inflammatory cytokines

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: 84.1 -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].