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Question continued: 80% of people taking immunosuppressive drugs live a normal lifespan and 20% die.  What are the causes of death for the other 20%?  Since viruses are implicated, how can researchers be sure that antibodies aren’t recognizing viral capsids on host tissue rather than true host tissue?

Why is mortality risk higher for some Systemic Lupus Erythematosus (SLE) patients? SLE can affect different organs such as skin, joints, kidneys, central nervous system (CNS) or bone marrow. Stands to reason that disease severity would depend on organs affected. One of the most dangerous lupus complications is glomerulonephritis, i.e., lupus autoantibodies targeting kidney and causing irreversible damage. When this happens long enough, it leads to end-stage renal disease (ESRD). Genes such as APOL1 determine how long it takes to reach ESRD (1, 2). So a combination of target organ plus genetic predisposition determines SLE mortality risk.

Definitive causes of SLE are as yet unidentified. There are 2 broad hypotheses for how SLE might start and they aren’t mutually exclusive. Aberrant cell death and inadequate dead cell clearance for one, and molecular mimicry between extrinsic or intrinsic viral triggers and tissue antigens for another.

Aberrant cell death and inadequate dead cell clearance. Cell death is part of normal physiology. Dead and dying cells normally don’t come to the attention of T and B cells because they’re quickly and efficiently captured and eaten by phagocytes. Excess cell death for some reason could overwhelm the local clearance mechanism or cell death may be normal but clearance mechanism not. In either circumstance cell death may start normally but end up as secondary necrosis, i.e., dead/dying cells fall apart releasing their cytoplasmic and nuclear contents. Since circulating T and B cells don’t normally encounter such antigens, some of them may bind to such antigens. As well, since extracellular exposure of such intracellular antigens is abnormal, stands to reason such antigens would be presented to T and B cells in circumstances likely to activate them, i.e., full package necessary and sufficient to kick-start an adaptive immune response. Plenty of evidence for abnormal dead cell clearance in SLE (3, 4, 5, 6 [more primary human data in references 50 thru’ 64]). See figure below from 7 for how the SLE process might unfold.

What could underlie such problems in dying/dead cell clearance? That’s where epigenetic analyses implicate aberrant patterns of DNA methylation. Since methylation serves to repress gene expression, hypomethylation could predispose lupus T and B cells to easier activation for e.g. (8). However, why such aberrant patterns in the first place? Current thinking implicates a combination of genetic predisposition and environmental triggers. The latter are an unavoidable consideration since SLE concordance between monozygotic twins is ~20 to 57% (9, 10, 11, 12, 13, 14, 15, 16).

Since viruses are implicated, how can researchers be sure that antibodies aren’t recognizing viral capsids on host tissue rather than true host tissue?‘ Molecular mimicry between viral and tissue antigens would make the latter a target if the viral triggers for SLE were extrinsic. However, intrinsic viral elements could also trigger it.

  • Extrinsic Viral Triggers. How could viral infection trigger SLE? Through molecular mimicry, i.e., infection with an infectious agent whose antigens overlap with tissue antigens. Infection would trigger specific immune responses against itself, responses that would end up targeting that tissue as well. Called cross-reactivity, genetic factors play a role in its likelihood. Cytomegalovirus (CMV), Dengue virus, Epstein-Barr Virus (EBV), Human Herpes Virus (HHV-6), HHV-7, HHV-8, Human Papilloma Virus (HPV), human T cell lymphotropic virus (HTLV), HIV, parvovirus B19, transfusion-transmitted virus are among the several viruses linked to SLE (17). However, evidence for virus involvement in SLE is indirect, not direct. For e.g., high proportion of SLE patients have anti-retroviral antibodies even in the absence of retroviral infection (18, 19, 20, 21).
  • Intrinsic Viral Triggers. Human endogenous retroviruses (HERV) constitute ~8% of the human genome (22). Inherited like other genomic elements, their activation and expression can be influenced by sex hormones, DNA methylation as well as external triggers such as ultraviolet light. As such HERVs constitute intrinsic viral triggers for SLE (17).

Molecular mimicry, i.e., immune response recognizing antigenic structures similar between viruses and tissues would be the mechanism by which viruses could trigger SLE. Cross-reactive lupus T and B cells would be recognizing antigens similar between viruses and tissues while they’d be recognizing intrinsic antigens in the case of HERVs. Thus far, there is no definitive proof for a viral trigger for SLE.


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2. Lin, Chee Paul, et al. “Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.” Genes and immunity 13.3 (2012): 232-238. http://www.ncbi.nlm.nih.gov/pmc/…

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15. Rhodes, B., and T. J. Vyse. “The genetics of SLE: an update in the light of genome-wide association studies.” Rheumatology 47.11 (2008): 1603-1611. an update in the light of genome-wide association studies

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22. Nelson, Paul, Graham Freimanis, and Denise Roden. “Human endogenous retroviruses; evolutionary dynamics, chromosomal location and host benefit.” eLS (2008).