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PATHOPHYSIOLOGY
Acknowledgment: Based on GlomCon’s Glomerular Disease Virtual Fellowship seminar “The Guiding Principles for Evaluation of Glomerular Disorders” by Dr. Richard Glassock. Following an exciting first seminar, the GlomCon fellows learned about the principles governing glomerular disease evaluation. The House of Deposits dived into the literature to find answers to three pertinent related questions:
What is the burden of glomerular disorders driven by systemic or secondary causes?
How useful are the tools we have at our disposal for detecting and evaluating glomerular diseases?
The aim of the game is to preserve kidney function – but do we measure kidney function the right way?
This report takes a closer look at these questions and examines the evidence for common practices.
Dr. Tanuj Moses Lamech Nephrology Fellow Madras Medical College India
Genetics
Evidence for a genetic basis:
6x increased risk of SLE among first-degree relatives of an index case
11-12x increased risk of related autoimmunity (including thyroid disease) among first-degree relatives of an index case
The risk of SLE among monozygotic twins is 25-50% [risk among dizygotic twins is only 1-2%]
Monogenic forms of SLE have been identified (genes: DNASE1, TREX1)
The female predominance of SLE
Genome-wide association studies (GWAS) have identified several groups of genes associated with systemic lupus
Genes involving the classical complement pathway (C2, C4, C1q) – highest risk!
Genes involving interferon regulation and Toll-like receptor (TLR) repression
Genes involving B cell and dendritic cell function
Environmental Factors
Ultraviolet light
Infections: Epstein-Barr virus, parvovirus
Drugs: hydralazine, isoniazid, procainamide
Toxins
Pathophysiology of Lupus
Immunological anomalies in lupus:
High serum levels of Type 1 interferon, overexpression of genes relating to interferon 1
Increased anergic B cell response
Increased plasmablast response
Increased plasmacytoid dendritic cells (PDCs), which are professional antigen-presenting cells
Widespread antigen presentation overwhelms natural immunological tolerance
Impaired T-reg function
Increased low-density neutrophils, which produce neutrophil extracellular traps (NETs)
What is type 1 interferon, and what is the role of TLRs?1
Toll-like receptors (TLRs) are an evolutionarily ancient system inherited from invertebrates
They recognize ‘patterns’ from invading viral nucleic acids (often identified by their hypomethylation)
The recognition of viral nucleic acids sets off a cascade of cytokine signaling, eventually resulting in the production of type 1 interferon (T1 IFN), which is an important anti-viral cytokine
It aids the transformation of peripheral mononuclear cells into PDCs
These PDCs produce large amounts of type 1 interferon
T1 IFN, in turn, can transform other granulocytes into PDCs, thus creating a self-sustaining process
What is an anergic B cell?2
In the process of V(D)J recombination, an enormous number of B cells with different specificities are generated; some of these cells, however, are autoreactive
One of the ways in which the body’s natural tolerance mechanisms deal with such autoreactive B cells is to render them irresponsive (‘anergic’) to antigenic stimulation
Such anergic B cells remain in circulation but have a much shorter lifespan and are eventually culled
However, in the presence of very high levels of B-cell activating factor (BAFF), as occurs in lupus, such anergic B cells can survive and generate auto-antibodies
A Unified Theory for the Development of Systemic Lupus
DNA/RNA release occurs in response to normal cellular injury, viral infections, environmental factors such as UV light, or increased production of NETs
The mechanisms by which such DNA/RNA lead to autoimmunity include:
Abnormalities in the metabolic pathways that clear DNA/RNA, resulting in accumulation of nucleic acids and likely stimulation of TLR-mediated interferon production -Associated with Mendelian forms of lupus
Abnormalities in complement-mediated opsonization of apoptotic debris (including DNA/RNA), preventing clearance -Genetic variants increase the risk of lupus 5-10-fold
Recognition of human DNA by TLRs due to abnormalities in genes that normally repress their activity -Genetic variants increase the risk of lupus 1.3-1.4-fold
Increased production of type 1 interferon via TLR signaling due to irregularities in genes that regulate type 1 interferon -Genetic variants increase the risk of lupus 1.2-1.3-fold
Increased production of autoantibodies due to defects in T cell and B cell function -Genetic variants increase the risk of lupus 1.1-1.2-fold
Thus, there appears to be a step-wise hierarchy of risk influencing the eventual development of lupus
Pathophysiology of Lupus Nephritis
The critical step in lupus nephritis is the occurrence of antigen-antibody complexes in the kidney
Previously, it was thought that autoantibodies bind to circulating antigens, and these then deposit in the kidney
Recently, it has been demonstrated that antibodies may form at tertiary lymphoid tissues within the kidney itself3
Antibodies can deposit onto nuclear antigens that have become trapped in the kidney
These antigen-antibody complexes then set off an inflammatory cascade, which recruits neutrophils
These neutrophils produce inflammatory cytokines, apoptosis, and make NETs, resulting in further antigen exposure within the kidney
Serology
CRP is a complement protein and therefore does not correlate well with lupus activity
ESR reflects an inflammatory state and correlates better with lupus activity
ANAs
Initially thought to occur in 98% of cases at presentation
True prevalence closer to 85%, with detection sometimes requiring serial ANAs to be done over some time
Thus, though ANA-negative lupus is unusual, it should not exclude the diagnosis
Titres of 1:80 or less are seen in 5% of the general population
Therefore, only high titers, in the range of 1:240, should be considered to have clinical significance
dsDNA
Highly specific and associated with lupus nephritis
dsDNA has a high negative predictive value and a low positive predictive value
dsDNA may be detected by Crithidia luciliae indirect fluorescence assay or by ELISA
Crithidia assay is more specific
ELISA sometimes detects low-affinity dsDNA that is not pathogenic
C1q antibodies
Associated with proliferative LN and may be pathogenic
C3, C4
At a population level, the reliability of C3 and C4 for tracking disease activity is poor
The membrane attack complex (C5b-9) tracks best with lupus nephritis but is currently limited to the research environment
Anti-Smith antibody
When present, it is strongly predictive of lupus
However, it cannot be used to monitor disease activity
Urinary biomarkers in lupus (APRIL, BAFF) are currently of limited utility
References 1. Crow MK. Type I Interferon in the Pathogenesis of Lupus. J. Immunol. 192, 5459–5468 (2014). [https://www.jimmunol.org/content/192/12/5459] 2. Isnardi I, Ng YS, Menard L, Meyers G, Saadoun D, et al. Complement receptor 2/CD21− naive human B cells contain mostly autoreactive unresponsive clones. Blood 115, 5026–5036 (2010). [https://ashpublications.org/blood/article/115/24/5026/27217/Complement-receptor-2-CD21-human-naive-B-cells] 3. Robson KJ, Kitching AR. Tertiary lymphoid tissue in kidneys: understanding local immunity and inflammation. Kidney Int. 98, 280–283 (2020). [https://www.kidney-international.org/article/S0085-2538(20)30504-4/fulltext]