Causes of immune aggression
The development of the disease begins with the breakdown of natural immunological tolerance. Key factors in this process are polyclonal lymphocyte activation and congenital or acquired defects in cell apoptosis. Various microbial superantigens can serve as an additional trigger initiating the pathological process.
Cytokines play a crucial role in pathogenesis. In SLE, there is a pronounced overproduction of $T_H2$-type cytokines—primarily IL-4, IL-6, and IL-10. It is their excess that leads to uncontrolled hyperactivation of B lymphocytes, which begin to massively synthesize autoantibodies.
Spectrum of produced autoantibodies
In lupus, the immune system loses specificity and begins to produce antibodies against a wide variety of the body's own structures. Depending on the target, several groups of autoantibodies are distinguished:
- Antinuclear (ANA): directed against multivalent nucleoprotein complexes, such as nucleosomes and ribonucleoproteins.
- Anticytoplasmic: attack intracellular structures.
- Against surface structures: their targets are membrane components of cells that have undergone apoptosis (programmed cell death).
- Against blood cells: antibodies destroy erythrocytes, platelets, leukocytes, and lymphocytes, which clinically manifests as severe cytopenias.
- Antiphospholipid: a specific group of antibodies whose circulation inevitably causes dangerous thrombotic disorders.
Mechanisms of tissue destruction
Systemic inflammation is sustained by several pathways at once. First, immune complexes deposit in healthy tissues, causing complement system activation and leukocyte recruitment. Second, the vascular endothelium is damaged under the influence of cytokines (specifically, IL-1 and TNF-α). An additional contribution is made by an increase in the $T_H17$ lymphocyte pool: the IL-17 secreted by them significantly enhances inflammation and accelerates organ damage (kidneys, lungs, joints, CNS).
Chronification of the process is ensured by an amplification loop (vicious cycle of inflammation). This molecular cascade consists of five stages:
- Complex aggregates are formed, including antimicrobial peptides (cathelicidin), components of destroyed cells (DNA, HMGB1 protein), and DNA-specific IgG autoantibodies.
- Dendritic cells recognize and capture these aggregates via the FcγRIIa receptor.
- Inside the dendritic cell, Toll-like receptor 9 (TLR9) activation occurs.
- Receptor activation induces potent secretion of interferon-alpha (IFN-α).
- The release of IFN-α stimulates a new wave of autoantibody production, immune complex assembly, and complement activation, closing the loop.
Clinical and laboratory diagnostics
Diagnosis is based on identifying specific markers and assessing tissue damage. In addition to classic skin manifestations (dermatitis and a "butterfly" rash) and serositis (inflammation of serous membranes), the laboratory evaluates the following parameters:
- Immunofluorescence (IIF): a classic method for detecting antinuclear antibodies.
- Analysis for specific markers: screening for antibodies to double-stranded DNA.
- Skin biopsy examination: reveals characteristic deposits of IgG and IgM class immunoglobulins in affected tissues.
- Effusion analysis: immune complexes are localized and complement components (C3 and C4) are detected in the contents of serous cavities (pericardial, pleural, peritoneal).
- Cerebrospinal fluid (CSF) analysis: in neurological manifestations of SLE, specific LE cells—neutrophils that have phagocytosed nuclear material—are detected in it.
Briefly: answers to topical questions
What specific antibodies are included in the antiphospholipid group in SLE?
According to sources, the group of antiphospholipid markers/antibodies in SLE and APS includes:
- Anticardiolipin antibodies.
- Anti-beta-2-glycoprotein-1 antibodies (anti-β2-GPI).
- Lupus anticoagulant.
- Antiphospholipid antibodies.
Antiphospholipid antibodies in SLE cause the development of thrombotic disorders.
What immunological criteria are used in SLICC or EULAR/ACR classifications for diagnosing SLE?
In the SLICC 2012 and EULAR/ACR 2019 classification systems, clinical and immunological criteria are used to diagnose SLE.
Immunological markers indicated in the sources include:
- Antinuclear factor / antinuclear antibodies (ANF/ANA).
- Antibodies to double-stranded / native DNA (anti-DNA, anti-dsDNA).
- Antibodies to Smith antigen (anti-Sm).
- Antiphospholipid antibodies (aPL).
- Decreased levels of complement components C3 and C4 — hypocomplementemia.
According to EULAR/ACR 2019, a positive ANF is a mandatory entry criterion; then the sum of points for additional criteria must be at least 10. According to SLICC 2012, a diagnosis is reliable in the presence of 4 criteria, among which there must be at least 1 clinical and at least 1 immunological criterion.
Which antigens are included in the extractable nuclear antigen (ENA) panel in the serological diagnosis of SLE?
Nuclear ribonucleoproteins are included in the extractable nuclear antigen (ENA) panel in serological diagnostics. The main antigens of this group include:
- Ro antigen (SS-A) — targets are RNA and RNA polymerase.
- La antigen (SS-B) — the target is a protein within RNA.
Detection of antibodies to these antigens acts as a predictor of photosensitive dermatitis, as well as lung and central nervous system damage.
Which genetic factors and major histocompatibility complex (HLA) alleles predispose to the development of SLE?
According to sources, genetic and hereditary predisposition factors for SLE include:
- Association with HLA-DR2 and HLA-DR3 antigens.
- Carriage of Be and B15 antigens, associated with an increased risk of developing the disease.
- Hereditary deficiency of complement components C2 or C4.
- Genetically determined defect of immune regulation, leading to a breakdown of autotolerance.
Also, genetic predisposition, epigenetic disorders, ethnic factors, immunoregulation disorders, hormonal disorders, and environmental factors participate in the development of SLE.
LE cells are easy to remember as "Lupus Eaters" (from Lupus Erythematosus) — these are neutrophils that literally "ate" (engulfed) foreign nuclear material.
Class and exam questions
Which visual sign is considered most characteristic of SLE?
A pathognomonic sign is a specific reddish rash on the face, the shape of which resembles the silhouette of a butterfly's wings.
Which interleukins trigger the excessive activity of B-lymphocytes in lupus?
A key role is played by the overproduction of Th2-profile cytokines, which include IL-4, IL-6, and IL-10.
What is the development of thrombosis in patients with systemic lupus erythematosus associated with?
Thrombotic disorders develop as a consequence of the production of antiphospholipid autoantibodies.
What triggers the vicious cycle of chronic inflammation inside the dendritic cell?
The key link is the activation of the TLR9 receptor, which leads to massive secretion of interferon-alpha (IFN-α).
What else to study on this topic
- The influence of microbial superantigens on the process of breakdown of immunological tolerance.
- Features of the pathogenic action of antibodies to components of apoptotic cell membranes.
- The role of IL-17 in the progression of renal and pulmonary tissue damage.
- Molecular interaction of the FcγRIIa receptor and TLR9 in dendritic cells.
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