How the autoimmune process is triggered
The pathogenesis of systemic lupus erythematosus originates from altered programmed cell death pathways. Enhanced apoptosis causes surrounding cells to actively phagocytose the dead structures. Consequently, a massive accumulation of nucleosomes builds up in their phagolysosomes.
Plasmacytoid dendritic cells recognize DNA accumulated in phagolysosomes via specialized innate immune receptors—TLR-9. This interaction acts as a potent trigger, activating signaling pathways that ultimately lead to massive expression of interferon-alpha (IFNα).
Immunological imbalance and B-lymphocytes
The central link in the development of SLE is B-cell hyperactivation. This process is stimulated by several mechanisms simultaneously:
- Significant production of IFNα enhances the differentiation of Th2 cells, which directly boost B-lymphocyte activity.
- Macrophages and dendritic cells begin to overproduce the BAFF factor, further increasing B-cell activity.
- The resulting immune complexes interact with FcγRIIA (CD32) Fc receptors on the surface of B-lymphocytes themselves, closing the vicious circle of their activation.
Clinical confirmation: the leading role of this mechanism has been proven by the efficacy of targeted therapy. The use of agents aimed at B-cell elimination (e.g., rituximab, anti-CD20 monoclonal antibodies) significantly reduces disease activity.
Role of other cell populations
The pathological process in systemic lupus erythematosus affects not only B-lymphocytes. Other cells are also actively involved in the inflammation:
- T lymphocytes. They transition into an activated state due to the enhanced expression of the costimulatory molecule CD40, which is abundantly expressed on dendritic cells, microenvironmental cells, and B lymphocytes themselves.
- Myeloid cells. Activated via similar mechanisms, they begin to secrete pro-inflammatory cytokines in huge amounts—tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β), which sustain continuous tissue inflammation.
Clinical manifestations and hypersensitivity
Tissue damage in SLE is a classic example of an inappropriately strong immune response. In clinical practice, the P. Gell and R. Coombs (1969) classification of hypersensitivity remains in demand for describing such disorders, despite being somewhat limited and not fully aligning with modern concepts of immunopathology.
Main clinical manifestations and their mechanisms of development:
- Systemic autoimmune vasculitis. Serves as the pathogenetic basis for the development of lung inflammation (pneumonitis), joint, skin, and mucosal lesions.
- Lupus nephritis. One of the most severe complications. It develops through two mechanisms: as type III hypersensitivity (vasculitis due to immune complex deposition in renal glomerular vessels) and as type II hypersensitivity (direct damaging effect of autoantibodies on renal antigens).
- Antiphospholipid syndrome. Occurs due to the synthesis of autoantibodies against various lipid factors, including phospholipids and cardiolipin.
Regardless of the specific symptom, all components of SLE pathogenesis fit into a single chain: B-cell activation $\rightarrow$ autoantibody production $\rightarrow$ immune complex formation $\rightarrow$ tissue damage.
Briefly: answers to topical questions
Against which antigens are autoantibodies produced in systemic lupus erythematosus?
In systemic lupus erythematosus, autoantibodies are produced against a wide spectrum of nuclear, lipid, and tissue antigens. The main targets include:
- Double-stranded DNA (anti-dsDNA)—a highly specific marker of the disease.
- Nuclear autoantigens—Smith antigen (anti-Sm), Ro, La, ribonucleoproteins (RNPs), and other components of the cell nucleus (detected as antinuclear factor).
- Phospholipids and associated proteins—cardiolipin, β2-glycoprotein I (forming antiphospholipid syndrome).
- Renal antigens—affected in lupus nephritis via a type II hypersensitivity mechanism.
Which organs and tissues are affected as a result of systemic autoimmune vasculitis in SLE?
As a result of systemic autoimmune vasculitis in systemic lupus erythematosus, the following are affected:
- Lungs—pneumonitis.
- Joints.
- Skin.
- Mucous membranes.
Which targeted drugs, besides anti-CD20 monoclonal antibodies, are used for the pathogenetic treatment of systemic lupus erythematosus?
In addition to anti-CD20 monoclonal antibodies, the following targeted and biologic drugs are indicated in sources for the treatment of systemic lupus erythematosus:
- Belimumab—IgG class monoclonal antibodies that specifically bind and suppress the activity of soluble B-lymphocyte stimulator BLyS/BAFF.
- Anifrolumab—monoclonal antibodies to the type I interferon receptor.
- In refractory SLE with joint and/or skin manifestations, the following may be considered in individual cases: tocilizumab, abatacept, baricitinib, tofacitinib, upadacitinib.
Which immunological criteria (according to SLICC or EULAR/ACR classifications) are used to confirm the diagnosis of systemic lupus erythematosus?
To confirm the diagnosis of systemic lupus erythematosus according to the SLICC and EULAR/ACR classifications, the following immunological criteria are used:
- Antinuclear factor (ANF)—an obligatory primary criterion (positive at a titer $\ge$ 1:80 per EULAR/ACR or >1/160).
- Highly specific antibodies—antibodies to double-stranded DNA (anti-dsDNA / anti-DNA) and antibodies to Smith antigen (anti-Sm).
- Antiphospholipid antibodies (APA)—anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, or lupus anticoagulant.
- Complement system proteins—hypocomplementemia (decreased levels of C3 and/or C4 fractions).
The basic pathogenesis chain can be memorized using the acronym BACP: B cells → Antibodies → Complexes (immune) → Damage.
Class and exam questions
Which receptor is responsible for DNA recognition in lupus?
The innate immune receptor TLR-9 plays a key role. It is located predominantly in plasmacytoid dendritic cells and recognizes DNA (nucleosomes) inside phagolysosomes, triggering IFNα production.
Why does kidney function become impaired in lupus?
Kidney damage (lupus nephritis) is associated with the deposition of immune complexes in glomerular vessels, as well as the direct destructive action of autoantibodies reacting with renal antigens.
What is the mechanism of action of rituximab in SLE?
Rituximab is a monoclonal antibody against the CD20 molecule. It binds to B-lymphocytes and leads to their elimination, thereby interrupting the chain of massive autoantibody production.
What else to study on this topic
- Functions of innate immune receptors TLR-9
- Structure and role of the costimulatory molecule CD40
- Mechanisms of antiphospholipid syndrome formation
- BAFF factor: impact on the B-cell lifecycle
- Gell and Coombs classification of hypersensitivity reactions
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