The role of citrullinated proteins and genetics
One of the main pathogenetic factors in the development of rheumatoid arthritis is the formation of autoantibodies against specific proteins. This process begins with post-translational modification: the terminal amino acid arginine is replaced by citrulline. This biochemical reaction proceeds with the direct participation of the enzyme peptidylarginine deiminase 4.
The resulting citrullinated proteins play a critical role in the immune response:
- They stimulate the development of both humoral and T-cell immunity.
- Administration of such proteins to laboratory animals leads to the development of experimental autoimmune arthritis.
- Antibodies against them are detected in the vast majority of patients (60–70%), while they are completely absent in healthy individuals or persons with other pathologies.
An important aspect is genetic predisposition. Peptides containing citrulline are capable of embedding into the antigen-binding groove of the HLA-DRB1 molecule. The expression of this particular gene is reliably associated with an increased risk of developing rheumatoid arthritis.
Cellular mechanisms of inflammation and joint damage
A complex cellular reaction unfolds in the focus of inflammation, where the main role is assigned to CD4+ T cells. These lymphocytes actively synthesize pro-inflammatory cytokines, which in turn stimulate other cells of the immune system, including macrophages and neutrophils.
Additional activation of synovial fibroblasts and macrophages occurs via specific receptors — TLR (Toll-like receptors). They respond to two types of stimuli:
- Exogenous ligands — for example, bacterial cell wall elements (peptidoglycan).
- Endogenous ligands — the body's own molecules, such as heat shock proteins or cell breakdown products.
The final stage of this aggressive immune response is the physical destruction of joint structures. Neutrophils and macrophages release huge amounts of lysosomal enzymes and reactive oxygen species (ROS) into the environment, which literally melt the joint tissues.
Related autoimmune pathologies: Addison's disease
Disfunctions in the immune system can also affect other organs. An example is Addison's disease, an autoimmune process that leads to progressive destruction of the adrenal cortex. The consequence of this is a catastrophic decrease in the production of vital hormones: mineralocorticoids, glucocorticoids, and sex hormones.
This pathology rarely occurs in isolation. It is frequently associated with other autoimmune conditions, such as type 1 diabetes mellitus, thyroiditis, and pernicious anemia. In addition, Addison's disease can be part of autoimmune polyendocrine syndrome, where it is combined with chronic mucocutaneous candidiasis and hypoparathyroidism.
Immunopathogenesis of psoriasis
Another example of autoimmune inflammation is psoriasis. The initiation of the immune response begins when dendritic cells capture potential autoantigens (keratinocyte proteins) and transport them to regional lymph nodes, where CD4+ T cell activation occurs.
The further process involves strict differentiation and targeted migration:
- Activated lymphocytes transform into Th1 helpers.
- They express cutaneous lymphocyte antigen (CLA) and specific chemokine receptors (CCR4, CCR10) on their surface, which ensures their targeted movement into the skin.
- In parallel, the maturation of cytotoxic CD8+ T lymphocytes takes place, which also rush into the skin.
A clear distribution is observed within the tissue itself: CD4+ T cells settle predominantly in the dermis, while CD8+ cells penetrate the epidermis. In the lesion, T lymphocytes interact with Langerhans cells and dendritic cells, triggering massive production of TNFα and IFNγ cytokines. It is these molecules that determine the characteristic immunopathological picture.
As a result of the attack by cytotoxic cells and neutrophils, keratinocyte desmosomes and the basement membrane are destroyed. In response, activated T cells and keratinocytes themselves release growth factors in an attempt to repair the damage. This creates a vicious circle that makes the pathological process irreversible.
Briefly: answers to topical questions
What are the main pro-inflammatory cytokines secreted by macrophages and T cells in the joint cavity in rheumatoid arthritis?
In rheumatoid arthritis, macrophages secrete interleukin-1β, and CD4+ T cells produce other pro-inflammatory cytokines.
- Interleukin-1β (IL-1β) is secreted by local macrophages, causes cartilage and bone destruction, as well as pannus formation.
- Pro-inflammatory cytokines are synthesized by CD4+ T cells and activate macrophages, neutrophils, and other cells.
Tumor necrosis factor alpha (TNF-alpha) is also involved in the pathogenesis, and targeted therapy is used to block it.
What autoantibodies are marker antibodies for the laboratory diagnosis of rheumatoid arthritis?
Marker autoantibodies for the laboratory diagnosis of rheumatoid arthritis are rheumatoid factor and anti-citrullinated protein antibodies.
- Rheumatoid factor (IgM RF) is a specific protein present in the blood serum of most patients.
- Anti-cyclic citrullinated peptide antibodies (ACPA / anti-CCP) are formed as a result of post-translational replacement of arginine with citrulline, and are detected in 60–70% of patients.
Combined detection of these two markers indicates a high probability of the disease.
Which hand joints are typical targets at the onset of rheumatoid arthritis?
Typical targets at the onset of rheumatoid arthritis are the metacarpophalangeal, proximal interphalangeal, and wrist joints.
- Metacarpophalangeal joints (MCPs) — early changes are often localized in the 2nd and 3rd joints.
- Proximal interphalangeal joints (PIPs) — a classic target, especially the 3rd joints (involvement may predominate at onset).
- Wrist joints and carpal joints are involved symmetrically.
The disease never starts with involvement of the distal interphalangeal joints of the hands.
What synthetic and biological disease-modifying antirheumatic drugs are used for the pathogenetic therapy of rheumatoid arthritis?
Standard and targeted synthetic, as well as genetically engineered biological disease-modifying antirheumatic drugs are used for the pathogenetic therapy of rheumatoid arthritis.
- Synthetic drugs — methotrexate (first-line drug), leflunomide, azathioprine, sulfasalazine, penicillamine, gold preparations (auranofin), and 4-aminoquinolines (chloroquine). Targeted synthetic agents include JAK inhibitors and phosphodiesterase 4 inhibitors.
- Biological drugs — TNF-alpha inhibitors (etanercept, infliximab), IL-1 receptor antagonists (anakinra), IL-6, IL-17, IL-12/23 inhibitors, T-cell co-stimulation blockers, and anti-B-cell drugs (rituximab, belimumab).
Biological and targeted drugs are recommended to be used in combination with methotrexate.
To remember the mediators of psoriasis: the abbreviation "TIF" — TNFα and IFNγ form the basis of the immunopathological picture in the lesion.
Class and exam questions
Which antibodies are most specific for rheumatoid arthritis?
Antibodies to citrullinated proteins play the most significant diagnostic and pathogenetic role. They are detected in 60–70% of patients and are completely absent in healthy individuals.
What causes direct joint destruction in arthritis?
The joint is destroyed under the influence of reactive oxygen species (ROS) and aggressive lysosomal enzymes, which are abundantly secreted by macrophages and neutrophils in the focus of inflammation.
What genetic feature predisposes to rheumatoid arthritis?
The incidence is associated with the expression of the HLA-DRB1 gene. Citrullinated peptides ideally fit into the antigen-binding groove of the molecule encoded by this gene.
What is the vicious circle in psoriasis?
Damage to epidermal structures by immune cells causes the release of growth factors by keratinocytes and T cells for repair. This excessive stimulation sustains inflammation and makes the process irreversible.
What else to study on this topic
- Mechanism of action of the enzyme peptidylarginine deiminase 4 in protein modification
- The role of Toll-like receptors (TLRs) and their ligands in the activation of synovial fibroblasts
- Association of Addison's disease with autoimmune polyglandular syndrome
- Functions of CCR4, CCR10 receptors and cutaneous lymphocyte-associated antigen (CLA) in T-cell migration
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