Pathophysiology
I-31. General mechanisms of systemic autoimmune diseases
全身性自己免疫疾患の一般的発症機序
Autoimmunity Overview
- Autoimmunity = immune reaction against self-antigens.
- Organ-specific (one organ/cell type — Addison’s, T1DM) vs systemic (many organs, multiple autoantibodies/cell-mediated reactions, mainly connective tissue + blood vessels).
Immunological Tolerance
Central tolerance
- Deletion of self-reactive T/B lymphocytes during maturation (thymus, bone marrow).
- Autoreactive T-cells: apoptosis or differentiate into regulatory T-cells.
- Autoreactive B-cells: apoptosis or receptor editing.
Peripheral tolerance
- For lymphocytes slipping into the periphery: anergy (functional inactivation), suppression by regulatory T-cells, activation-induced cell death (Fas/Fas ligand).
Pathogenesis of Autoimmunity
- Main cause: loss of self-tolerance (predisposing genes ± tissue disorders, often triggered by infection/tissue injury altering antigen recognition).
- Two pillars:
- Genes that decrease immunological tolerance.
- Environmental factors (inflammation): influx + activation of self-reactive lymphocytes, tissue injury, DNA damage (nuclear antigens → DNA autoantibodies).
Genetic & Environmental Factors
- Genetic: HLA class II alleles (HLA-DR, HLA-DQ) — e.g. ankylosing spondylitis (B27), rheumatoid arthritis (DR4), primary Sjögren (DR3).
- Environmental (bacteria, mycoplasma, viruses):
- Molecular mimicry: microbial epitopes cross-react with self-antigens → immune attack on self.
- Tissue necrosis from infection: breaks T-cell anergy → T-cell activation.
- Epitope spreading: tissue injury reveals hidden epitopes → autoreactive T-cells invade.
- microRNA (20–22 nt, post-transcriptional regulation of apoptosis/differentiation/immunity): autoantibodies against miRNA machinery (anti-GWB — Sjögren’s, SLE, RA) or miRNA overactivity.
Biological Therapies
- Monoclonal antibodies against soluble cytokines (have side effects).
- Anti-TNF-α: inhibits pathological B-cell activity, with a risk of opportunistic infections.
- Anti-BAFF (B-cell activating factor): blocks B-cell proliferation signaling (also normal B-cells). Belimumab (first new lupus drug in 50 years) — ↑therapy efficacy/remission. Side effects: severe (sometimes fatal) infections, anaphylaxis.
一問一答
▶What is autoimmunity, and what distinguishes organ-specific from systemic forms?
An immune reaction against self-antigens. Organ-specific affects one organ/cell type (Addison's, T1DM); systemic affects many organs (multiple autoantibodies/cell-mediated reactions, mainly connective tissue and blood vessels).
▶What is central immunological tolerance?
Deletion of self-reactive lymphocytes during maturation (thymus, bone marrow): autoreactive T cells undergo apoptosis or become regulatory T cells; autoreactive B cells undergo apoptosis or receptor editing.
▶What are the mechanisms of peripheral tolerance?
For lymphocytes reaching the periphery: anergy (functional inactivation), suppression by regulatory T cells, and activation-induced cell death (Fas/Fas ligand).
▶What are the two main pillars of autoimmune pathogenesis?
(1) Genes that decrease immunological tolerance, and (2) environmental factors/inflammation (influx and activation of self-reactive lymphocytes, tissue injury, DNA damage).
▶Which genetic factors predispose to systemic autoimmune disease?
HLA class II alleles (HLA-DR, HLA-DQ): e.g., ankylosing spondylitis (B27), rheumatoid arthritis (DR4), and primary Sjögren (DR3).
▶What is molecular mimicry in autoimmunity?
Microbial epitopes cross-react with self-antigens, so the immune response against the microbe also attacks self.
▶What is epitope spreading?
Tissue injury reveals previously hidden (sequestered) epitopes, allowing autoreactive T cells to recognize and attack them.
▶How can infection-related tissue necrosis trigger autoimmunity?
It breaks T-cell anergy, leading to activation of self-reactive T cells.
▶What is the primary cause of autoimmunity?
Loss of self-tolerance from predisposing genes (± tissue disorders), often triggered by infection or tissue injury that alters antigen recognition.
▶How do nuclear antigens contribute to systemic autoimmunity?
DNA damage from tissue injury exposes nuclear antigens, generating anti-DNA autoantibodies (e.g., in SLE).
▶What is the role of microRNA in autoimmunity?
miRNAs (20–22 nt) regulate apoptosis/differentiation/immunity post-transcriptionally; autoantibodies against the miRNA machinery (anti-GWB in Sjögren's, SLE, RA) or miRNA overactivity contribute to disease.
▶What are the fates of autoreactive T cells in central tolerance?
Apoptosis (deletion) or differentiation into regulatory T cells.
▶How do autoreactive B cells handle self-reactivity centrally?
Through apoptosis or receptor editing (changing their antigen receptor).
▶What is the mechanism of anti-TNF-α biological therapy and its main risk?
It inhibits pathological B-cell activity (and inflammation), but carries a risk of opportunistic infections.
▶What is the mechanism of anti-BAFF therapy (belimumab)?
It blocks B-cell activating factor signaling for B-cell proliferation; belimumab was the first new lupus drug in 50 years, improving remission but risking severe infections and anaphylaxis.
▶What characterizes systemic autoimmune diseases pathologically?
Involvement of many organs with multiple autoantibodies and cell-mediated reactions, predominantly targeting connective tissue and blood vessels.
▶What is anergy in immune tolerance?
Functional inactivation of a lymphocyte that encounters antigen without proper co-stimulation, rendering it unresponsive.
▶What role does activation-induced cell death play in tolerance?
It uses Fas/Fas ligand signaling to eliminate self-reactive peripheral lymphocytes by apoptosis.
▶What is a general drawback of monoclonal antibody (cytokine-targeting) biologics?
By neutralizing soluble cytokines they suppress normal immune functions too, causing side effects such as increased infection risk.
▶Why are infections common triggers of systemic autoimmune disease?
Via molecular mimicry, infection-induced tissue necrosis breaking anergy, and epitope spreading exposing hidden self-antigens.