Autoimmunity and Autoimmune Diseases¶
Chapter 367 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 367
Key Clinical Points¶
- Autoimmunity is the development of adaptive immune responses (autoantibodies or T lymphocyte responses) against autoantigens (autoAgs).
- Approximately 150 autoimmune diseases (ADs) exist; US prevalence (2009) was 7.6–9.4% (~25–31 million people).
- ADs are chronic, incurable conditions that impact quality of life and can lead to accelerated mortality.
- HLA-DR haplotype is the best predictor of AD risk and linked to autoantibody development in family members.
- Environmental 'hits' (smoking, infections, diet, UV light) trigger AD in genetically predisposed individuals.
- Smoking promotes citrullination and carbamylation of proteins, promoting RA and other ADs in specific genetic carriers.
- Vitamin D deficiency is associated with increased risk for T1DM, Crohn's disease, SLE, and MS.
- Autoantibodies are central to the diagnosis, severity assessment, and pathogenesis of various ADs (e.g., anti-TSHR in Graves', anti-insulin in T1DM).
- Systemic Mastocytosis (SM) requires one major criterion plus one minor, or three minor criteria for diagnosis.
- Avapritinib is a first-line therapy for advanced systemic mastocytosis or refractory symptoms in indolent systemic mastocytosis.
1. DEFINITION & OVERVIEW¶
• Autoimmunity: ◦ Defined as the development of adaptive immune responses (autoantibodies [autoAbs] or T lymphocyte responses) that react with autoantigens (autoAgs). ◦ Present in all individuals; not always pathogenic; more prevalent with age. • Autoimmune Disease (AD): ◦ Aberrant response of innate and adaptive immune systems → loss of tolerance to self → clinically relevant pathogenic responses. ◦ Immune system attacks tissues/organs by mistaking them for external organisms, causing damage. • Scope & Prevalence: ◦ Approximately 150 ADs (organ-specific and systemic) have been described. ◦ US prevalence (2009): 7.6–9.4% of the general population (~25–31 million people). ◦ Characterized as chronic, incurable conditions with significant impact on quality of life and potential for accelerated mortality.
1.1 Classification of Autoimmune Diseases¶
• Organ-Specific ADs: Target specific organs. ◦ Examples: Hashimoto's thyroiditis, Graves' disease, Type 1 diabetes mellitus (T1DM), Addison's disease, Pernicious anemia, Celiac disease, Autoimmune hepatitis, Primary biliary cholangitis, Primary sclerosing cholangitis, Vitiligo, Pemphigus and other autoimmune bullous diseases, Myasthenia gravis, Autoimmune polyglandular syndromes, Autoimmune oophoritis, Autoimmune orchitis, Primary CNS angiitis, Isolated aortitis, Cutaneous arteritis, Cutaneous leukocytoclastic angiitis, Guillain-Barré syndrome, Immune thrombocytopenic purpura, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Dermatitis herpetiformis, Autoimmune autonomic ganglionopathy, Autoimmune encephalitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune myelofibrosis, Autoimmune retinopathy, Autoimmune sudden sensorineural hearing loss, Chronic inflammatory demyelinating polyneuropathy, Cutaneous lupus. • Systemic ADs: Affect multiple organs or systems. ◦ Examples: Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), Primary antiphospholipid syndrome, Ankylosing spondylitis, Idiopathic inflammatory myopathies, Sjögren syndrome, Progressive systemic sclerosis, Mixed connective tissue disease, Giant cell arteritis, Takayasu arteritis, Polyarteritis nodosa, ANCA-associated vasculitis, Anti-glomerular basement membrane disease, Cryoglobulinemic vasculitis, IgA vasculitis (Henoch-Schönlein), Hypocomplementemic urticarial vasculitis, Kawasaki disease, Behcet's disease, Cogan's syndrome, Psoriasis/psoriatic arthritis, Inflammatory bowel disease, Rheumatic fever, Sarcoidosis, Undifferentiated connective tissue disease.
2. EPIDEMIOLOGY¶
• Trends: Ongoing trend for increased incidence and prevalence of many ADs. • Demographics: ◦ Can occur at any age. ◦ Predominantly affect females; top 10 leading causes of death in women. • Complications & Risks: ◦ High risk of developing additional autoimmune conditions. ◦ Increased risk for specific cancers and premature cardiovascular disease.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Multistep Process: Genetic + Environmental factors → immune dysregulation → loss of tolerance (often years before clinical symptoms). • Genetic Factors: ◦ Poly_genic in most cases; monogenic forms exist. ◦ HLA-DR haplotype: Best predictor of AD risk and linked to autoAb development in family members. ◦ Specific Genetic Risk Markers: ◦ STAT4: Associated with SLE, RA, and primary Sjögren syndrome. ◦ PTPN22: Associated with T1DM, SLE, RA, vitiligo, and other ADs. ◦ Other risk factors include deficiencies in complement genes, mutations in the type I IFN pathway, and defects in B- and T-cell function. • Epigenetic Factors: ◦ DNA methylation, histone modifications, and altered 'trained immunity' in innate immune cells. ◦ Environmental factors may alter genes through epigenetic modifications, affecting offspring. • Mechanism of Tolerance Break: ◦ Impaired clearance of dead cell debris → exposure of autoAgs (DNA/RNA) to the environment. ◦ Sensing by TLRs (7–9) or other sensors → activation of innate/adaptive immune responses. ◦ Formation of Immune Complexes (ICs) → deposit in organs → tissue damage. • Cell Death Pathways: ◦ Dysregulation of pyroptosis, necroptosis, and NETosis linked to chronic inflammation. ◦ NETosis: Oxidation of nucleic acids by ROS/enzymes → increased half-life of modified RNA/DNA → failure of degradation.
3.1 Genetic and Epigenetic Factors¶
• Autoantigen Exposure: ◦ Misfolded or posttranslationally modified antigens (e.g., citrullinated) presented by MHC class II. ◦ Failure of nuclease activity or phagocyte engulfment → prolonged exposure of autoAgs. • Table 367-2 Highlights: ◦ HLA-DRB1: MS, RA, T1DM, JIA, IIM, IBD, Graves', Hashimoto's, Addison's. ◦ IL10: SLE, RA, MS, psoriasis. ◦ IL6: RA, SLE, vasculitis, JIA. ◦ IFNG: SLE, RA, MS. ◦ TLR7: SLE. ◦ MIF: RA, MS, SLE. ◦ C4A: SLE. ◦ STAT4: RA, SLE, primary Sjögren syndrome. ◦ PTPN22: SLE, RA, JIA, T1DM, vitiligo, etc.
3.2 Environmental Factors¶
• General Triggers: UV light, infections, mucosal dysbiosis, silica, solvents, pesticides, mercury. ◦ Mechanism: ROS production → DNA damage → lipid peroxidation → protein modification → neoAg formation. • Smoking: ◦ Risk factor for RA, Graves' disease, SLE, and MS. ◦ Mechanism: Promotes citrullination and carbamylation of proteins in the lung. • Dietary Factors: ◦ High sugar/red meat → risk for T1DM, IBD, and RA. ◦ Vitamin D Deficiency → increased risk for T1DM, Crohn's disease, SLE, and MS. ◦ Other T1DM factors: No breastfeeding in infancy, higher gluten intake in early childhood, lower omega-3 fatty acid intake.
4. CLINICAL FEATURES¶
• General Features: ◦ Chronic, incurable conditions. ◦ Significant impact on quality of life; often associated with accelerated mortality.
4.1 Systemic Mastocytosis Clinical Features¶
• Clinical Presentation: ◦ Symptoms of mast cell activation (e.g., anaphylaxis with hypotensive syncope). ◦ Potential for systemic involvement and multi-organ impact. • Complications: ◦ Osteoporosis → risk of pathologic fractures. ◦ Potential for underlying clonal hematologic processes (e.g., KIT D816V mutation).
5. DIFFERENTIAL DIAGNOSIS¶
• Systemic Mastocytosis Differentiation: ◦ Must be distinguished from Hereditary α-tryptasemia (autosomal dominant, extra-allelic copies of the α-tryptase gene). ◦ Distinguish from IgE-induced anaphylaxis (typically involves urticaria, angioedema, and bronchospasm).
6. INVESTIGATIONS & DIAGNOSIS¶
- Initial Screening: → Clinical history and physical examination → identify symptoms of mast cell activation.
- Preliminary Lab Work: → Basal serum tryptase level (preliminary step before bone marrow biopsy).
- Tissue Diagnosis (Required for Confirmation): → Lesional biopsy to evaluate for Systemic Mastocytosis (SM) criteria (Table 366-3).
- Criteria Evaluation: → Confirm one major criterion AND one minor OR three minor criteria.
- Ancillary Investigations: → Bone densitometry/scan → assess for osteoporosis. → CT scan or endoscopy → evaluate internal involvement. → Neuropsychiatric evaluation → assess for neurological impact.
6.1 Diagnostic Criteria for Systemic Mastocytosis¶
• Major Criterion: → Multifocal dense infiltrates of mast cells (>15 mast cells per aggregate) in bone marrow or other extracutaneous tissues. • Minor Criteria (Any 3 required if no major): → Abnormal morphology (spindle shape/atypical immature) in >25% of mast cells. → Aberrant phenotype (expression of CD25, CD2, or CD30). → KIT D816V mutation or other activating mutations in blood, marrow, or organs. → Total serum tryptase >20 ng/mL.
6.2 Autoantibody-Mediated Disease Mechanisms¶
• Rheumatoid arthritis: → ANCA, anti-carbamylated Abs, rheumatoid factor → Osteoclast activation; activation of macrophages, synovial fibroblasts, neutrophils, mast cells, DCs, platelets; immune complex formation with modified autoAgs. → Also involves Anti-RNP, anti-dsDNA. • Goodpasture's disease: → Anti-type IV collagen Abs → target basal membrane and promote kidney and lung injury. • Pernicious anemia: → Anti-parietal cell antibodies → damage to parietal cells → lack of intrinsic factor. → Other markers: Anti-aminoacyl-transfer RNA synthetase, anti-Mi2, anti-MDA5, anti-TIF1 gamma, anti-HMGCR. • Sjögren syndrome: → Anti-Ro, anti-La, rheumatoid factor. → Note: Anti-Ro can cause neonatal lupus or congenital heart block (if IgG crosses placenta). → Also involves Anti-myeloperoxidase; anti-proteinase 3. • Graves' disease: → Anti-TSHR → target TSHR on thyroid cells → enhanced hormone synthesis. → Also includes anti-thyroid peroxidase and anti-thyroglobulin. • Myasthenia gravis: → Anti-acetylcholine receptor → antagonizes acetylcholine receptor on cells.
7. MANAGEMENT & TREATMENT¶
- Initial Management: → Clinical stabilization and symptom management based on organ involvement.
- Diagnostic Confirmation: → Perform tissue biopsy to confirm Systemic Mastocytosis (SM) via Table 366-3 criteria.
- Targeted Therapy for SM: → Avapritinib: First-line therapy for advanced systemic mastocytosis or refractory symptoms in indolent systemic mastocytosis.
- Monitoring: → Monitor for complications like osteoporosis and potential fractures.
8. PROGNOSIS & COMPLICATIONS¶
• General ADs: ◦ Chronic, incurable conditions. ◦ Significant impact on quality of life. ◦ Potential for accelerated mortality. • Mastocytosis Specifics: ◦ Osteoporosis → pathologic fractures. ◦ Risk of progression to clonal hematologic processes (e.g., KIT D816V mutation).
9. SPECIAL CONSIDERATIONS¶
• Pregnancy and Autoimmunity: → Anti-Ro antibodies can cross the placenta → cause neonatal lupus or congenital heart block in offspring of Sjögren/SLE patients. • Pediatric Considerations: → Some conditions (e.g., Mastocytosis) may have a history of childhood-onset cutaneous disease.
10. KEY PEARLS & CLINICAL TRAPS¶
• Autoimmunity vs. Autoimmune Disease: Not all autoimmunity is pathogenic; only 'autoimmune diseases' involve a loss of tolerance leading to clinical damage. • Genetic Markers: HLA-DRB1 is the most significant genetic predictor for various ADs. • Environmental Triggers: Smoking → Citrullination → RA; Vitamin D deficiency → T1DM, Crohn's, SLE, MS. • Systemic Mastocytosis (SM): → Diagnosis requires tissue biopsy. → Major: >15 mast cells/aggregate. → Minor: Spindle shape, CD25/CD2/CD30 expression, KIT D816V mutation, Tryptase >20 ng/mL. • Avapritinib: First-line for advanced or refractory SM.
Reference Tables¶
TABLE 366-3 Diagnostic Criteria for Systemic Mastocytosis a Major:¶
Harrison's 22e, p.2821
| Major: Multifocal dense infiltrates of mast cells (>15 mast cells per aggregate) in bone marrow or other extracutaneous tissues |
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|---|---|
| Minor: Abnormal mast cell morphology (spindle shape or atypical immature morphology) in >25% of mast cells Aberrant mast cell phenotype with expression of CD25, CD2, or CD30 Detection of KIT D816V mutation or other activating KIT mutation in peripheral blood, bone marrow, or an extracutaneous organ Total serum tryptase >20 ng/mL |
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| 367 | Autoimmunity and Autoimmune Diseases Mariana J. Kaplan |
TABLE 367-1 Examples of Some Organ-Specific and Systemic Autoimmune Diseases (ADs) ORGAN-SPECIFIC AD Hashimoto’s…¶
Harrison's 22e, p.2822
| ORGAN-SPECIFIC AD | SYSTEMIC AD |
|---|---|
| Hashimoto’s thyroiditis Graves’ disease Type 1 diabetes mellitus Addison’s disease Pernicious anemia Celiac disease Autoimmune hepatitis Primary biliary cholangitis Primary sclerosing cholangitis Vitiligo Pemphigus and other autoimmune bullous diseases Multiple sclerosis Myasthenia gravis Autoimmune polyglandular syndromes Autoimmune oophoritis Autoimmune orchitis Primary CNS angiitis Isolated aortitis Cutaneous arteritis Cutaneous leukocytoclastic angiitis Guillain-Barré syndrome Immune thrombocytopenic purpura Autoimmune hemolytic anemia Autoimmune pancreatitis Dermatitis herpetiformis Autoimmune autonomic ganglionopathy Autoimmune encephalitis Autoimmune inner ear disease Autoimmune myocarditis Autoimmune myelofibrosis Autoimmune retinopathy Autoimmune sudden sensorineural hearing loss Chronic inflammatory demyelinating polyneuropathy Cutaneous lupus |
Systemic lupus erythematosus Rheumatoid arthritis Primary antiphospholipid syndrome Ankylosing spondylitis Idiopathic inflammatory myopathies Sjögren syndrome Progressive systemic sclerosis Mixed connective tissue disease Giant cell arteritis Takayasu arteritis Polyarteritis nodosa ANCA-associated vasculitis Anti glomerular basement membrane disease Cryoglobulinemic vasculitis IgA vasculitis (Henoch-Schönlein) Hypocomplementemic urticarial vasculitis Kawasaki disease Behcet’s disease Cogan’s syndrome Psoriasis/psoriatic arthritis Inflammatory bowel disease Rheumatic fever Sarcoidosis Undifferentiated connective tissue disease |
TABLE 367-2 Genetic Polymorphisms Associated with Autoimmune Disease Risk¶
Harrison's 22e, p.2823
| GENE | DISEASE ASSOCIATIONS WITH SOME ADs |
|---|---|
| HLA-DRB1 | MS, RA, T1DM, JIA, IIM, IBD, Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease |
| IL10 | SLE, RA, MS, psoriasis |
| IL6 | RA, SLE, vasculitis, JIA |
| IFNG | SLE, RA, MS |
| TLR7 | SLE |
| MIF | RA, MS, SLE |
| C4A | SLE |
| STAT4 | RA, SLE, primary Sjögren syndrome |
TABLE 367-3 Examples of Autoantibody-Mediated Disease Mechanisms DISEASE Rheumatoid arthritis¶
Harrison's 22e, p.2825
| DISEASE | AUTOANTIBODIES | PATHOGENIC MECHANISM |
|---|---|---|
| Rheumatoid arthritis | ANCA, anti-carbamylated Abs, rheumatoid factor |
Osteoclast activation promoting bone resorption; activation of macrophages, synovial fibroblasts, neutrophils, mast cells, DCs, platelets; immune complex formation with modified autoAgs with activating properties |
| Anti-RNP, anti-dsDNA, etc. | ||
| Goodpasture’s disease | Anti-type IV collagen Abs | Abs target basal membrane and promote kidney and lung injury |
| Anti-insulin, glutamic acid decarboxylase, protein tyrosine phosphatase |
||
| Pernicious anemia | Anti–parietal cell antibodies | Damage to parietal cells by Abs leads to lack of intrinsic factor |
| Anti-aminoacyl-transfer RNA synthetase Abs, anti-Mi2, anti-MDA5, anti-TIF1 gamma, anti-HMGCR, etc. |
||
| Sjögren syndrome | Anti-Ro, anti-La, rheumatoid factor | Anti-Ro Abs can induce neonatal lupus in offspring of SLE and Sjögren patients. IgG anti-Ro can cross the placenta and damage the fetal heart, inducing congenital heart block |
| Anti-myeloperoxidase; anti-proteinase 3 | ||
| Graves’ disease | Anti-TSHR | Anti-TSHR Abs target TSHR on thyroid cells, leading to enhanced thyroid hormones’ synthesis |
| Anti-thyroid peroxidase and anti- thyroglobulin |
||
| Myasthenia gravis | Anti-acetylcholine receptor | Antagonizes acetylcholine receptor on cells |