Autoimmunity and Autoimmune Diseases¶
Chapter 367 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KEY CLINICAL POINTS¶
- Autoimmunity involves immune system attacks on self-antigens, leading to chronic, incurable diseases with accelerated mortality.
- Systemic mastocytosis (SM) is diagnosed using criteria including mast cell infiltrates (>15 cells/aggregate), KIT D816V mutations, and serum tryptase >20 ng/mL.
- Genetic factors (e.g., HLA-DRB1, STAT4, PTPN22) and environmental triggers (infections, toxins, diet) contribute to autoimmunity pathogenesis.
- Autoantibodies (e.g., anti-dsDNA, ANCA) and T-cell responses drive tissue damage in diseases like SLE, RA, and vasculitis.
- Targeted therapies (e.g., tyrosine kinase inhibitors, JAK inhibitors) and immunomodulation are critical for managing severe autoimmune conditions.
1. DEFINITION & OVERVIEW¶
Autoimmunity is the development of adaptive immune responses (autoantibodies or T-cell responses) that react with self-antigens. The immune system normally distinguishes self from nonself, but dysregulation leads to tissue damage. Autoimmune diseases (ADs) are chronic, incurable conditions with accelerated mortality, affecting ~7.6–9.4% of the population.
1.1 Immune System Function¶
The immune system provides innate and adaptive defenses. Innate immunity recognizes pathogens via pattern recognition receptors, while adaptive immunity involves T and B cells. Autoimmunity arises when tolerance to self-antigens is lost, leading to pathogenic immune responses.
1.2 Autoimmune Disease Spectrum¶
ADs include organ-specific (e.g., Hashimoto’s thyroiditis) and systemic (e.g., SLE, RA) diseases. They are associated with increased cancer risk, comorbidities, and family clustering due to shared genetic and environmental factors.
2. EPIDEMIOLOGY¶
ADs are the 10th leading cause of death in women. Prevalence in the U.S. (2009) was 7.6–9.4% (~25–31 million people). Risk factors include age, sex (predominantly female), genetic predisposition (HLA haplotypes), and environmental exposures (infections, toxins, diet).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Autoimmunity results from genetic (HLA, STAT4, PTPN22), epigenetic, and environmental factors. Mechanisms include molecular mimicry (e.g., EBV linked to MS), epitope spreading, bystander effects, and dysregulated innate/adaptive immunity (e.g., trained immunity, NETosis).
Table 367-2: Genetic Polymorphisms Associated with Autoimmune Disease Risk¶
| GENE | DISEASE ASSOCIATIONS |
|---|---|
| HLA-DRB1 | MS, RA, T1DM, JIA, IIM, IBD, Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease |
| TNF | SLE, RA, ankylosing spondylitis |
| IL10 | SLE, RA, MS, psoriasis |
| IL2/IL2R | MS, RA, celiac disease, T1DM, psoriasis |
| IL6 | RA, SLE, vasculitis, JIA |
| IL17A | SLE, RA, MS, spondyloarthropathies |
| IFNG | SLE, RA, MS |
| FOXP3 | T1DM, autoimmune thyroid disease, MS |
| TLR7 | SLE |
| IL23A | Graves’ disease, psoriasis, IBD, MS |
| MIF | RA, MS, SLE |
| HLA-B | Ankylosing spondylitis |
| C4A | SLE |
| IL33 | RA, ankylosing spondylitis, psoriatic arthritis |
| STAT4 | RA, SLE, primary Sjögren syndrome |
| PTPN22 | SLE, RA, JIA, T1DM, vasculitides, autoimmune thyroid diseases, vitiligo |
3.1 Genetic Factors¶
HLA-DRB1, STAT4, PTPN22, and other polymorphisms increase AD risk. HLA haplotypes predict disease susceptibility and autoantibody production.
3.2 Environmental Triggers¶
Infections (EBV, coxsackievirus, influenza), toxins (silica, solvents), diet (vitamin D deficiency, gluten, sugar), and lifestyle factors (smoking, alcohol) contribute to autoimmunity.
3.3 Immune Dysregulation¶
Dysfunctional innate immunity (e.g., TLR7/8 activation, NETosis) and adaptive immunity (e.g., T-cell autoreactivity, B-cell dysregulation) drive pathogenesis. Trained immunity and epigenetic modifications exacerbate inflammation.
4. CLINICAL FEATURES¶
Symptoms vary by disease but include fatigue, joint pain, skin rashes, and organ-specific manifestations (e.g., nephritis in SLE, hypothyroidism in Hashimoto’s). Complications include osteoporosis, anaphylaxis, and comorbidities (e.g., cardiovascular disease).
Table 367-1: Examples of Organ-Specific and Systemic Autoimmune Diseases¶
| ORGAN-SPECIFIC AD | SYSTEMIC AD |
|---|---|
| Hashimoto’s thyroiditis | Systemic lupus erythematosus |
| Graves’ disease | Rheumatoid arthritis |
| Type 1 diabetes mellitus | Primary antiphospholipid syndrome |
| Addison’s disease | Ankylosing spondylitis |
| Pernicious anemia | Idiopathic inflammatory myopathies |
| Celiac disease | Sjögren syndrome |
| Autoimmune hepatitis | Progressive systemic sclerosis |
| Primary biliary cholangitis | Mixed connective tissue disease |
| Primary sclerosing cholangitis | Giant cell arteritis |
| Vitiligo | Takayasu arteritis |
| Pemphigus and other autoimmune bullous diseases | Polyarteritis nodosa |
| Multiple sclerosis | ANCA-associated vasculitis |
| Myasthenia gravis | Anti-glomerular basement membrane disease |
| Autoimmune polyglandular syndromes | Cryoglobulinemic vasculitis |
| Autoimmune oophoritis | IgA vasculitis (Henoch-Schönlein) |
| Autoimmune orchitis | Hypocomplementemic urticarial vasculitis |
| Primary CNS angiitis | Kawasaki disease |
| Isolated aortitis | Behcet’s disease |
| Cutaneous arteritis | Cogan’s syndrome |
| Cutaneous leukocytoclastic angiitis | Psoriasis/psoriatic arthritis |
| Guillain-Barré syndrome | Inflammatory bowel disease |
| Immune thrombocytopenic purpura | Rheumatic fever |
| Autoimmune hemolytic anemia | Sarcoidosis |
| Autoimmune pancreatitis | Undifferentiated connective tissue disease |
4.1 Organ-Specific vs. Systemic¶
Organ-specific diseases (e.g., Hashimoto’s thyroiditis) target specific tissues, while systemic diseases (e.g., SLE) affect multiple organs. Systemic manifestations include arthritis, rash, and multi-organ involvement.
4.2 Complications¶
Osteoporosis, anaphylaxis, and comorbidities (e.g., cardiovascular disease, cancer) are common. Autoimmune myelofibrosis and myocarditis may present with systemic symptoms.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate ADs from infections (e.g., carcinoid tumors, pheochromocytoma), hereditary conditions (e.g., α -tryptasemia), and other autoimmune disorders. Key tests include urine 5-HIAA for carcinoid tumors and tryptase levels for mastocytosis.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis of SM requires major/minor criteria (Table 366-3). For ADs, autoantibody testing (e.g., ANCA, anti-dsDNA), imaging (e.g., bone densitometry), and genetic testing (HLA typing) are critical. Urine analysis for 5-HIAA and metanephrines excludes neuroendocrine tumors.
Table 366-3: Diagnostic Criteria for Systemic Mastocytosis¶
| MAJOR CRITERIA | MINOR CRITERIA |
|---|---|
| Multifocal dense infiltrates of mast cells (>15 cells/aggregate) in bone marrow or extracutaneous tissues | Abnormal mast cell morphology (spindle shape or atypical immature morphology) in >25% of mast cells |
| Aberrant mast cell phenotype with CD25, CD2, or CD30 expression | |
| Detection of KIT D816V mutation or other activating KIT mutation | |
| Total serum tryptase >20 ng/mL |
6.1 Diagnostic Criteria for SM¶
Major criteria: >15 mast cells/aggregate in bone marrow. Minor criteria: Abnormal mast cell morphology, KIT D816V mutation, or tryptase >20 ng/mL. Diagnosis requires major + minor or three minor criteria.
6.2 Laboratory Tests¶
Serum tryptase, urine 5-HIAA/metanephrines, autoantibody panels (e.g., ANCA, anti-dsDNA), and genetic testing (HLA, PTPN22) are essential for diagnosis.
7. MANAGEMENT & TREATMENT¶
Symptom-directed therapy includes antihistamines, corticosteroids, and tyrosine kinase inhibitors (e.g., avapritinib). For ADs, immunosuppressants (e.g., JAK inhibitors, rituximab) and biologics (e.g., TNF inhibitors) are used. Targeted therapies (e.g., BTK inhibitors) address specific pathways.
7.1 Mastocytosis Treatment¶
Cytoreductive therapy (midostaurin, avapritinib) for advanced SM. Epinephrine for anaphylaxis. Avoid NSAIDs in patients with mast cell activation.
7.2 Autoimmune Disease Therapies¶
Immunosuppression (e.g., corticosteroids, methotrexate), biologics (e.g., TNF inhibitors, rituximab), and targeted agents (e.g., JAK inhibitors, BTK inhibitors) are used based on disease type and severity.
8. PROGNOSIS & COMPLICATIONS¶
ADs are chronic and incurable, with accelerated mortality due to organ damage and comorbidities. Complications include osteoporosis, anaphylaxis, and increased cancer risk. Early diagnosis and management improve outcomes.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Monitor for drug interactions (e.g., corticosteroids, anticoagulants). Pediatrics: Early detection of T1DM, celiac disease. Elderly: Increased risk of comorbidities and drug toxicity. Genetic counseling for hereditary conditions (e.g., α -tryptasemia).
10. KEY POINTS & CLINICAL PEARLS¶
Autoimmune diseases are complex, multifactorial conditions requiring tailored management. Early diagnosis via autoantibody testing and genetic screening is critical. Targeted therapies (e.g., tyrosine kinase inhibitors) improve outcomes in specific subtypes. Monitor for comorbidities and drug interactions in all patient groups.