Autoimmune Diseases

Introduction

• Autoimmune diseases represent a failure of self-tolerance, where the immune system mistakenly identifies self-antigens as foreign.
• The inflammatory processes are mediated by hypersensitivity reactions, specifically types II, III, and IV:
  • Type II (Cytotoxic): Antibodies ($IgG$ or $IgM$) bind to antigens on specific cell surfaces or tissues. This leads to complement activation, opsonization, and antibody-dependent cellular cytotoxicity (ADCC).
  • Type III (Immune Complex): Formation of soluble antigen-antibody complexes that circulate and eventually deposit in blood vessel walls or tissues (e.g., kidneys, joints), triggering systemic inflammation.
  • Type IV (Delayed-Type): T-cell mediated response ($Th1$ and $Th17$ cells) that activates macrophages or cytotoxic $T$ cells, leading to direct tissue destruction. This usually manifests $24-72$ hours after exposure.
• These diseases can be classified into:
  • Organ-specific: Damage is localized to a single organ (e.g., Type 1 Diabetes).
  • Generalized/Systemic: Multiple organs and tissues are involved simultaneously (e.g., SLE).

Spectrum of Autoimmune Diseases

• Organ-specific Autoimmune Diseases:
  • Hashimoto's thyroiditis: Presence of anti-thyroglobulin and anti-microsomal antibodies.
  • Addison's disease: Destruction of the adrenal cortex, often involving anti-21-hydroxylase antibodies.
  • Graves' disease: Stimulating antibodies ($LATS$ - Long-Acting Thyroid Stimulator).
  • Pernicious anemia: Antibodies against gastric parietal cells or intrinsic factor, leading to $B_{12}$ malabsorption.
• Non-organ specific (Systemic) Autoimmune Diseases:
  • Systemic lupus erythematosus (SLE): Characterized by a wide array of antibodies, notably anti-nuclear antibodies (ANA).
  • Rheumatoid arthritis: Chronic systemic inflammation primarily affecting synovial joints.
  • Multiple sclerosis: Inflammation and demyelination of the Central Nervous System (CNS) white matter.

Specific Systems and Diseases

• Nervous System:
  • Multiple sclerosis: $T$ cell-mediated attack on myelin sheath.
  • Myasthenia gravis: Muscle weakness due to receptor blockage.
  • Guillain-Barr Syndrome (GBS): Acute inflammatory demyelinating polyneuropathy.
• Endocrine Glands:
  • Type 1 Diabetes Mellitus: Selective destruction of insulin-producing $β$ cells in the Islets of Langerhans.
  • Graves' Disease: Clinically presents with hyperthyroidism and exophthalmos (protruding eyes).
• Skin:
  • Psoriasis: Rapid skin cell turnover mediated by $T$ cells.
  • Vitiligo: Loss of melanocytes resulting in depigmented patches.

Key Autoimmune Disease Profiles

1. Graves' Disease (Thyrotoxicosis)

• Mechanism: Auto-antibodies (Thyroid Stimulating Immunoglobulins) bind to the $TSH$ receptor on thyroid follicular cells.
• Effect: Unlike $TSH$, these antibodies are not subject to negative feedback, leading to constitutive production of $T<em>{3}$ and $T</em>{4}$.

2. Myasthenia Gravis

• Mechanism: Auto-antibodies against nicotinic acetylcholine receptors ($AChR$) at the postsynaptic membrane of the neuromuscular junction.
• Consequences:
  • Increased internalisation and degradation of receptors.
  • Complement-mediated damage to the postsynaptic membrane.
  • Clinically characterized by ptosis (drooping eyelids) and diplopia (double vision).
• Association: Often linked with thymic abnormalities such as thymic hyperplasia or thymoma.

3. Systemic Lupus Erythematosus (SLE)

• Pathogenesis: Type III hypersensitivity where immune complexes deposit in small vessels.
• Clinical Features:
  • Malar Rash: Sun-sensitive "butterfly" distribution over the cheeks and nasal bridge.
  • Renal: Lupus nephritis is a major cause of morbidity.
  • Serology: ANA is highly sensitive (>95\%), while anti-dsDNA and anti-Smith (anti-Sm) are highly specific.
• Diagnostics: Significant ANA titers are often defined as $1:160$ or higher.

4. Rheumatoid Arthritis (RA)

• Pathogenesis: Synovitis leads to the formation of a Pannus—an abnormal layer of fibrovascular tissue that erodes articular cartilage and bone.
• Markers:
  • Rheumatoid Factor (RF): An auto-antibody ($IgM$) directed against the $Fc$ fragment of $IgG$.
  • Anti-CCP: More specific than RF for early diagnosis.
• Clinical: Symmetric joint involvement, typically sparing the distal interphalangeal (DIP) joints.

Investigations and Management

• Laboratory Findings:
  • Elevated Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP) indicating systemic inflammation.
  • Low complement levels ($C3$, $C4$) during SLE flares due to consumption in immune complexes.
• Pharmacological Treatment:
  • Anti-inflammatory: NSAIDs for symptomatic relief.
  • Corticosteroids: Prednisone for acute flares.
  • DMARDs: Disease-Modifying Anti-Rheumatic Drugs (e.g., Methotrexate).
  • Biologics: TNF-alpha inhibitors ($TNF-\alpha$) and B-cell depleting agents (e.g., Rituximab).

Take Home Message

Autoimmune disorders are chronic conditions requiring long-term management. The shift from organ-specific to systemic involvement dictates the severity of the clinical presentation and the intensity of the required immunosuppression.