Systemic Autoimmune Diseases

• Systemic autoimmune diseases involve a broad immune response against various target antigens, affecting multiple organs and tissues.

Systemic vs. Organ-Specific Autoimmune Diseases

• Autoimmune diseases can be classified based on whether they are systemic or organ-specific, but this is not a clear division.
• Diseases often affect one or more organs with some overlap.

Systemic Lupus Erythematosus (SLE)

• SLE is a classic example of a systemic autoimmune disease, commonly appearing in women aged 20-40.
• SLE symptoms include fever, weakness, arthritis, skin rashes, and kidney dysfunction.
• SLE is more frequent in African American and Hispanic women.
• Affected individuals develop autoreactive antibodies against various tissue antigens like DNA, RBCs, platelets, leukocytes, and clotting factors, potentially leading to hemolytic anemia and thrombocytopenia.
• Deposition of immune complexes on small blood vessel walls triggers a type III hypersensitivity reaction.
• Complement activation results in blood vessel damage.
• A characteristic symptom is the butterfly rash over the cheeks.

Multiple Sclerosis (MS)

• MS affects the central nervous system, with symptoms ranging from numbness in the limbs to paralysis or loss of vision.
• Patients with MS produce autoreactive T cells, leading to inflammatory lesions along the myelin sheath of nerve fibers.
• The cerebrospinal fluid of MS patients contains activated T cells that induce inflammation and tissue damage in the brain, destroying myelin.

Rheumatoid Arthritis (RA)

• RA is a common systemic autoimmune disorder primarily affecting women aged 40-60.
• Patients with RA produce rheumatoid factors, which are autoantibodies that react with determinants in the FC region of IgG.
• Autoantibodies bind to normal circulating IgG, forming IgM-IgG complexes that deposit in the joints, resulting in chronic inflammation.
• RA can also affect hematologic, cardiovascular, and respiratory systems.

Etiology of Chronic Autoimmune Conditions

• The exact cause of chronic autoimmune conditions like lupus and idiopathic inflammatory myopathies is unknown.
• Genetic, hormonal, immunologic, and environmental factors are thought to play a role.
• Clinical manifestations may be mediated by antibody formation and immune complex creation.
• Antibodies can target surface antigens, such as those of the phospholipid beta-two lipoprotein complex, potentially causing thrombotic complications.
• Ultraviolet (UV) light exposure is suspected to have local effects on the skin and may increase autoimmunity in lupus.

Inflammatory Myopathies

• Inflammatory myopathies, including dermatomyositis, polymyositis, anti-synthetase syndrome, immune-mediated necrotizing myopathy, and inclusion body myositis, share the feature of immune-mediated muscle injury.
• Different pathogenic processes may underlie each myopathy.
• The precise method leading to tissue injury in inflammatory myopathies is not yet fully defined.

Clinical Manifestations

• Manifestations are heterogeneous, ranging from skin lesions to severe organ involvement.
• Lupus can present with malar rash or discoid lesions, scarring or non-scarring patches, and oral or nasal ulcers, as well as inflammatory joint symptoms, which tend to be polyarticular and symmetric.
• Muscular manifestations typically involve a gradual onset of proximal muscle weakness, with elevated muscle enzymes.
• Extra-muscular presentations can include cutaneous manifestations, lung involvement (e.g., interstitial lung disease), rheumatoid arthritis, or systemic sclerosis.

Differential Diagnosis

• Differential diagnoses for autoimmune conditions include mixed connective tissue disease, Sjögren's syndrome, vasculitis, and malignancies like leukemia or myelodysplastic syndromes.
• For myopathies, consider any myopathy related to hypothyroidism, muscular dystrophies, as well as drug-induced or metabolic myopathies.

T Cell and B Cell Activation in SLE

• In SLE, antibodies target multiple components of the nucleosome, including histone proteins (like H1) and DNA.
• A clone of T cells recognizing a peptide from histone H1 can activate B cells specific for both DNA and H1 through epitope spreading and bystander activation.
• The nucleosome comprises DNA wrapped around histone proteins.
• In SLE, the immune system mistakenly targets nucleosome components.
• Histone H1, a self-protein, becomes an immunogenic target in autoimmunity.
• Antigen-presenting cells (APCs) present peptide fragments derived from histone H1 on MHC class II molecules, activating T helper cells which then secrete cytokines to further the immune response.
• Activated T helper cells specific for histone H1 can interact with B cells that present histone H1 peptides or DNA on their surface. This interaction leads to B cell activation, isotype switching, affinity maturation, and autoantibody production.
• Epitope spreading leads to cross-reactivity where an immune response spreads from histone H1 to other epitopes like DNA.
• Activation of T helper cells specific for H1 peptides results in antibodies produced by B cells that recognize histone H1 and DNA, contributing to immune complexes and tissue inflammation in SLE.
• Because the DNA and histone are part of the same complex, B cells specific for either component would process the entire complex and present histone H1 peptides. The T cell recognizing histone H1 could “help” both B cells in a cognate interaction. In a cognate interaction, T cells and B cells recognize different epitopes of the same molecule/molecular complex