Systemic Autoimmune Disorders (Overview)

Self-Tolerance Failure of self-tolerance results in autoimmune disorders, in which abnormal immune cells provoke a damaging immune response to otherwise benign molecules. These disorders have genetic components, often related to HLA alleles, and are often triggered by environmental or infectious stimuli. Furthermore, women are more often affected than are males, though the reasons for this are undetermined. Tolerance is achieved by selective removal of T and B cells that respond to self-antigen via central and peripheral mechanisms Hematopoietic bone marrow houses the B and T cell precursors. Central Tolerance B cells in the bone marrow are exposed to self-antigen. B cells that respond to self-antigen can undergo receptor editing, in which they develop new receptors that do not recognize self-antigen, or, they can undergo apoptosis. Peripheral Tolerance When self-reactive B cells in the periphery are exposed to self-antigen, they enter an unresponsive state of anergy. It is thought the absence of co-stimulation by T cells renders B cells anergic. Central Tolerance T cells in the thymus are exposed to self-antigen by antigen-presenting epithelial cells. In response, they can differentiate to become T regulatory cells, or, undergo apoptosis. Peripheral Tolerance T cells reactive to self-antigens may become anergic and unresponsive (particularly in the absence of co-stimulation); or, they may be suppressed by T regulatory cells, which inactivates them; or, they may undergo apoptosis. AUTOANTIBODIES Unfortunately, some self-reactive B and T cells end up in the circulation, where they act as autoantibodies that cause chronic, often progressive, damage. Autoimmunity can also be organ-specific, as in multiple sclerosis or Type I diabetes mellitus. Tends to affect the synovial joints of the hands and feet early in the disorder. Key mediators and their effects: Helper T cells release interferon gamma and IL-17. Interferon gamma activates macrophages IL-17 recruits inflammatory neutrophils and monocytes. Macrophages release tumor necrosis factor and IL-1. Trigger the release of degradative proteases. Activated T cells Express RANKL, which promotes bone resorption. RA damage: Inflammation of the synovium results in pannus formation, which comprises thickened synovial fluid with infiltrating inflammatory cells, fibroblasts, and synovial cells that erode the cartilage. Over time, the pannus on opposing bones forms a fibrous ankylosis, which may then become bony ankylosis. These changes cause stiffness, swelling, and joint deformities. Swan neck deformity is a common consequence of rheumatoid arthritis in which the proximal interphalangeal joint is hyperextended and the distal interphalangeal joint is flexed (thus, it looks like the neck of a swan). Serum Markers: Antibodies against citrullinated protein antigens (ACPAs), such as citrullinated fibrinogen, which is produced during inflammation. Rheumatoid factor is also found in patients with rheumatoid arthritis; however, despite its name, rheumatoid factor is non-specific to rheumatoid arthritis and is present in other autoimmune disorders. Aka, scleroderma Key mediators and their effects: Caused by a combination of autoimmunity, vascular damage, and fibrosis. Tumor growth factor Beta is a key mediator of this disorder. Serum Markers: Anti-centromere antibody (ACA) Anti-Scl-70 Affects the skin of the fingers, forearms, and face; visceral involvement, if any, occurs late. Limited systemic sclerosis is characterized by the presence of anti-centromere antibodies. CREST Calcinosis = calcified nodules form under the skin; they may progress to lesions. Raynaud's phenomena = the small vessels of the fingers and toes severely constrict in response to stress and/or cold. Initially, reduced blood flow turns the fingers white; as oxygen levels fall, the fingers appear bluish; and, finally, after blood flow is re-established, they become red. Esophageal dysmotility = caused by collagen replacement of the muscularis layer of the esophagus; dysphagia and/or heart burn can result. Sclerodactyly = occurs when hands take on a claw-like appearance because fibrosis of the dermis pulls the skin taught; dermal tightening can also occur in the face. Telangiectasia = dilation of superficial micro-vessels; it commonly looks like a rash on the face or chest. Manifests as widespread cutaneous fibrosis with quick progression to the viscera. It is associated with Scl-70. Examples of Organ Effects:

• Pulmonary fibrosis, in which the interstitial tissue becomes thick and fibrotic, can occur. Pulmonary fibrosis and hypertension are the leading causes of death from systemic sclerosis.
• Renal failure, due to systemic vascular damage and hypertension.
• Pericarditis and pericardial effusion.
• Damage to the villous structures in the small intestine, which leads to malabsorption.

Characterized by damage to the lacrimal and salivary glands, and is largely mediated by interferons (types 1 & 2). Key autoantibodies are anti-SSA/Ro, anti-SSB/La, which are anti-nuclear autoantibodies (which are also implicated in the pathogenesis of systemic lupus erythematosus). Aka, dry mouth Can lead to ulcers and increased dental caries Aka, dry eye. Occurs when the lacrimal gland, which is located laterally above the eye, does not produce tears. Thus, the eyes become dry, irritated, and more susceptible damage; vision may be impaired. Furthermore, Sjörgen's syndrome may have non-glandular effects, particularly in the joints, lungs, kidneys, and cardiovascular system. Be aware that systemic lupus erythematosus is another autoimmune disorder with multi-organ effects; we discuss it in more detail, elsewhere.