T Cell-Mediated Autoimmune Diseases

• Autoimmune diseases can be studied in animals, with experimental autoimmune encephalomyelitis (EAE) being the most common animal model
• EAE is a T cell-mediated disease that resembles chronic, relapsing-remitting multiple sclerosis (MS) in humans
• CD4+ T cells are considered the primary mediators of autoimmune diseases
• EAE disease development can be prevented by treating animals with anti-CD4 antibodies
• T cell recognition of an antigen involves a complex of the T cell receptor, an MHC molecule, and the antigen

T Cell-Mediated Autoimmune Diseases

• T cell-mediated experimental autoimmune diseases can be induced in normal animals by T cells, resulting in disease development due to self-reactive CD4+ T cells
• The Th1/Th2 balance can affect autoimmune development, with Th1 implicated in disease progression
• Th2 cells may protect against or mitigate disease progression
• T cell-mediated autoimmunity is likely associated with disruption between B and T cells, which causes pathogenesis instead of protective immunity
• Dysfunction may occur during the selection of naive B cells in the periphery
• Dysfunctional lymphocyte subset events
  • Peripheral escape of pathogenic B cells from T cell-mediated control
  • Mutual activation of pathogenic B and T cells within germinal centers
  • Reactivation of infiltrating B and T cells

Multiple Sclerosis (MS)

• MS is the most common cause of neurological disability associated with disease in Western countries
• Auto-reactive T cells participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers
• Cerebral spinal fluid of MS patients contains activated T cells that infiltrate the brain tissue and attack myelin, leading to neurological dysfunctions

Celiac Disease

• Celiac disease is characterized by gluten-specific CD4+ T cells in the lamina propria
• Interepithelial T cell infiltration and epithelial layer contribute to small intestine inflammation
• Excessive production of interferon-gamma may enhance specific protein expression by epithelial cells and promote cytotoxic response via CD8+ T cells

Rheumatoid Arthritis

• Rheumatoid arthritis is a common autoimmune disorder of the joints, affecting about 1% of the population worldwide, more often women than men
• The exact causes are unknown, but risk is increased by a combination of genetic and environmental factors
• Many genes associated with rheumatoid arthritis are involved in immune system function
• Non-genetic risk factors include age, diet, infectious agents, and smoking
• The immune system attacks the body's own cells and tissues (self cells); autoimmunity can be present years before joint symptoms
• Doctors use blood tests to identify a pre-clinical phase using autoantibodies and inflammatory factors
• Early autoantibodies may first develop outside the joints, possibly in the gut, mouth, or lungs
• Smoking can modify self-cell proteins, making them targets for the immune system
• Citrullination is one modification
• The immune system recognizing modified self-cell proteins leads to a breach of self-tolerance and the production of autoreactive B cells and autoantibodies, and later autoreactive T cells
• By the time symptoms appear, the immune response is intensified, and antibodies are produced over a broader range of self-cell proteins
• Systemic autoimmunity progresses to joint inflammation, possibly triggered by increased joint permeability and antibody access
• Small joints of the hands and feet are most commonly affected after gaining access to the joint
• Immune cells and autoantibodies bind to modified self-cell proteins in cartilage and synovium, which induces an inflammatory response and activates cells in the joints, such as macrophages, neutrophils, osteoclasts, and blood monocytes
• Activated monocytes differentiate to macrophages, which, together with other cells in the joints, produce soluble inflammatory factors (cytokines)
• Drugs targeting these cytokines are highly effective treatments
• Untreated, damage caused by the inflammatory environment can expose new self-cell antigens in the immune system, continuing the cycle
• Symptoms include joint pain, swelling, and warmth
• Some patients recover, but progression to a chronic, destructive disorder is more common
• As the disease progresses, dendritic cells display the newly exposed self-cell antigens and activate T cells in the joint or the local lymph node
• B cells infiltrate joints where they proliferate and produce antibodies and other factors, amplifying the autoimmune response
• Fibroblasts also proliferate and grow into the joint space, spreading across the cartilage surface
• B cells secrete matrix-degrading enzymes, which erode the cartilage tissue
• Bone is eroded as osteoclasts become hyperactive
• Bone erosion, cartilage destruction, and joint swelling cause severe pain, restrict movement, and can cause joint deformities
• Other organs and body systems can be affected by the ongoing inflammation
• Inflammation in blood vessels increases the risk of heart disease
• Early and aggressive therapy is recommended to prevent systemic complications