Pathogenesis of systemic lupus erythematosus

Question 1

Systemic lupus erythematosus (SLE)

Answer 1

• Systemic d/o of generalized autoimmunity
• Characterized by production of Abs to the nucleus
• Predominantly affects young women

Question 2

Pathogenesis of SLE

Answer 2

• It is a T and B cell dependent d/o of immune regulation caused by loss of tolerance to self-ays
• Genetic, gender, and environmental factors influence onset
• Due to altered immune homeostasis often triggered by infections and followed by a decreased clearance of apoptotic cells and impaired Treg function

Question 3

Altered self-tolerance mechanisms

Answer 3

• Clonal deletion abnormal (not all self reactive T cells deleted in thymus)
• Clonal anergy (requiring costimulatory for leukocyte activation) is defective in SLE (B and T cells get activated w/ just self-Ag presentation)
• Apoptosis is affected in 2 ways: decreased apoptosis of T cells that should be clonally deleted in thymus, and decreased clearance of apoptotic cells (results in higher amounts of self-DNA and RNA near infection sites)
• Regulatory T cells (that usually prevent autoimmunity) have impaired function in SLE (FOXP3 maybe involved)

Question 4

Toll-like receptors involved in SLE

Answer 4

• TLR7 binds to RNA, TLR9 binds to DNA
• Both are intracellular and are on APCs
• These cells can initiate the reaction to self-nuclear Ags via the TLRs

Question 5

Environmental factors of SLE

Answer 5

• Infectious agents
• Sunlight
• Drugs: activate “ignorant” self-reactive T cells by inhibiting DNA methylation

Question 6

Overview of SLE pathogenesis

Answer 6

• Failure to clear apoptotic cells
• Ag processing of nucleosomal peptides by APCs triggers autoreactive T cells
• Failure of Tregs to block autoreactive leukocytes
• Failure of inhibitory molecules (FcR receptors) to control B cell activation
• Failure to eliminate self-reactive T and B cells

Question 7

Cause of tissue damage in SLE

Answer 7

• Autoreactive T cells trigger B cells to produce pathogenic IgG anti-nuclear autoAbs
• Immune complex-induced inflammation
• Multi-system tissue injury

Question 8

Summary of SLE pathogenesis

Answer 8

• Potentially harmful self-reactive T cells not eliminated
• Self-nuclear Ag presentation by APCs and hyper-responsive B cells
• Tregs fail to control autoimmunity
• Failure of activation-induced apoptosis
• T cell dependent autoAb production
• Multi-system inflammatory disease