A 23-year-old woman comes to the physician with migratory joint pains involving her hands and knees. Physical examination shows bilateral tenderness in her wrists and proximal interphalangeal joints. There is also a malar skin rash and generalized lymphadenopathy. A urinalysis reveals proteinuria. Further evaluation shows that the patient's lymphocytes contain a mutated and functionally defective Fas gene product. Which of the following immunologic mechanisms is most likely impaired in this patient as a result of this molecular defect?
Show Explanatory Sources
Apoptosis can be triggered by a number of mechanisms, including deprivation of growth factors, DNA damage, intracellular accumulation of misfolded proteins, mediation by cytotoxic T lymphocytes, and activation of receptors in the TNF receptor family (such as Fas). Fas receptors initiate the extrinsic pathway of apoptosis through a cytoplasmic component known as the death domain. Upon binding Fas ligand (FasL), the receptors trimerize, allowing their death domains to form a binding site for an adapter protein called Fas-associated death domain (FADD). Receptor-bound FADD then stimulates the activation of initiator caspases (8 & 10) that begin an activation cascade culminating in the activation of executioner caspases (3 & 6). These initiate the terminal processes of apoptosis, including cleavage of DNA, fragmentation of the nucleus, organelle autodigestion, and plasma membrane blebbing.
The Fas receptor is expressed on T-lymphocytes and plays an important role in the pathogenesis of numerous diseases, including cancer and autoimmune disorders. Once activated, T lymphocytes begin to express FasL, which can bind to Fas on the same cell or adjacent lymphocytes. During initial clonal expansion, activated T lymphocytes are resistant to Fas-induced apoptosis. However, they become more sensitive with progressive stimulation. In the constant presence of stimulating self-antigens, activated T lymphocytes eventually undergo apoptosis in a process known as activation-induced cell death. Mutations involving Fas or FasL impair this process, resulting in excessive accumulation of autoreactive T-cells and the development of autoimmune diseases such as systemic lupus erythematosus (which this patient appears to have).
(Choice B) As B lymphocytes undergo affinity maturation, cells that exhibit a stronger affinity for the antigen (which acts as a limited growth resource) are able to proliferate more than cells with lower affinity. This results in cells that are more efficient and accurate in binding to pathogens. Affinity maturation does not involve the Fas pathway.
(Choice C) Anergy is a state of prolonged unresponsiveness that occurs in T lymphocytes as a form of immune tolerance. It occurs when self-reactive T cells bind MHC molecules without receiving the necessary costimulatory signal (ie, binding of CD28 on T cells with the B7 on antigen-presenting cells).
(Choice D) Isotype switching is the process through which activated B lymphocytes switch production from IgM immunoglobulins to IgG and IgA isotypes. This process requires the interaction of CD40 on activated B cells with CD40 ligand expressed by activated T cells and is modulated by cytokines secreted by T cells.
(Choice E) On exposure to an antigen, naïve T helper (TH0) cells differentiate into TH1 (cell-mediating) and TH2 (antibody-mediating) subtypes based on the local cytokine milieu. IFN-γ and IL-12 induce TH1 formation; IL-4 stimulates TH2 development.
Educational objective:
The Fas receptor acts to initiate the extrinsic pathway of apoptosis. Mutations involving the Fas receptor or Fas ligand can prevent apoptosis of autoreactive lymphocytes, thereby increasing the risk of autoimmune disorders such as systemic lupus erythematosus.