Reversal of Vasectomy and Orchitis

• Vasectomy Reversal Complications

  • When a man has a vasectomy and later gets it reversed, his body may develop a complication due to immune system access to the testes.

  • Orchitis:

  • Definition: Inflammation of the testes.

  • This occurs because the immune system can now recognize sperm as foreign.

Immune System Recognition of Sperm

• Female Reproductive Tract and Sperm:

  • After sperm are deposited, the woman's immune system may recognize the sperm as non-self cells, leading to potential attacks on the sperm.

• Fast, Fast Ligand System:

  • Function: Prevents the woman's immune system from destroying sperm before they reach the egg.

FAD and Procaspase Eight Activation

• FAD (Fas-Associated Death Domain):

  • Serves as a docking site for inactive procaspase eight molecules, which are crucial for apoptosis.

  • Procaspases exist as zymogens (inactive forms) within cells as a safety mechanism to prevent unintended activation.

• Need for Activation:

  • Procaspase eight molecules require engagement with a domain that contains a death domain.

  • This engagement is necessary for proteolytic cleavage, which activates the procaspases into active forms.

• Trimerization:

  • Activation happens when three receptors interact on the cell surface due to ligand binding, allowing formation of a complex capable of triggering apoptosis.

Role of FLIP and Its Mechanism

• FLIP (Fas-Associated Death Domain-Interacting Protein):

  • Recognized as an essential regulatory protein that prevents procaspase eight activation.

  • Full Definition: FLICE inhibitory protein (FLIP) stands for FAD-like IL-1 beta-converting enzyme inhibitory protein.

  • Production: Constantly synthesized by cells but has a short half-life, leading to degradation within minutes.

• Function in Apoptosis:

  • FLIP ensures commitment to apoptosis by preventing premature activation of procaspase eight.

  • If damage progresses, FLIP production diminishes, allowing for activation of procaspase eight and subsequent apoptosis.

Viral Inhibition of Apoptosis

• Viral Functions:

  • Some viruses produce their own FLIP-like proteins to inhibit apoptosis in infected cells, allowing for viral replication and spread.

  • Examples include:

  • Radinoviridae

  • Kaposi Sarcoma Herpes Virus

Execution Phase of Apoptosis

• Converging Pathways:

  • Regardless of induction route (intrinsic or extrinsic), all pathways converge on the execution phase where initiator caspases activate executioner caspases that carry out cell death.

• Caspases in Action:

  • Other cellular components such as the inhibitor of DNase are activated, leading to chromatin degradation and formation of nucleosome-sized fragments.

• Cytoskeleton Degradation:

  • Controlled degradation of the cytoskeleton occurs, particularly tubulin, leading to cell shrinkage.

• Formation of Apoptotic Bodies:

  • Phosphatidylserine:

  • Receptors on apoptotic bodies attract phagocytes, signaling for removal.

  • Thrombospondin:

  • Released by phagocytes, aiding their adhesion to endothelium for effective clearance of dying cells.

Apoptosis Triggers

• Withdrawal of Growth Factors:

  • Activation of intrinsic apoptotic pathways and reduction of anti-apoptotic proteins lead to cell death.

• Examples of Sensitive Cells:

  • Neurons deprived of nerve growth factor, lazy lymphocytes removed for not responding to antigens or cytokines, and hormone-sensitive tissues (like endometrial and prostate cells) undergo apoptosis when hormones are withdrawn.

• p53 Activation:

  • DNA damage from various sources activates p53, thus activating pro-apoptotic proteins (Bax, Bak) and leading to cell death if repair fails.

• Protein Misfolding and UPR (Unfolded Protein Response):

  • Accumulation of misfolded proteins triggers UPR, leading to chaperone protein production, increased proteasomal activity, and halting of translation.

  • If resolution fails, apoptosis is triggered through caspase activation.

Heat Shock Proteins and Cellular Stress

• Heat Shock Proteins (HSPs):

  • Induced by thermal insults, they help prevent protein denaturation.

  • Aging reduces effective UPR, leading to higher instances of apoptosis.

Tumor Necrosis Factor and Apoptosis

• Tumor Necrosis Factor (TNF):

  • Can induce apoptosis; however, animal models yield conflicting results about its roles in survival pathways.

  • TNF supports inhibiting blood vessel growth, which leads to ischemic regions in tumors.

Cytotoxic T Cells and Granzyme-Induced Apoptosis

• Mechanism:

  • CTLs release perforin and granzyme which activate caspases and lead to apoptosis in target cells, including virus-infected and cancer cells.

  • HIV-infected cellular mechanisms include high metal and calcium levels which are pivotal in apoptosis through granzyme activation.

Balancing Cell Death

• Maintaining Equilibrium:

  • A balance between apoptosis and anti-apoptotic signals is crucial; disruptions can lead to conditions like cancer or neurodegenerative diseases.

Granzyme Mediated and Autophagic Cell Death

• Granzyme Mechanism:

  • Granzyme activates caspases, triggering apoptosis. It can also activate DNases, leading to cell death via chromatin degradation.

• Autophagy:

  • Process where cells degrade unnecessary components under stress to survive; helps recycle materials and remove damaged organelles.

  • Can lead to forms of cell death where the machinery assist in degenerate cells under extreme stress (autophagy dependent cell death).

Mechanisms of Autophagy

• Three Forms of Autophagy:

  • Chaperone-Mediated Autophagy (CMA)

  • Targeting single proteins, specific to mammals.

  • Macroautophagy

  • Surrounds multiple organelles or cellular components, often breaking down damaged mitochondria.

  • Microautophagy

  • Directly engulfs smaller cellular structures.

• Molecular Pathways:

  • Involves interactions with various proteins such as mTORC pathways which are linked to cell survival signals, alongside AMP-activated kinase (AMPK) that signals energy stress and triggers autophagy.

Conclusion

• Autophagy Pathway and Cell Survival:

  • Cells with defective autophagy tend to die, especially under oxidative stress or nutrient deprivation.

  • Critical to note is the connection between autophagy, apoptosis, and potential pathways leading to necrotic-like death forms while attempting balance within cellular mechanics.