On Self and Nonself A Case Study of the Cytosolic LPS Sensor Caspase-11

Abstract

The cornerstone of immunology lies in the distinction between Self and Non-self, where the immune system must differentiate threats (Non-Self) from innocuous elements (Self) to trigger appropriate responses. Traditionally, this dichotomy has been conceptualized as a mutually exclusive relationship, where Non-Self is defined as the absence of Self. Within this classical framework, autoimmune diseases represent aberrations, and immune tolerance toward tumors is seen as a failure of the immune system. This thesis explores an alternative framework, proposing that recognition of Self is a prerequisite for recognizing Non-self. In this model, recognition of endogenous ligands, which can be loosely defined as “Self” in the traditional framework, provides a contextual basis for the immune system to fine-tune its responses. Focusing on caspase-11, traditionally described as a sensor for cytosolic lipopolysaccharide (LPS)—a molecule exclusively associated with Gram-negative bacteria—this thesis uncovers the molecular mechanisms underlying caspase-11's ligand recognition. Furthermore, it identifies the self-equivalent of LPS, shedding light on the duality of Self and Non-Self in immune recognition