T-bet binds to the promoter of the gene encoding IL-2 and is present in TH1 but not TH2 cells. Mice with a gene-targeted deletion of T-bet (T-bet–/–) manifest impaired TH1 responses, and show spontaneous differentiation of TH2 cells and development of an asthma-like phenotype in the lungs. Left-hand panels: lung and airways in normal mice. Right-hand panels: T-betdeficient mice show lung inflammation, with lymphocytes and eosinophils around the airway and blood vessels (top) and airway remodeling with increased collagen around the airway (bottom). Photographs courtesy of L. Glimcher.
They also develop nonspecific airway hyperreactivity to nonimmunological stimuli, similar to what is seen in human asthma. These changes occur in the absence of any exogenous inflammatory stimulus and show that, in extreme circumstances, a genetic imbalance toward TH2 responses can cause allergic disease. The availability of a large number of genetically deficient mouse strains has permitted testing of the roles of many inflammatory effector cells and cytokines in this experimental model, providing hypotheses that are now being tested in human asthma.
Although allergic asthma is initially driven by a response to a specific allergen, the subsequent chronic inflammation seems to be perpetuated even in the apparent absence of ongoing exposure to allergen. The airways become characteristically hyperreactive, and factors other than antigen can trigger asthma attacks. Asthmatics characteristically show hyperresponsiveness to environmental chemical irritants such as cigarette smoke and sulfur dioxide. Viral agents, especially rhinovirus, or, to a smaller extent, bacterial respiratory tract infections can also exacerbate the disease. Both irritant agents and the infectious agents can induce IL-25 and IL-33 release from airway epithelial cells, leading to activation of ILC2s and exacerbation of the chronic asthmatic inflammation. The significance of viral augmentation of the asthmatic response is evident from the fact that rhinovirus infection is one of the main causes of hospitalizations for asthma and is associated with the majority of deaths from asthma.
14-12 Allergy to particular foods causes systemic reactions as well as symptoms limited to the gut.
Adverse reactions to particular foods are common, but only some are due to an immune reaction. ‘Food allergy’ can be classified into IgE-mediated allergic reactions, non-IgE-mediated food allergy (celiac disease, discussed in Section 14-17), idiosyncrasies, and food intolerance. Idiosyncrasies are abnormal responses to particular foods whose cause is unknown but which can provoke symptoms resembling those of an allergic response. Food intolerances are nonimmune adverse reactions due mainly to metabolic deficits, such as intolerance of cow’s milk due to the inability to digest lactose.