Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described. Interestingly, increased BTK protein expression in patients with systemic autoimmune disease appears to be correlated with autoantibody production. In addition, BTK may promote autoimmunity as an important driver of an imbalance in B-T cell interaction. Because of this overwhelming evidence of a pathogenic role of BTK in autoimmunity, several clinical trials in rheumatoid arthritis and systemic lupus erythematosus patients with BTK inhibitors are currently running. Here, we review BTK function in different signaling pathways and in different cell lineages, focusing on the growing body of literature indicating a critical role for BTK in autoimmunity. We also discuss BTK and the promising results of BTK inhibition in animal models of autoimmune disease.

Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.

Recent studies using animal models have generated profound insight into the functions of various subsets of innate lymphoid cells (ILCs). The group 2 ILC subset (ILC2) has been implicated in tissue homeostasis, defense responses against parasites, tissue repair, and immunopathology associated with type-2 immunity. In addition, progress has also been made in translating these findings from animal studies into a context of human immunity. Importantly, recent observations strongly support a role for ILC2s in several diseases of the human respiratory system. However, many aspects of human ILC2 biology are still unclear, including how these cells develop and which signals control their activity. As a result, the exact role played by ILCs in human health and disease remains poorly understood. Here, we summarize our current understanding of human ILC2 biology and focus on their potential involvement in various human respiratory disorders.