Jonathan Braun, MD, PhD

Professor and Chair,Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA

The intestinal mucosal surface plays diverse and critical roles in normal physiology and disease. With the renaissance of microbiome research, we have begun rethinking such microbial-host interfaces as an ecology of microbial niches, using systems biology and immunological approaches. An exciting and important challenge is to understand how the local host mucosa is entrained into such niches, and how to detect and visualize them. Dr Braun and his group have recently established high throughput methods of microbial and protein analysis to sample and analyze the function of the mucosal interface as an integrated host-commensal biologic unit, and in a manner suitable for human investigation. Using this strategy, Dr Braun has uncovered seven clusters of highly correlated proteins (modules), representing distinct ecologic niches. Each of these modules was positively or negatively associated with non-disease, ulcerative colitis, and/or Crohn’s disease (CD) states.  This reveals a previously undetected micro-geographic mosaic of the mucosal surface, with features of functional specialization (e.g., iron regulation, microbial defense), cellular origin (epithelial or hemopoeitic), and selective disease association. These modules may represent higher-order states of the mucosal surface that integrate the intestinal mucosa with the luminal microbial ecology, and to host susceptibility to disease states.  Such modules may be uniquely informative to understanding mucosal biology, and as targets for therapeutic manipulation.

Dr Braun is also interested in understanding how Natural Killer (NK) cells, and the genetic diversity of their function via licensing, affect susceptibility to disease or response to treatments affecting NK cells. NK cells are innate effector lymphocytes important in the response to infection, chronic inflammatory disease, and cancer. NK cells gain proficiency after genetic licensing that involves interaction of the genetically diverse killer immunoglobulin-like receptors and their Human Leukocyte Antigen (HLA) class I ligands.   He and his collaborators have discovered that NK licensing in humans results in a profound reprogramming of cytokine expression by NK cells, which enables them to engage in adaptive immune interaction via augmentation of CD4+ T cell proliferation.  Moreover, patients with the genetics to undergo licensing are much more susceptible to Crohn’s disease. The current work is establishing that a functional consequence of NK licensing is the previously unappreciated capacity of NK cells to produce a wide spectrum of immune mediators that modulate the CD4+ T cell activation threshold.  These findings offer a biologic basis for the correlation between NK licensing and KIR-associated susceptibility to CD and other chronic inflammatory syndromes, and their response to lymphocyte-targeting therapies.