Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease

The current hypothesis for the etiology of Crohn's disease proposes an exce ssive immune response, largely T-cell driven, possibly against endogenous b acteria. Standard therapy is therefore directed towards suppression of this immune response. An alternative theory of pathogenesis accounts for epidem iologic and pathophysiologic observations that have been hitherto underemph asized, namely, (1) genetic disorders with deficiencies in neutrophil funct ion can give rise to a clinical and pathologic syndrome indistinguishable f rom Crohn's; (2) abnormal neutrophil function is well described in Crohn's disease; (3) a group of bacteria implicated in other chronic inflammatory d isorders causes impairment of neutrophil function; and (4) 20th century env ironmental risk factors for Crohn's disease may directly suppress neutrophi l function and may have led to a shift in the dominant gut flora with simil ar effects. We propose that some cases of Crohn's disease result from the i nteraction of environmental and genetic influences leading to impaired muco sal neutrophil function, resulting in failure to effectively clear intramuc osal microbes effectively. While encompassing existing data, this hypothesi s proposes a proximate defect in the mucosal immune response. If this parad igm were correct, new therapeutic approaches might involve strategies to al ter intestinal flora and stimulate neutrophil function.