first described in 1932 , cd is an inflammatory disease of the digestive tract that affects 0.10.2% of the adult population . despite decades of investigation , the pathogenesis of cd has remained elusive ( baumgart and carding , 2007 ) . the inflammation associated with cd can occur anywhere along the route from the mouth to the anus . although clinically defined as a digestive condition , there is no evidence that cd involves defects in epithelial or other digestive cells . in essence , cd is an immunological disease in the hematopoietic sense of the term . this classification had long been suggested by the tissue lesions associated with cd , which consist primarily of granulomas , and by the fact that patients often respond to immunosuppressive therapy . perhaps the best proof of an immunological etiology is the observation that cd was cured in several patients who received allogeneic hematopoietic stem cell transplantation ( hsct ) . although cd is immune mediated , it is not an autoimmune disease , as the immunological process appears to be triggered by the content of the gut lumen rather than a self - antigen . cd is also a genetic disease , as suggested by the higher concordance in monozygotic versus dizygotic twins , the higher risk of disease in first - degree relatives of probands , and the high rate of family history among patients . however , cd does not follow a uniform mode of inheritance , a finding that has been conservatively interpreted to suggest a polygenic predisposition at both the individual and population levels ( baumgart and carding , 2007 ; van limbergen et al . , 2009 ) . to date , cd is widely accepted as a genetically determined immunological disease that manifests principally in the gut and is triggered by bowel contents . the immunological basis of cd has been studied primarily in various mouse models of colitis . most of these models have suggested that colitis , and by inference cd , are mediated by t lymphocytes ( ostanin et al . , 2009 ) . in the late 1990s , human genome - wide linkage ( gwl ) studies were performed , followed by genome - wide association ( gwa ) studies in the late 2000s . interestingly , the locus with the most robust association with cd and the first gene identified by gwl studies , nod2/card15 , was expressed in the myeloid rather than the lymphoid lineage ( hugot et al . , 2001 ; ogura et al . , 2001 ) . nod2 is a cytosolic receptor that recognizes bacterial peptidoglycans , particularly mycobacterial n - glycolyl muramyl dipeptide ( coulombe et al . , 2009 ) . after the identification of nod2 as a cd - associated gene , some studies claimed that the cd - predisposing nod2 mutant alleles were hypomorphic , others that they were hypermorphic . most , however , attributed cd pathogenesis to nod2-mediated recognition of bacterial peptidoglycan and subsequent activation of the nf-b pathway . the observation that other alleles of nod2 caused a clearly distinct , remotely related , and highly penetrant mendelian autosomal dominant systemic disorder called blau syndrome was left unexplained ( miceli - richard et al . , 2001 ) . only recently did a superb study reveal the surprising fact that cd - predisposing nod2 mutant proteins , unlike their wild - type counterparts , actively and specifically suppress the transcription of il-10 in a peptidoglycan- and nf-b  independent manner ( noguchi et al . , 2009 ) . this phenomenon was restricted to human nod2 and il-10 and was not found in their mouse orthologues , a distinction that highlights the necessity of human immunological studies ( casanova and abel , 2004 ; davis , 2008 ; hayday and peakman , 2008 ) . other loci were identified by gwl studies , but the impact of these loci on disease was lower and , like nod2 , they were not universal cd susceptibility loci . moreover , these loci were not found in gwa studies , which instead identified yet another set of loci . altogether , up to 32 cd candidate loci have been identified by gwa studies and replicated in at least two population samples ( barrett et al . , 2008 ) . however , for none of these loci do we have a fine characterization of the immunological impact of the cd - predisposing alleles . nod2 provides us with a preview of how long and arduous a path this is likely to be ( noguchi et al . , 2009 ) . paradoxically , experimental difficulties in studying cd - associated alleles may not be the most challenging roadblock ahead . a more difficult issue is that the myriad of identified loci do not account for the heritability of cd , a problem referred to as missing heritability ( maher , 2008 ) . even given the unproven assumptions that these loci are individually causal and collectively additive , the relative risk conferred by each locus is very small , and their overall contribution would account for only 20% of cd heritability . even for the three main cd - associated nod2 variants , the penetrance  or the proportion of homozygotes / compound heterozygotes who develop disease  is < 2% . and out of 1,000 cd patients , the number of homozygotes / compound heterozygotes and heterozygotes is relatively low , at an estimated 80 and 270 , respectively , as compared with 6 and 145 in a healthy population ( hugot et al . , 2007 ) . moreover , nod2 was found to have no role in some populations in which cd is endemic , such as the japanese . an equally important problem with these genetic data is that they do not add up to a unified or plausible immunological scenario for the pathogenesis of cd . it is difficult to make immunological sense of these multiple loci and pathways , at either the cellular or the molecular level . in addition to missing heritability , and perhaps even more troubling , is the problem of missing intelligibility . why would cd , which is epidemiologically , clinically , and pathologically definable , not obey some understandable causal relationship at the cellular , individual , and population levels ? if the immunological basis of cd is scientifically intelligible , one can also hope that this knowledge would be helpful to patients . this is unlikely to be the case if cd is the result of a myriad of genetic polymorphisms in various genes involved in multiple pathways , each conferring a very modest relative risk . what is more likely is that missing heritability and missing intelligibility are two sides of the same coin that account for the poor clinical impact of past investigations . the first breakthrough toward an understanding of the pathogenesis of cd came in 1976 when anthony segal demonstrated impaired influx of granulocytes into skin windows in cd patients ( segal and loewi , 1976 ) , a finding that was confirmed and extended to the gut in 2006 ( marks et al . , 2006 ) . as cd is an inflammatory disease , it was hard to imagine a more paradoxical and provocative finding than impaired inflammation ( korzenik , 2007 ) . moreover , although cd is principally localized to the gut , these studies claimed that the inflammatory defect was systemic and affected various tissues , such as the skin , that were not affected clinically . however , as the hungarian physiologist albert szent - gyrgyi pointed out ,  a discovery is a discovery because it is at variance with accepted knowledge . a discovery should also provide an explanation for the phenomenon studied . in a clinical investigation reported by smith et al . ( 2009 ) in this issue , segal 's group studied inflammation in response to skin wounded with heat - killed bacteria . consistent with their past studies , patients with cd had impaired inflammation at the wound site , as demonstrated by tracking intravenously injected , radio - labeled granulocytes . clearance of escherichia coli at the sites of injection was also impaired in patients with cd , but not in those with another inflammatory disease , ulcerative colitis , or in healthy subjects . notably , impaired bacterial clearance was evident for high , but not low , bacterial doses . overall , these experiments suggest a causal link between impaired inflammation and impaired bacterial clearance . the intestine was not wounded with bacteria , but the skin defect was proposed to be systemic and to involve the gut in particular . in fact , e. coli was chosen for these studies because of its abundance in the intestinal flora . it is important to reiterate that the defect was seen only with high bacterial loads , given that the highest bacterial load in the human body is found in the intestinal tract , which is the primary target of cd . impaired bacterial clearance presumably results in chronic inflammatory responses , accompanied by accumulation of granulomas consisting of macrophages and t lymphocytes . therefore , in this model , excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of cd pathogenesis ( fig . 1 ) . a model of intestinal chronic inflammation caused by inborn errors of macrophages in patients with cd . macrophages from the patients are intrinsically defective , with impaired secretion of cytokines that are normally translated but internally degraded . because of insufficient production of cytokines and chemokines , there is impaired attraction of granulocytes to mucosal breaches . impaired acute , granulocytic inflammation results in impaired clearance of bacteria and debris from the gut wall , itself resulting in chronic , granulomatous inflammation . that impaired inflammation hampers bacterial clearance is understandable , but what causes the impaired attraction of granulocytes to experimental wounds , and by extension , to natural mucosal breaches , in cd patients ? the patients ' granulocytes appear to be intrinsically intact , as they responded normally to in vitro exposure to known chemoattractants . however , macrophages derived from blood monocytes of cd patients failed to secrete proinflammatory cytokines and chemokines , including some that attract granulocytes ( smith et al . , 2009 ) . remarkably , like the impaired attraction of granulocytes and bacterial clearance , this phenotype was shared by all cd patients tested , regardless of the nod2 genotype in particular , and was markedly distinct from healthy controls . the defect applied to various experimental conditions , including macrophages stimulated by e. coli or microbial products . the mechanism underlying the cytokine defect was not impaired transcription of the corresponding genes , nor was it impaired translation of the corresponding mrnas . instead treatment with lysosomal inhibitors restored cytokine production , suggesting that some normally secreted proteins were erroneously targeted to the lysosomes . in conclusion , these studies provide a plausible , unified explanation for the cellular pathogenesis of cd . this groundbreaking theory proposes that resident gut macrophages in cd patients display a phenotype marked by enhanced destruction of cytokines , which results in insufficient ignition of inflammation upon mucosal invasion by the luminal content . in turn , insufficient inflammation results in impaired clearance of bacteria and debris , leading to a t cell  mediated granulomatous response . first , if the macrophage phenotype is systemic , why does cd principally occur in the gut ? as suggested by the bacterial load  dependent clearance defect , the anatomical selectivity of disease may reflect the uniquely high bacterial load in the intestinal lumen , which is not found at any other interface . the bacterial content in the gastrointestinal tract is huge when compared with other locations , such as the skin or the respiratory , urinary , or genital tracts . in fact , the immunodeficiency might explain the apparently high rate of appendicitis in patients with cd ( fujita , 2009 ) . moreover , although the gut is the primary target of disease , immunodeficiency in patients with cd is not strictly limited to the gastrointestinal tract , as patients appear to be somewhat more prone to infectious diseases elsewhere ( e.g. , urinary tract infections ; kyle , 1980 ) . a systemic macrophage defect is also consistent with the occurrence of extraintestinal manifestations of cd ( ephgrave , 2007 ) . if cd is a phagocyte immunodeficiency that combines a primary macrophage defect and a secondary granulocytic defect , one might expect cd to occur in patients with well - known phagocyte disorders . indeed , cd is known to occur frequently in patients with chronic granulomatous disease ( cgd ) , which is caused by a group of genetically determined defects of the phagocyte respiratory burst ( marks et al . , 2009 ) . patients with cgd often present with an intestinal disease indistinguishable from cd . other phagocyte primary immunodeficiencies ( pid ) also cause cd in some patients ( rahman et al . , 2008 ) . interestingly , however , other phagocytic disorders , such as those caused by irak-4 and myd88 deficiency , do not seem to predispose to cd ( ku et al . although patients with the latter defects are too young and too few for researchers to draw firm conclusions , this observation suggests that the cd - causing macrophage phenotype and the resulting immunodeficiency may be tlr- and il-1r  independent . the fact that cd patients display a macrophage immunodeficiency in turn begs the question whether the macrophage defect is truly a genetically determined , cd - causing phenotype . ironically , we learned from gwl and gwa studies that the genetic architecture of cd may not be purely polygenic . with up to 30% familial forms and a prevalence of only 0.1% of the population , cd may very well result from a collection of single - gene lesions that affect macrophages and display incomplete penetrance at the clinical level , at least in a fraction of patients , including most familial and some sporadic cases . even herpes simplex encephalitis , which is almost always sporadic , turned out to be mendelian in at least some patients ( zhang et al . , 2007 ) . interestingly , even a small proportion of mendelian forms of cd may largely explain the overall missing heritability . a simple computation shows that the contribution of mendelian forms to the overall sibling relative risk is rrm , where  is the proportion of mendelian forms and rrm is the relative risk of cd in siblings of probands with mendelian cd . for example , if we assume an overall prevalence of cd of 1 in 1,000 ( 10 ) and a dominant model ( heterozygotes can be affected ) with a clinical penetrance of 40% for mutation carriers , the cd risk in individual siblings of probands who are heterozygous for the mutation would be 0.5 ( probability of carrying the mutation )  0.4 ( clinical penetrance for mutation carriers ) , or 0.2 . if we also conservatively assume that only 5% of cd cases are mendelian (  = 0.05 ) , a rrm of 200 leads to an estimate of the overall sibling relative risk of 10 ( 0.05  200 = 10 ) , which is close to the observed relative risk among first - degree relatives ( 535 ) , despite being solely the result of the mendelian forms . as these rare mendelian mutations could not be found by the gwa studies and may not be detected by gwl studies if there is genetic heterogeneity , this mendelian hypothesis may , to a large extent , account for the missing heritability . oddly enough , the genes found by gwl and gwa studies may be merely cd - modifying genes , as opposed to cd - causing genes . studies that incriminate macrophages in the pathogenesis of cd will facilitate the genetic dissection of disease . the body of work by smith et al . ( 2009 ) has made it possible for researchers to focus on a cellular phenotype , both to select candidate genes expressed in macrophages and to test in macrophages the genes found by gw approaches in selected multiplex or consanguineous families . regardless of the proportion of mendelian forms of cd , and regardless of whatever genetic architecture of cd is revealed by comprehensive genetic studies , the macrophage theory and the known heritability of cd together provide a sufficient justification for referring to cd as a pid of macrophages . this classification further expands the field of pid beyond its traditional and admittedly somewhat arbitrary phenotypic boundaries ( casanova and abel , 2007 ) . cd may actually turn out to be a typical pid , affecting patients whose host defense is unable to control their commensal , intestinal microbial flora . this scenario is reminiscent of the recent description of pulmonary alveolar proteinosis ( pap ) in patients with granulocyte monocyte colony stimulating factor receptor mutations ( martinez - moczygemba et al . , 2008 ; suzuki et al . , 2008 ) impaired surfactant destruction by alveolar macrophages results in a selective pulmonary phenotype , although the defect is shared by macrophages present in all tissues . there is a striking resemblance between cd and pap , as both conditions are organ - specific manifestations of an inherited , systemic macrophage deficiency . the pivotal role of macrophages in multiple physiological processes and the diverse phenotypes related to macrophage defects found in the mouse model ( vidal et al . , 2008 ) suggest that other human diseases , besides cd and pap , may eventually turn out to be the result of macrophage anomalies .
despite two decades of mouse immunology and human genetics studies , the pathogenesis of crohn 's disease ( cd ) remains elusive . 
 new clinical investigations suggest that cd may be caused by inborn errors of macrophages . 
 these errors may result in impaired attraction of granulocytes to the gut wall , causing impaired clearance of intruding bacteria , thereby precipitating the formation of granulomas . 
 this theory paves the way for a macrophage - based mendelian genetic dissection of cd .