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Chapter 1

Inflammation and its resolution

“Inflammation is a normal and vital protective response to the harmfulstimuli such as infectious agents, antigen-antibody reactions, thermal, chemical, physical agents, and ischemia [injury from low blood flow].”  ~Kulkarni et al., 2006

“The usual result of inflammation is protection from the spread of infection, followed by resolution—the restoration of affected tissues to their normal structural and functional state.           

The problem with inflammation is not how often it starts, but how often it fails to subside.  Perhaps no single phenomenon contributes more to the medical burden in industrialized societies than nonresolving inflammation.”   ~Nathan and Ding, 2010, emphasis added

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You have a real problem on your hands.  It is called nonresolving inflammation.  You call it Crohn’s.  Something triggered it.  It will not go away.  Surprisingly, it is the immune system—engineered to amaze and defend—that is causing the problem.  Clearly, what should have resolved and perhaps gone unnoticed, persists.

“Inflammation is the complex biological response of tissues to harmful stimuli, such as pathogens, damaged cells or irritants.  It is a protective attempt by the organism to remove the injurious stimuli as well as to initiate the healing process for the tissue.  In mucosal tissues, the inflammatory response is central to effective host defense against invading pathogens, yet must be tightly regulated to prevent abnormal responses to innocuous environmental antigens and commensal [typically present] organisms that result in allergy or chronic inflammatory diseases.”  (Kelsall, 2008, emphasis added)

Inflammation is how we deal with threats.  The threat could be from an injury, even a simple injury, after which an inflammatory response is called upon to heal the damage then fade away.  The threat could be from a pathogen.  This is serious business, and an enormous amount of proinflammatory activity is directed at destroying the offending pathogen as well as healing injuries sustained in the battle, injuries inflicted not only by the pathogen but also caused by the inflammatory response itself.  Thankfully, there are pro-resolving responses that come into play, just at the right time, and the healing process begins and eventually comes to an end.  The immune system collectively breathes a sigh of relief, having saved you once again.  For some reason, it thinks you are worth it.

But circumstances can come together and make an immune response proportionally out of control, dysfunctional, less than successful, or simply persistent when things should be winding down and headed for the history books.  If the threat persists, of course you want the immune system to continue in its efforts.  No surprises here!  But what may be surprising is that resolving inflammation is an “active phenomenon,” a process programed at the very onset of the inflammatory response, always present, poised, ready to swing into action to heal the damage that has occurred (Ortega-Gómez et al., 2013; Buckley et al., 2013; Serhan et al., 2007).  The process of resolution is quite a story.  It is a very long story.  I will be brief.

After a successful battle with, say, a pathogen, there is an urgent need to calm things down.  But I’m getting a little ahead of myself here.  Let’s go back in time to when the fight was just beginning.  In the beginning, a white blood cell called the neutrophil was recruited in great numbers to the site of what, by all accounts, appeared to be a bacterial invasion.  This is no ordinary immune cell.  The neutrophil is a killing machine!  It possesses of an arsenal of weapons, chemical weapons, that, during battle, are progressively unleased for to kill the enemy with (I know, awkward wording).  Neutrophils have killing on their mind.  That’s just about all they have in mind.  They even kill when they are dead!  (More in the following chapter.)  But now, having defeated the enemy, killing is no longer needed.  The neutrophils have completed their mission, untold numbers have been lost in the battle, and further recruitment is unnecessary.  And since the war is basically over, the army of neutrophils that remain on the battlefield must be persuaded to put down their weapons and live in peace.

So how do you dissuade a neutrophil from continuing to wage war?  You can signal it to stop what it is doing (using chemical messengers called cytokines) and hope it will simply slip away.  Or you can outright kill it—that’ll stop ’em!  But in all likelihood, the neutrophil has noticed it is no longer needed (if it was paying any attention at all), and actually hastens its own demise, either by suicide or “inviting” another warrior cell, the macrophage, to take its life (Bratton and Henson, 2011).  In the latter case, the neutrophil is subsequently “eaten alive” by the macrophage (macrophage means “big eater”).  Problem solved.  However, other problems can emerge.

“If, for instance, neutrophils . . . that migrated to the site of inflammation stayed unchecked after elimination of the injurious stimulus, they could cause excessive tissue damage.”  (Buckley et al., 2013)

Indeed, a neutrophil is a force to be reckoned with before inflammation can resolve.  If it stays in the neighborhood, continues its killing spree, it must be removed for a variety of reasons, one of which is to promote healing.  “In the absence of defects of clearance, removal is an efficient, high capacity process that in fact actively promotes resolution and restoration of tissue structure and function.”  (Bratton and Henson, 2011, emphasis added)  So, the removal of the neutrophil, dead or alive, from the site of inflammation is a must for resolution to take place.  If neutrophil clearance were impaired, now that would be a problem!  Indeed, any problem associated with the neutrophil, such as a delay in arriving on the battlefield or recruitment in insufficient numbers at the beginning of the war, would be a problem for the patient with Crohn’s.  Get used to the word problems.

Aside from the issue of neutrophil clearance, “there is a complex interplay of cellular mechanisms and soluble mediators that are actively turned on” and come into play in order to resolve inflammation (Buckley et al., 2013).  Unfortunately, this “interplay of cellular mechanisms and soluble mediators” business may not be working out too well for you the patient with Crohn’s, so inflammation persists.  I think it is safe to say, factors that impair the process of resolution should be targeted in the battle against the greatest evil you may ever know.  That being said, actively promoting resolution is easier said than done.  And it may be that the threat (think bacterial threat) persists, making resolution an objective for a later date.

I must point out one more thing before we move on, regarding how complicated matters can become during the course of an infection.  Listen carefully.

The macrophage, during the course of an infection—before it is called upon to “eat” the neutrophil in order to remove it from the field of battle—has been, behind the scenes, actively shaping the inflammatory response (Bratton and Henson, 2011).  But times, they have changed.  The sweet smell of success is in the air and it’s time for the inflammatory response to wind down.  The macrophage is still in control and knows exactly what to do.  It will look for a molecular “eat me” signal intentionally displayed on the surface of the neutrophil, indicating that it’s time for the neutrophil to meets its maker.  The macrophage will then eat the neutrophil, dead or alive.  Surprisingly, this very action—the violent and systematic removal of neutrophils that are no longer needed—stimulates the release of pro-resolving factors and actively suppresses the killing efforts of the macrophage.  Sounds like nothing could go wrong here!  But a serious problem can emerge.

Certain pathogens that have somehow survived in the field of battle, or pathogens that have somehow slipped behind the front lines, or have otherwise invaded, unnoticed, now become exceptionally opportunistic.  They actually hope and pray to be eaten by the macrophage during this mop-up operation, somehow knowing that they have the skills to survive if they can somehow find their way inside this cell.  “Macrophages are the preferred host cells for bacterial intracellular pathogens, and intramacrophage residence and multiplication are crucial phases in the life cycle of those pathogens.”  (Silva, 2010)  In a quest for survival at all costs, these bad boys take advantage of the resolution phase—a phase wherein the macrophage becomes immunosuppressed and therefore more vulnerable—in order to arrive within the macrophage where they can survive and raise a family (Bratton and Henson, 2011).  Boy, I hope your macrophages are on their toes, realize what they are up against, and are not impaired in their ability to handle an enemy once it has arrived inside, or the result could be a disaster.   

This disaster, Crohn’s . . . in you . . . begs for resolution.  There is a war being fought.  It must come to an end.  Thankfully, there are programs already in place, ready to be unleashed to pull this off and allow you to live a normal life, at least for a while.  What is standing in the way?  Maybe it is the manner in which we treat this disease.

“With the past few years has been a growing recognition that, although targeting infiltrating immune cells can control the inflammatory response, it does not lead to remission or permanent resolution.”  (Serhan et al., 2007)

“Current treatments only target the consequences of the disease and not the underlying pathogenic mechanisms.”  (Knight et al., 2008)

“The current immunosuppressant-based treatment of Crohn’s disease reduces inflammation in the advanced phase, but could exacerbate its underlying abnormalities and contribute to maintaining a reduced acute inflammatory response.”  (Fava and Danese, 2010)

BOOK REFERENCES:

Bratton DL, Henson PM 2011 Neutrophil Clearance: When the Party is Over, Cleanup Begins. Trends Immunol; August; 32(8):350–357

Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP 2013 The Resolution of Inflammation. Nature Reviews Immunology; January; 13(1):59–66

Fava R, Danese S 2010 Bacterial Clearance in Crohn’s Disease Pathogenesis. Nature Reviews Gastroenterology and Hepatology; March; 7(3):126–128

Knight P, Campbell BJ, Rhodes JM 2008 Host-Bacterial Interaction in Inflammatory Bowel Disease. British Medical Bulletin 88:95–113

Kulkarni RG, Achaiah G, Sastry GN 2006 Novel Targets for Antiinflammatory and Antiarthritic Agents. Current Pharmaceutical Design 12:2437–2454

Nathan C, Ding A 2010 Nonresolving Inflammation. Cell 140:871–882

Ortega-Gómez A, Perretti M, Soehnlein O 2013 Resolution of Inflammation an Integrated View. EMBO Mol Med 5:661–674

Serhan CN, Brian SD, Buckley CD, Gilroy DW, Haslett C, O’Neill AJ, Perretti N, et al 2007 Resolution of Inflammation: State of the Art, Definitions and Terms. FASEB J 21:325-332

Silva MT 2010 When Two Is Better Than One: Macrophages and Neutrophils Work in Concert in Innate Immunity as Complementary and Cooperative Partners of a Myeloid Phagocyte System. J. Leuko. Biol.; January; 87:93–106

 

 

MACD_resize3dChapter 2

What is it that I have?

 

“A discovery is a discovery because it is at variance with accepted knowledge.”  ~Casanova and Able, 2009, quoting A. Szent-Györgi

 

“Crohn’s disease is now also discussed as an impaired immune reaction and no longer as a hyper-responsiveness of the mucosal immune system.”  ~Vavricka and Robler, 2009

 

“A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn’s disease is actually one of relative immunodeficiency.”  ~Marks et al., 2010

 

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It is becoming increasingly clear: Crohn’s disease involves an impaired response to bacteria—and you thought you had some kind of autoimmune disease!  You don’t, so promptly lay this notion to rest.  The body is not attacking itself for some crazy, diabolical reason.  The major discoveries of late regarding susceptibility to Crohn’s involve defects in how we identify and respond to threatening bacteria and how we kill those that need to be destroyed.  Thus autoimmunity is becoming less and less attractive as a theory to explain all the madness.  It just isn’t there.

“Erroneously, the term autoimmunity is often used for any disease in which the immune response causes tissue injury.

“Emerging genetic and immunological data suggest that Crohn’s disease is not an autoimmune disease disorder, and represents instead either an immune deficiency or a secondary immune response to altered intestinal microbiota [bacteria].”  (Behr et al., 2010)

It’s nice to have this “autoimmunity issue” now out of the way.  But there is a good chance you have been told other things that are probably just as incorrect.

Perhaps you been told that you have some sort of “aberrant response to normal gut bacteria,” making you very sick and in need of expensive medications.  Not so fast!  True, you may be very sick.  And true, you may need expensive medications.  But you have always had gut bacteria that seemed to be your friends and not out to kill you.  I’m not so sure we should embrace this notion.  I am not alone.

“The notion that Crohn’s disease occurs as an aberrant reaction to commensal (typically present) microbiota in genetically susceptible hosts is widely regarded by physicians as fact.  Yet although it is undisputed that Crohn’s disease is immune-mediated, an aberrant reaction to one’s own native flora is far from proven.”  (Campbell et al., 2012)

Certainly, this sort of thing (aberrant responses to normal, aka   commensal bacteria) does happen in a disease as complex as Crohn’s and should certainly be considered and be addressed, but this causation theory sets aside so much evidence indicating that Crohn’s disease is, indeed, something else, something more than a disordered, perhaps “over-exuberant” reaction to normal bacterial flora.

Actually, it is something less.  It is a less-than-adequate immune response to bacteria on several levels, leading to a failure to destroy those that have invaded, that more closely defines the disease we call Crohn’s.  This is why things that impair the immune response to bacteria, such as smoking, and things that damage the lining of the gut, like NSAIDs (aspirin and ibuprofen, for example), greatly increase the risk of contracting Crohn’s.  Astonishingly, smoking increases the risk of Crohn’s disease five-fold (Marks, et al., 2010), and the regular use of aspirin increases the risk of Crohn’s 6-fold (McLarnon, 2011).  Let’s continue.

Injury, combined with dampened immune responses, can allow bacteria to advance.  And if certain bacteria get the chance, they will find a nice little niche inside of you and start a family.  Should this occur, it will take war—War!—to try to contain and eliminate the threat.  This war, a war waged against an invader—an invader that somehow found its way inside an immunodeficient host—is the disease that you have.  You have a disease that is, in effect, a desperate attempt to save you.  But the immune system, your immune system, is operating at a disadvantage, for you have an immunodeficiency disease.   Now follow along closely!

 

Crohn’s as an immunodeficiency disease

 

“Both ulcerative colitis and Crohn’s disease are characterized by the disruption of the epithelial cell barrier and the dysfunction of the immune system.  Disruption of the intestinal epithelial barrier in IBD allows the invasion of commensal bacteria.  This leads to influx of inflammatory cells and their constant activation.”  ~Kristek and Loscher, 2014, emphasis added

 

“Neutrophils provide the first cellular line of immune defense once epithelial barriers have been breached and predominate in the initial phase of acute inflammatory reactions.  Macrophages become the principle cells in the chronic phase, and eosinophils have a specialized role in parasite infections.”  ~Rahman et al., 2008

 

“We found that neutrophil accumulation was grossly impaired in all Crohn’s patients regardless of their clinical phenotype . . . .  This indicated that the failure of acute inflammation was a generic problem in Crohn’s disease and not attributed to any single genetic lesion.

 

“We postulate that it is the combination of a weak genetic reaction      to mucosal breach together with a failure of secondary protective mechanisms that predisposes to Crohn’s.”  ~Marks et al., 2010, emphasis added 

 

One of the “defects” identified in Crohn’s patients is of great significance. It makes you less competent in dealing with bacterial threats.  And once again, we’re talkin’ neutrophil!  The neutrophil plays a key role in the pathogenesis of Crohn’s, not because the neutrophil is evil or misguided, but because it is—well, you’ll see.

In Crohn’s, there is a recognized delay in mobilization of the neutrophil to the field of battle.   An injury may have occurred.  An invasion is under way.  A rapid response is needed.  Bacteria are everywhere!  But due to a delay in the recruitment of neutrophils, bacteria are given an advantage.  The neutrophils involved are not necessarily defective, they are just not effectively mobilized (Smith et al., 2009), in which case things can only go from bad to worse.

“Should the digestive capacity of neutrophils be impaired or overwhelmed, a second chronic phase of inflammation commences.  To limit the collateral spread of potentially noxious material, undigested microorganisms and particulates are surrounded by macrophages.  These secrete cytokines that attract and activate T-lymphocytes [a type of white blood cell], thus stimulating the adaptive immune response.  The foci of macrophage clusters with the surrounding mantle of lymphocytes constitutes a granulomata and can be viewed as a secondary protective, containing response should the acute inflammatory reaction fail.”  (Rahman et al., 2008)

“The consequence of this delayed recruitment results in bacteria remaining in the tissue, macrophages engulf the remaining bacteria and fecal matter inciting an inflammatory response culminating in granuloma formation.”  (Petersen and Smith, 2013)

In patients with Crohn’s, it is common to find what are called granulomas—formations of immune cells present in the lining of the bowel, indicating there an epic battle has been fought . . . and continues (Petersen and Smith, 2013).  Granulomas are not scar tissue, as one might assume.  They are dynamic, defensive structures.  The very existence of a granuloma is in some respects a sign of immunodeficiency.  It is also a sign that the immune system is fighting the good fight.

“The dynamic structure of the granuloma servers to protect the body from microbiological challenge.  This organized aggregate of immune cells seeks to contain this challenge and protect against dissemination, giving host immune cells a chance to eradicate the threat.”  (Peterson and Smith, 2013)

My intention, here, is to drive home the concept that Crohn’s disease is a battle between pathogen and host . . . and the host is impaired.  The story of the neutrophil attests to this fact.  The initial responses against bacteria have been ineffectual, things have gone from bad to worse, and you have Crohn’s.  The reason?  In Crohn’s, macrophage function is impaired.  The very cell that coordinates, regulates, and eats the living and the dead, is somehow incapable of performing effectively.

 

Defective macrophage function is fundamental to the pathogenesis of Crohn’s

 

“Recent work provides evidence of a failure of acute inflammation in Crohn’s disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release.

 

CD (Crohn’s disease) is a complex disease comprising multiple stages and phenotypes.  We recently demonstrated that CD patients clear bacteria less rapidly than control individuals, which was associated with delayed recruitment of neutrophils and defective macrophage function.”  ~Sewell et al., 2012, emphasis added

 

“When macrophages in the inflamed intestine show an enhanced pro-inflammatory phenotype, their ability to eradicate intracellular pathogens is decreased as their phagocytosis [of bacteria] is significantly reduced.  This probably accounts for recurrent infection in IBD patients with pathogens that target macrophages . . . .”  ~Kristek and Loscher, 2014, emphasis added   

 

The macrophage is a most important cell.  In all probability, life as we know it would not exist without the macrophage.  They are called “the sentinels of the immune system,” and for good reason (Sewell et al., 2012).   The macrophages that live and work within our tissues are constantly on the alert for even the slightest hint that bacteria are on the move.  And, should a threat be identified, they will know exactly what to do.  (We can only hope.)  In response to a threat, the macrophage will signal, by the release of messenger molecules called cytokines and chemokines, for neutrophils to change their plans and show up to do battle, and show up in great numbers.  (Circulating about the bloodstream, seemingly hours on end, gets pretty boring after a while, so they are actually quite eager to do something new and exciting.)  But there is a problem associated with Crohn’s that may determine the fate of an infection, and it has to do with macrophage-mediated neutrophil recruitment.  I’ve mentioned this before (and I’ll probably mention it again).

“These leucocytes [referring to neutrophils] constitute the first line of defense after microbes and organic debris breach the mucosal barrier.  A delay in their accumulation might lead to abnormal presence of exogenous material within the bowel wall.”  (Harbord et al., 2006)

“The neutrophils themselves appear functionally normal.  And their diminished migration to acute sites to the skin or bowel have been attributed to defective local cytokine production.   These mediators [cytokines] are primarily secreted by resident tissue macrophages . . . .”  (Smith et al., 2009, emphasis added)

I can’t imagine how unfortunate it is to have a macrophage community that is defective or impaired, but perhaps you can, for you have Crohn’s.  A defective or impaired macrophage will not serve you well.  It sounds like, as a result of impaired neutrophil recruitment caused by the macrophage, the stage may have been set for you to experience a disease most dreadful.

I don’t want to beat this neutrophil business to death—actually I would like to, but time will not allow.  Besides, I’m fairly confident that by now you have come to the realization that a delay in neutrophil recruitment has never really been your friend.  It may be one of the primary reasons you have the immunodeficiency disease that you now have.  Lay the blame, not on the neutrophil.  Lay the blame at the feet of the macrophage.  Good luck with that!  Macrophages do not have feet.  But they certainly can have defects!  Major defects!

A brief discussion of defects that negatively affect the macrophage in Crohn’s follows, then we can move on.  We must move on.  I can’t wait to take you to the next chapter.  It will be quite a ride.  So, briefly:

The macrophage is a very complex cell (it is also very ugly).  Many are the defects it may possess.  One major defect, present in approximately 20% to 40% of patients with Crohn’s, is a defect that impairs the ability of the macrophage to detect the presence of a pathogen that has gained entry within its cell wall and trigger the necessary signaling events required to properly destroy the invader (Vavricka and Rogler, 2009).  Another major defect impairs the ability of the macrophage to withhold essential nutrients from the pathogen once it has arrived within (Nairz et al., 2014).  If this “nutrient withholding” business is impaired, I see nothing but trouble.  Trouble!  Another defect—actually a variety of defects that a macrophage may possess—relates to the ability of the macrophage to properly signal in order to favorably regulate the various inflammatory responses required in the battle against evil (Marks et al., 2010).

Although it’s not necessarily a defect, “Bacteria can also suppress macrophage responses.”  (Knight et al., 2008) Perhaps this form of immunodeficiency is why the presence of one type of bacteria may favor the persistence of another type of bacteria (Flanagan et al., 2011).  And while some bacteria have the power to suppress macrophage killing, other bacteria seem to have the power to amplify certain macrophage responses.

One Crohn’s-associated bacterium, a member of the E. coli family, can somehow induce the macrophage to produce high levels of the proinflammatory cytokine TNF-α, in a strategy “essential” to their replication within this host cell (Carrière et al., 2014).  This is a most unusual form of immunodeficiency—a macrophage so out of control that it favors pathogen persistence, and at a time when the macrophage would like nothing more than to kill.  In consideration of all that can go wrong with the macrophage, I would put the macrophage on my prayer list, if I were you.

I hope you are getting the message, loud and clear.  It is immunodeficiency, immunodeficiency on several levels, that answers the question, “What is it that I have?”  Certainly by now, you have come to the realization that this immunodeficiency disease called Crohn’s is one very complex disease.  I will help you understand it more fully in the following chapter.  But before we enter the next chapter, consider the following:

“The case for an immunodeficiency origin for Crohn’s disease is being constantly strengthened, with profound implications for the clinical management of this disorder.”  (Marks et al., 2009, emphasis added)

“This innate immunodeficiency hypothesis may also have therapeutic implications.  The current immunosuppressant-based treatment of Crohn’s disease reduces inflammation in the advanced phase, but could exacerbate its underlying abnormalities and contribute to maintaining a reduced acute inflammatory response.”  (Fava and Danese, 2010)




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BOOK REFERENCES:

Behr MA 2010 The Path to Crohn’s Disease: Is Mucosal Pathology a Secondary Event? Inflam Bowel Dis; May; 16(5):896–902

Behr MA, Divangahi M, Lalande J-D 2010 What’s in a Name?  The (Mis)Labelling of Crohn’s as an Autoimmune Disease.  Lancet 376:202–203

Campbell J, Borody TJ, Leis S 2012 The Many Faces of Crohn’s Disease: Latest Concepts in Etiology. Open Journal of Internal Medicine 2(2012):107–115

Carrière J, Darfeuille-Michaud A, Nguyen HT 2014 Infectious Etiopathogenesis of Crohn’s Disease. World J Gastroenterol; September 14; 20(34):12102–12117

Casanova J-L, Able L 2008 Revisiting Crohn’s Disease as a Primary Immunodeficiency Disease. J. Exp. Med. 206(9):1839–1843

Fava R, Danese S 2010 Bacterial Clearance in Crohn’s Disease Pathogenesis. Nature Reviews Gastroenterology and Hepatology; March; 7(3):126–128

Flagagan P, Campbell BJ, Rhodes JM 2011 Bacteria in thePathogenesis of Inflammatory Bowel Disease. Biochem. Soc. Trans. 39(4):1067–1072

Harbord MWN, Marks DJB, Forbes A, Bloom SL, Day RM, Segal AW 2006 Impaired Neutrophil Chemotaxis in Crohn’s Disease Relates to Reduced Production of Chemokines and Can Be Augmented by Granulocyte-Colony Stimulating Factor. Aliment Pharmacol Ther 24:651–660

Knight P, Campbell BJ, Rhodes JM 2008 Host-Bacterial Interaction in Inflammatory Bowel Disease. British Medical Bulletin 88:95–113

Kristek M, Loscher CE 2014 The Emerging Roles of Intestinal Macrophages in Sickness and in Health.  Periodicum Biologorum 116(2):125–129

Marks DJB, Rahman FZ, Sewell GW, Sewell AW 2010 Crohn’s Disease: An Immune Deficiency State. Clinic Rev Allerg Immunol 38:20–31

McLarnon A 2011 Regular, Prolonged Aspirin Use and an Increased Risk for Crohn’s Disease. Nature Reviews Gastroenterology & Hepatology; September; doi:10.1038/nrgastro.2011.147

Nairz M, Haschka D, Demetz E, Weiss G 2014 Iron at the Interface of Immunity and Infection. Frontiers in Pharmacology; July; 5:1–10

Petersen HJ, Smith AM 2013 The Role of the Innate System in Granulomatous Disorders. 2013 Frontiers in Immunology; May; 4 (Article 120):1–11

Rahman FZ, Marks D JB, Hayee BU, Smith AM, Bloom SL, Segal AW 2008 Phagocyte Dysfunction and Inflammatory Bowel Disease.  Inflamm Bowel Dis 14:1443–1452

Sewell GW, Rahman FZ, Levine AP, Jostins L, Smith PJ, Walker AP, Bloom SL, et al 2012 Defective Tumor Necrosis Factor Release from Crohn’s Disease Macrophages in Response to Toll-Like Receptor Activation: Relationship to Phenotype and Genome-Wide Association Susceptibility Loci. Inflamm Bowel Dis 18(11):2120–2127

Sheikh SZ, Plevy SE 2010 The Role of the Macrophage in Sentinel Responses in Intestinal Immunity. Curr Opin Gastroenterol; November; 26(6):578–582

Smith AM, Rahman FZ, Hayee BH, Grahm SJ, Marks DJ, Sewell GW, Palmer CD, et al 2009 Disordered Macrophage Cytokine Secretion Underlies Impaired Acute Inflammation and Bacterial Clearance in Crohn’s Disease. J. Exp Med. 106(9):1883–1897

Vavricka SR, Rogler G 2009 New Insights into the Pathogenesis of Crohn’s Disease: Are They Relevant for Therapeutic Options? Swiss Med Weekly 139(37–38):527–534

© 2016, Eugene L. Heyden, RN

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