A discussion on Cystic Fibrosis, pathologies and monogenic diseases – Festive City

Published: 2019/12/04 Number of words: 3516

Section 1: Imagine that you had to give a lecture on the pathogenesis of Cystic Fibrosis. Produce a short but comprehensive summary of the lecture. Do not go into therapy etc.

Pathogenesis of Cystic Fibrosis (CF):

Cystic Fibrosis, an inherited disease (autosomal recessive) usually involves disruption of the exocrine function of the pancreas but also affects intestinal glands, biliary tree, bronchial glands and sweat glands. Occurrence in both males and females equally causes disruption of their reproductive capabilities.

A mutation in the gene (7q31.2) encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein results in the disease occurrence. Of the 1500 identified CFTR mutations, the class II mutations involving the absence of a Phenylalanine at position 508(Phe508del) accounts for the most common type of functional alteration that results in majority cases of Cystic Fibrosis. CFTR mutations can be grouped as in table 1(Ratjen, 2009).

Table 1.

Class of CFTR MutationsCharacteristics
ICFTR not synthesised.
IICFTR inadequately synthesised.
IIICFTR not regulated.
IVCFTR shows abnormal conductance.
VCFTR has partially defective production.

The fact that CFTR dysfunction leads to the phenotypic disease can be explained by simply narrating the hypotheses concluded from various researches.

High salt Hypothesis: When the functional CFTR is absent, retention of the sodium and chloride is tremendously increased and this results in increased concentration of chloride in the periciliary layer (Zabner et al., 1998). Such an event leads to the functional disruption of important innate antibiotic molecules such as human β-defensin 1, thus permitting the persistent occurrence of bacteria that are normally cleared from the airway surface liquid (Goldman et al., 1997).

Low-volume Hypothesis: Another hypothesis involving the CFTR dysfunction reveals that excess of sodium and water reabsorption results in the dehydration of the periciliary liquid layer and abolishes the mucus transport. Such a failure causes a massive reduction of the lubricating layer between the epithelium and the mucus, thus inhibiting the normal ciliary function of cough clearance. Plaque formation occurs and harbours bacteria particularly the Pseudomonas aeruginosa (hypoxic niche) that initiates the Cystic Fibrosis airway infection (Matsui et al., 1998). The airway surface liquid volume regulation is dependent on ATP, a single extracellular signaling system and a dysregulation increases susceptibility to disease causing pathogens (Boucher, 2007). As a result of the occurrence above, a loss of chloride efflux thus prevents the epithelium from regulating the airway surface liquid volume to normal levels.

Dysregulation of the Host inflammatory response: This is considered as the most basic defect in the Cystic Fibrosis. The abolishment of cAMP-stimulated anion transport due to non-functional CFTR in the apical membranes of epithelial cells results in the bacterial accumulation in mucus. These bacteria release Flagellin that triggers the Toll-like receptor 5 and the NF-B signaling pathway, thus resulting in a hyperinflammatory response involving the release of proinflammatory cytokines that recruit neutrophils to the infected regions and damage CF lung tissue. Chloride, bicarbonate and glutathione insufficiencies affect the airway surface liquid. Loss of apical CFTR results in the hyperpolarisation of the membrane potentials leading to increase in the cytosolic and intracellular calcium levels and the NF-B signaling (Machen, 2006). An imbalance is observed between the proinflammatory molecules (interleukin 8, interleukin 6, tumour necrosis factor α and arachidonic acid metabolites) and the anti inflammatory substances (interleukin 10, lipoxin, docosahexaenoic acid). Platelet hyper-reactivity and neutrophil apoptosis abnormalities have also been reported in association with CF (Reviewed in O’Sullivan and Freedman, 2009).

Predisposition to infection: A comparative study of the interaction of the P. aeruginosa in normal hosts and CF patients postulates this hypothesis. In normal hosts the bacteria binds to the functional CFTR and initiates an immune response where as in CF patients the P. aeruginosa and Staphylococcus aureus attach to the airway epithelium causing no CFTR mediated immune response. Such activity is associated with an increase in asialo-GM1 in apical cell membranes that facilitate the bacterial attachment and display decreased self-limiting response (Reviewed in O’Sullivan and Freedman, 2009).

Summary: Though most aspects of the CF pathophysiology have been clarified, yet many intriguing facts still need to be considered. Thus summarising the cascade of pathophysiology of CF, the steps include the CFTR gene being defective, that results in defective ion transport and depletion of airway surface liquids. This causes a defective mucociliary clearance and the obstructive mucous results in infection and inflammation, thus explaining the pathogenesis of Cystic Fibrosis (Reviewed in Ratjen, 2009).


1. Boucher, RC. (2007) Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annual Review of Medicine, 58, pp. 157–70.

Review on the pathogenesis of cystic fibrosis with detailed explanations related to disease.

2. Goldman, MJ., Anderson, GM., Stolzenberg, ED., Kari, UP., Zasloff, M., Wilson, JM. (1997) Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell, 88, pp. 553–60.

The original source of information on high salt hypothesis explaining the effect of innate antibiotic molecules.

3. Machen, TE. (2006) Innate immune response in CF airway epithelia: hyperinflammatory? Am J Physiol Cell Physiology, 291, pp. C218–30.

Clear explanations in relation to the dysregulation of host inflammatory responses.

4. Matsui, H., Grubb, BR., Tarran R., Randell SH., Gatzy, JT., Davis, CW. and Boucher, RC. (1998) Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell, 95, pp. 1005–15.

Detailed description on low volume hypothesis explains the effect of depleted periciliary liquid layer.

5. O’Sullivan, BP. and Freedman, SD. (2009) Cystic fibrosis. Lancet, 373 pp. 1891-904.

Latest review dealing with the hypotheses for pathogenesis and also explanative about the original papers related to the various hypotheses.

6. Ratjen FA. (2009) Cystic Fibrosis: Pathogenesis and Future Treatment Strategies. Respiratory Care, 54(5), pp. 595– 602.

Latest review on the pathogenesis of Cystic fibrosis explaining the effects in lungs and also the genetic aspects involved in dysregulatory activities during the disease.

7. Zabner, J., Smith, JJ., Karp, PH., Widdicombe, JH., Welsh, MJ., (1998) Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell, 2, pp. 397–403.

The original source of information on high salt hypothesis explaining the effect in absence of functional CFTR.

SECTION 2: Describe in details three pathologies characterised by Type IV immune reactions.

Hypersensitivity is the body’s exaggerated response to an allergen. The type IV hypersensitivity is also called delayed type hypersensitivity (DTH) as it takes 2-3 days for reaction to develop after exposure is a cell mediated immune response. The reaction does not involve antibodies but is due to interaction of T cells with antigens. The T cells involved in reactions are the memory cells derived from prior stimulation to same antigen. Two common examples of DTH are the tuberculin type and contact type hypersensitivity (Playfair and Chain, 2009). The step wise activity in Type IV is as follows:

Antigen►►APC►►macrophage►►macrophage activated ►►granuloma formation

The tuberculin test, allergy to metal salts and small reactive chemicals coupled to haptens, rejection of transplanted organs and skin contact reaction to poison ivy are examples of type IV hypersensitivity.

Tuberculosis: Mycobacterium tuberculosis, an obligatory aerobic intracellular pathogen enters the host via the respiratory route. The alveolar macrophages cause phagocytosis of bacteria and cell mediated immunity develops and there is an influx of lymphocytes and activated macrophages into the lesion resulting in granuloma formation. These bacilli remain in the granuloma and may get reactivated (Reviewed in Raja, 2004). When the host fails to defend itself, the persisting antigen provokes a chronic local DTH reaction. Continuous release of cytokines from the sensitized T lymphocytes leads to macrophage accumulation many of which form epithelioid cells while others form multinucleate giant cells. Macrophages bearing bacterial antigen become targets for cytotoxic T-cells. Tissue damage occurs due to cytokine-activated macrophages. The Mantoux reaction is characterized by erythema and induration on injecting tuberculin into cell mediated immune individual. Chronic granulomas are results of the above (Delves and others, 2006).

Contact Dermatitis: This is a type of DTH response. It can occur in people who become sensitised while working with chemicals such as picryl chloride and chromates, formaldehyde, trinitrophenol, nickel, turpentine and active agents in various cosmetics and hair dyes. Poison oak and poison ivy are mediated by Th1cells. The mechanism involves the contact between the low molecular weight materials that are able to bind to the peptides within the MHC grooves on the surface of the Langherhans’ cells (antigen presenting cells) to form antigens. The Th1 cells sensitise to form sensitised Th1 cells. Subsequent interaction or exposure results in cytokine production that takes along time. Reaction is accompanied by edema of the epidermis with microvesicle formation. Skin testing is done to detect hypersensitivity. A patch test is used to diagnose patients with DTH (Kindt and others, 2007; Delves and others,2006)

Contact sensitivity (CS), a form of DTH having a T cell mediated response that occurs after exposure to haptens is characterised by subsequent leukocyte infiltration into tissue and edema on re exposure. A study on this was done to understand the function of mast cells and their role in contact hypersensitivity. (Norman et al., 2008)

Type 1 Diabetes mellitus: It is a metabolic disorder characterised by hyperglycemia and is associated with total or nearly deficient insulin due to pancreatic beta cell destruction. The pathogenesis involves the cytotoxic T lymphocyte infiltration that leads to insulitis and affects the beta cells. Activated T lymphocytes cause cytokines formation resulting in CD8+ cytotoxicity. The advances converge towards the goal of developing an antigen-specific immunotherapy for Type 1Diabetes (Tsai et al., 2008).

Summary: Cell mediated hypersensitivity has been demonstrated in fungal diseases such as candidiasis, dermatomycosis,coccidioidiomycosis and histoplamosis and parasitic disease leshmaniasis. Crohn’s disease and ulcerative colitis belonging to the inflammatory bowel disease (IBD) exist as entities resulting from dysregulated mucosal immune response to microbial antigens. Crohn’s disease is characterised by transmural granulomatous inflammation involving the entire wall form mucosa to serosa. There is development of fibrosis, micro perforations, and fistulas. Through out the gastrointestinal tract inflammation seen. Organ specific autoimmune diseases such as type 1 diabetes, is a cell mediated hypersensitivity reaction. Psoriasis and Sarcoidosis are also disorders of the delayed type of hypersensitivity (James, 2000). All of the above mentioned diseases demonstrate the type IV Hypersensitivity reactions.


1. Delves PJ., Martin SJ., BurtonDR., Roitt IM.(2006) Roitt’s Essential Immunolgy. 11th ed.Blackwell publishing.

The different types of type IV hypersensitivity reaction are explained along with clinical manifestations.

2. Fauci, Braunwald, et al.(2009). Harrison’s Principles of Internal Medicine, 17th Ed, vol. 1, 2. McGraw Hill Medical.

3. James, DG.(2000) A clinicopathological classification of granulomatous disorders. Post grad Med Journal, 76(898) Aug, pp. 457-465.

Detailed information on granuloma formation.

4. Kindt TJ., Goldsby RA. and Osborne BA.,(2007) Kuby Immunology. 6th ed. New York .W.H.Freeman and company.

5. Norman MU.,Hwang J,Hulliger S,Bonder CS,Yamanauchi J,Santamaria P and Kubes P. (2008) Mast Cells Regulate the Magnitude and the Cytokine Microenvironment of the Contact Hypersensitivity Response. Am J Pathology,172(6) June, pp.1638-1649.

Detailed explanation about contact hypersensitivity and mast cells functional role in ths hypersensitivity.

6. Playfair, JHL. And Chain, BM.(2009) Immunology at a Glance.9th ed. London,Wiley-Blackwell.

Introduction and background knowledge to type IV hypersensitivity.

7. Raja, A. (2004) Review article: Immunology of Tuberculosis. Indian Journal of Medical Research 120, October, pp. 213-232.

Detailed description of Tuberculosis and related immunological aspects.

8. Tsai, S., A. Shameli, Santamaria P. (2008). CD8+ T cells in type 1 diabetes. Adv Immunol 100, pp. 79-124.

SECTION 3: Describe in detail at least two monogenic diseases characterised by recurrent fever as main symptom.

The autoinflammatory diseases are a group of monogenic inflammatory diseases that were earlier summarised as ‘periodic fever syndromes’. Under this spectrum we have the familial Mediterranean fever, mevalonate kinase deficiency and tumor necrosis factor receptor associated disease, which are characterised by inflammation causing fever along with rashes, serositis, lymphadenopathy, arthritis and other clinical manifestations. The cryopyrinopathies are another group of autoinflammatory diseases that include familial cold associated syndrome, Muckle-Wells syndrome and the most severe form being the neonatal onset multisystem inflammatory disease.

Familial Mediterranean Fever (FMF): A recessively inherited, systemic autoinflammatory disorder called FMF, is characterised by recurrent fever and serosal along with synovial or cutaneous inflammation. The occurrence of this disorder is highest in eastern Mediterranean populations (Chae et al., 2009).

This monogenic disorder is caused by mutation in MEFV gene. The position of the MEFV gene is 16p13·3 that was obtained by positional cloning. MEFV gene contains ten exons encoding 781 amino acids, and the protein product has been named pyrin (or marenostrin).

So far, more than 60 FMF-associated mutations have been detected. The mutation occurs in C terminal end of the protein encoding B30.2 domain. Most mutations are single amino acid substitutions and a few are duplication/deletion mutations. Truncated protein product has been obtained only in two cases of mutation involving frameshift in exon2 and nonsense mutation in exon10 (Chae et al., 2009).

The expression of pyrin occurs in the granulocytes, monocytes, dendritic cells and synovial fibroblasts. It is a multi domain protein. The major role of pyrin is considered in the regulation of caspase-1 activation. The protein has various roles in innate immune response. Pyrin is cleaved by caspase-1. Translocation of the cleaved N terminal fragment to the nucleus enhances ASC-independent nuclear factor (NF)-κB activation.this is achieved by interactions with p65 NF-κB and IκB-α.

Colchicines treatment is the effective therapy is use for treating the patients. This prevents the inflammation by inhibiting neutrophil chemotaxis and reducing serum cytokine levels by suppressing the NF- κB activation (Chae et al., 2008). Research for new therapeutic targets to treat FMF is still ongoing.

TNF Receptor Associated Periodic Syndrome (TRAPS)/Familial Hibernian Fever:

It is an autosomal dominant disorder caused by mutation in the tumor necrosis factor receptor- 1 gene and the gene locus is 12p13.2. TRAPS was initially characterised to the Nordic origin but now the mutations are visible in many populations. Clinical symptoms include abdominal pain, rashes, lesions, thoracic and scrotal pain, arthritis, orbital oedema and conjunctivitis. A recurrent attack of periodic high fever is also observed (Grateau, 2004).

The cysteine substitutions associated with TRAPS mutations are localized to tow cysteine-rich domain (CRD) region of the protein.

Treatment with colchicine is not efficient enough as is in the case of FMF. Corticosteroids seem to be useful in many cases. TNF inhibitors are best for disease treatment. Etanercept,a fusion molecule, mimicsthe effect of the normal soluble TNF receptor and thus compensatesfor its deficit in TRAPS patients (Grateau, 2004).

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS):

This disease is also associated with recurrent fever and presence of high levels of serum immunoglobulin (Ig) D. Inflammatory attacks are a week long and recur every 4-8 weeks. Fever is the main symptom in the majority of the cases. Other clinical symptoms include abdominal pain, diarrhea, vomiting, non-destructive arthritis and various types of skin rashes.

HIDS is associated with an enzyme deficiency. The deficit of mevalonate kinase enzyme is due to mutation in the MVK gene (Grateau, 2004).

HIDS diagnosis can be done by measurement of enzyme in lymphocytes or presence in urine. Treatment involves corticosteroids that are only moderately efficient. New treatments are yet to be obtained.

Muckle –Wells Syndrome:

Muckle-Wells syndrome (MWS) is characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis (Dode et al., 2002). In Muckle -Wells syndrome urticaria and renal amyloidosis association is observed. Autosomal dominant mode of inheritance is observed.

Mutation in the CIAS1 gene codes for a protein cryopyrin/PYPAF1/NALP3 is underlying the three diseases, which are Muckle-Wells syndrome. familial cold autoinflammatory syndrome and chronic infantile neurological cutaneous and articular disease. Three domains are present and constitute a new family called PYPAF or NALP (Grateau, 2004). There is no efficient treatment yet but colchicine provides some relief to the arthropathy of Muckle-Wells syndrome.

Summary: All the above mentioned disease is associated with recurrent fever and their treatment is not well established. This has raised more generalquestion of how to organise trials for rare diseases. Elucidation of disease mechanism has already led to unraveling the unknown pathways. These are thus important examples of howrare diseases can help us in understanding the pathogenesisof more general phenomena.


1. Chae, JJ., Aksentijevich, I. and Kastner, DL.(2009) Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. British Journal of Haematology, 146(5) Sep, pp. 467-78.

Complete explanation about the entire scenario in and around the disease is obtained

2.Chae, JJ., Wood, G., Richard, K., Jaffe, H., Colburn, NT., Masters, SL., Gumucio, DL., Shoham, NG., Kastne,r DL.(2008) The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood, 112(5) Sep, pp.1794-803.

Information related to the cleavage of pyrin by caspase -1.and activation of NF- kappaB.

3. Dode, C.; Le Du, N.; Cuisset, L.; Letourneur, F.; Berthelot, J.-M.; Vaudour, G.; Meyrier, A.; Watts, R. A.; Scott, D. G. I.; Nicholls, A.; Granel, B.; Frances, C.; Garcier, F.; Edery, P.; Boulinguez, S.; Domergues, J.-P.; Delpech, M.; Grateau, G. (2002). New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. American Journal of Human Genetics, 70, pp.1498-1506.

Detailed information on Muckle-Wells syndrome related to the mutation and clinical symptoms observed.

4. Grateau, G.(2004) Review :Clinical and genetic aspects of the hereditary periodic fever syndromes. Rheumatology, 43(4) pp. 410-415.

Excellent information is presented on the entire topic with relevant detailing and clear understanding of the various types of recurrent fever diseases.

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