Scientific Reference Papers

SCIENTIFIC REFERENCE PAPERS 

Below a list of the most relevant papers regarding inflammation and particularly the mechanisms of action of BAFF and PAF and of their effects.

• Elevated B cell-activating factor of the tumour necrosis factor family in coeliac disease Fabris M. et al Scand J Gastroenterol. 2007 Dec;42(12):1434-9. doi: 10.1080/00365520701452225 https://www.ncbi.nlm.nih.gov/pubmed/17852877
• Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review. – Lied GA et al, Scand J Immunol. 2011 Jan;73(1):17. doi: 10.1111/j.13653083.2010.02470.x
  http://www.ncbi.nlm.nih.gov/pubmed/21128997
• B cell activating factor (BAFF) in the natural history of chronic hepatitis C virus liver disease and mixed cryoglobulinaemia. – Lake-Bakaar G et al., Clin Exp Immunol. 2012 Nov;170(2):2317. doi: 10.1111/j.13652249.2012.04653.x.
  http://www.ncbi.nlm.nih.gov/pubmed/23039894
• B cell activation factor (BAFF) is a novel adipokine that links obesity and inflammation. – Kym YH et al, Exp Mol Med. 2009 Mar 31;41(3):20816. doi: 10.3858/emm.2009.41.3.024.
  http://www.ncbi.nlm.nih.gov/pubmed/19293640 
• B cell-activating factor controls the production of adipokines and induces insulin resistance. – Hamada M et al., Obesity (Silver Spring). 2011 Oct;19(10):191522. doi: 10.1038/oby.2011.165. Epub 2011 Jun 23
  http://www.ncbi.nlm.nih.gov/pubmed/21701571 
• The role of platelet-activating factor in mesangial pathophysiology. – Reznichenko et al., Am J Pathol. 2015 Apr;185(4):88896. doi: 10.1016/j.ajpath.2014.11.025. Epub 2015 Feb 2.
  http://www.ncbi.nlm.nih.gov/pubmed/25655028 
• Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. – Vadas P et al., J Allergy Clin Immunol, January 2013 Volume 131, Issue 1, Pages 144–149
  http://www.jacionline.org/article/S0091-6749(12)01377-2/fulltext 
• Intestinal B cell-activating factor: an indicator of non-IgE-mediated hypersensitivity reactions to food? – Lied GA et al, Aliment Pharmacol Ther. 2010 Jul;32(1):6673. Epub 2010 Mar 26,
  http://www.ncbi.nlm.nih.gov/pubmed/20353497

BAFF and PAF two inflammatory cytokines that behave similarly.

• B cell activating factor (BAFF) and platelet activating factor (PAF) could both be markers of non-IgE-mediated reactions. – Piuri G, Soriano J, Speciani MC, Speciani AF (2013) Clin Transl Allergy 3:O5. doi: 10.1016/j.jaci.2007.07.033
  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723786/
• Two innovative inflammation biomarkers for the measurement of inflammation in pregnancy. – Piuri G, Bulfoni C, Mastricci AL, Speciani AF, Ferrazzi E (2014) Paper presented at the 24th European Congress of Perinatal Medicine (ECPM), Florence, 47June 2014 (pdf available on request).
• Individual Food Clusters Excess and Low-Grade Inflammation in Pregnancy. –Piuri G. Metabolic syndrome and complication of pregnancy, pp. 22-33 (2015) . doi: 10.1007/978-3-319-16853-1_2

Evidence of food reactivities and induction of tolerance

• Fritscher-Ravens A et al,Confocal Endomicroscopy Shows Food-Associated Changes in the Intestinal Mucosa of Patients With Irritable Bowel Syndrome Gastroenterology. 2014 Nov;147(5):1012-20.e4. doi: 10.1053/j.gastro.2014.07.046. Epub 2014 Jul 30 https://www.ncbi.nlm.nih.gov/pubmed/25083606
• Establishment of intestinal homeostasis during the neonatal period. – Stockinger S et al. (2011), Cell Mol Life Sci. 2011 Nov; 68(22):3699-712. doi: 10.1007/s00018-011-0831-2. Epub 2011 Sep 28 http://www.ncbi.nlm.nih.gov/pubmed/21952827
• Successful oral tolerance induction in severe peanut allergy. – Clark AT et al.,(20099 Allergy. 2009 Aug;64(8):1218-20. doi: 10.1111/j.1398-9995.2009.01982.x. Epub 2009 Feb 17 http://www.ncbi.nlm.nih.gov/pubmed/19226304
• Specific oral tolerance induction in children with very severe cow’s milk-induced reactions. – Longo G. et al., (2008) J Allergy Clin Immunol. 2008 Feb;121(2):343-7. Epub 2007 Dec 26 http://www.ncbi.nlm.nih.gov/pubmed/18158176
• Oral tolerance induction by low-dose nickel solution. Effective and safe treatment of nickel-induced pompholyx. – Speciani AF et al., (2001) Allergy, 2001; 56(s68):146

Keeping in mind the close interconnection between BAFF and food-related inflammation, as documented by Lied on Alimentary Pharmacology and Therapeutics in 2010 (cited above), we have also developed a definition of the Personal Food Profile.
This definition has its birth from the innovative point of view presented in an immunological context, linking the growth of IgG towards different foods to the proportional consumption of those foods in the individual nutrition.

The scientific support about IgG related to food comes from Finkelman and Khodoun.

IgG may be responsible for a process of attenuation of the immune response, but at the same time, this class of immunoglobulins is also able to activate inflammatory processes.

• Anaphylaxis: lessons from mouse models. – Finkelman FD (2007)J Allergy Clin Immunol 120:506–15– quiz 516–7. doi: 10.1016/j.jaci.2007.07.033
  http://www.ncbi.nlm.nih.gov/pubmed/17765751
• Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis. – Khodoun MV, Strait R, Armstrong L, et al. (2011) Proc Natl Acad Sci USA 108:12413–12418. doi: 10.1073/pnas.1105695108
  http://www.ncbi.nlm.nih.gov/pubmed/21746933
• Nutrition around the clock and inflammation: the right food at the right time makes the difference (Speciani A., Piuri G.)  in Metabolic Syndrome and Complications of Pregnancy: The Potential Preventing Role of Nutrition – Ferrazzi E., Sears B. Eds.: Springer Science Publisher, New York, Heidelberg, 2015
• Human IgE-independent systemic anaphylaxis -Finkelman FD et al, J Allergy Clin Immunol. 2016 Jun;137(6):1674-80. doi: 10.1016/j.jaci.2016.02.015. Epub 2016 Apr 26 https://www.ncbi.nlm.nih.gov/pubmed/27130857
• IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF. – Kang S et al, J Immunol. 2016 Jan 1;196(1):196-206. doi: 10.4049/jimmunol.1402527. Epub 2015 Nov 30 http://www.jimmunol.org/content/196/1/196.abstract

The levels of IgG towards foods reflect nutritional exposure as shown by Ligardeen. He demonstrates how the IgG for food are indicators of excess or prevalence in terms of frequency or quantity of consumption. Also to note is our team’s comment, along with Prof. Ferrazzi:

• IgG and IgG4 antibodies in subjects with irritable bowel syndrome: a case control study in the general population – Ligaarden SC, Lydersen S, Farup PG (2012). BMC Gastroenterol 12:166. doi: 10.1186/1471-230X-12-166 http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-12-166

• IgG levels to food correlate with nutritional exposure to food antigens but a methodological weakness of this research prevents the recognition of yeast-related foods as a possible cause of Irritable Bowel Syndrome (IBS). – Speciani AF, Piuri G, Ferrazzi E (2014)  – Comment to “IgG and IgG4 antibodies in subjects with irritable bowel syndrome: a case control study in the general population”. Ligaarden SC, Lydersen S, Farup PG. BMC Gastroenterology 2012, 12:166. BMC Gastroenterol. doi: 10.1186/1471-230X-12-166
  http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-12-166/comments

The definition of Personal Food Profile is proposed with a new criteria for organizing foods, following “analogy clusters”, defined Great Food Groups, as emerged by the epidemiological and statistical reading of the IgG levels and statistically analyzed by Dr Soriano (Duke University, NC- USA).

• Five great food clusters of specific IgG for 44 common food antigens. A new approach to the epidemiology of food allergy – Speciani AF, Soriano J, Speciani MC, Piuri G (2013). Clin Transl Allergy 3:P67. doi: 10.1186/2045-7022-3-S3-P67 http://ctajournal.biomedcentral.com/articles/10.1186/2045-7022-3-S3-P67
• A larger study of food-related IgG confirms the possible new epidemiological approach to non-IgE-mediated reactions and suggests five great food clusters – Speciani AF, Piuri G, Soriano J, Ferrazzi E (2014) Clinical and Translational Allergy 2015 5(Suppl 3):P39 DOI: 10.1186/2045-7022-5-S3-P3
  http://ctajournal.biomedcentral.com/articles/10.1186/2045-7022-5-S3-P39

The reference to food is strictly linked to the measurement of the levels of inflammation, in an evolutionary view of the food reactions (antibodies for “food knowledge and recognition”, not antibodies against food).
A recent paper published by Speciani and Piuri highlights the integration between the measurement of inflammation level and the detection of the Personal Food Profile in order to suggest the correct nutritional plan for everybody.

• Measuring Biomarkers for an Innovative Personal Food Profile – Speciani AF and Piuri G. (J Am Coll Nutr. 2015;34 Suppl 1:34-8. doi: 10.1080/07315724.2015.1080109
  http://www.ncbi.nlm.nih.gov/pubmed/26400432

The importance of a therapeutic perzonalized diet

• Personalized Nutrition by Prediction of Glycemic Responses– Zeevi D et al, Cell. 2015 Nov 19;163(5):1079-94. doi: 10.1016/j.cell.2015.11.001.https://www.ncbi.nlm.nih.gov/pubmed/26590418

Over the last few years, many conditions have been recognised as connected with BAFF and/or PAF affecting different organs and systems. In this way, it has been possible to correlate food intake with well-defined health conditions or diseases, such as:

1. Autoimmune diseases
2. Dermatologic disorders (Psoriasis, Discoid Lupus Erythematosus, Systemic Lupus Erythematosus, Systemic sclerosis, Behcet’s syndrome, Alopecia areata, Eczema, Atopic dermatitis, Rosacea)
3. Ophthalmological disorders
4. Various forms of arthritis and osteoarthritis
5. Irritable Bowel syndrome
6. Inflammatory Bowel Disease
7. Migraine
8. Metabolic syndrome

and also in physiological conditions, like

1. Pregnancy

Below the list of the most relevant papers highlighting the relation between BAFF, PAF and health conditions or diseases.

Autoimmunity:

• Cell Activating Factor (BAFF) and BAFF Receptor Expression in Autoimmune and Nonautoimmune Thyroid Diseases. Campi I et al, Thyroid. 2015 Sep;25(9):1043-9. doi: 10.1089/thy.2015.0029. Epub 2015 Aug 13. https://www.ncbi.nlm.nih.gov/pubmed/26214745
• Overexpression of the Cytokine BAFF and Autoimmunity Risk. Steri M. et al, N Engl J Med. 2017 Apr 27; 376(17): 1615-1626. doi:10.1056/NEJMoa1610528 https://www.ncbi.nlm.nih.gov/pubmed/28445677

Dermatology:

• Receptor antagonist of platelet activating factor inhibits inflammatory injury induced by in situ formation of immune complexes in renal glomeruli and in the skin. – Camussi G et al., J Lab Clin Med. 1987 Aug;110(2):196-206 http://www.ncbi.nlm.nih.gov/pubmed/2955066

Psoriasis:

• BAFF is elevated in serum of patients with psoriasis: association with disease activity – Samoud ElKissi S et al., Br J Dermatol. 2008 Sep;159(3):7658. doi: 10.1111/j.13652133.2008.08737.x. Epub 2008 Jul 10. http://www.ncbi.nlm.nih.gov/pubmed/18637006

Discoid Lupus Erythematosus:

• Differential expression of BAFF and its receptors in discoid lupus erythematosus patients – Chong BF et al., J Dermatol Sci. 2014 Mar;73(3):21624. doi: 10.1016/j.jdermsci.2013.11.007. Epub 2013 Nov 16.
  http://www.ncbi.nlm.nih.gov/pubmed/24315762

Systemic Lupus Erythematosus:

• Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus. 2016 May;25(6):582-92. doi: 10.1177/0961203315608254. Epub 2015 Sep 29. Salazar-Camarena DC et al. https://www.ncbi.nlm.nih.gov/pubmed/26424128

Systemic sclerosis:

• Elevated serum APRIL levels in patients with systemic sclerosis: distinct profiles of systemic sclerosis categorized by APRIL and BAFF – Matsushita T et al, J Rheumatol. 2007 Oct;34(10):205662. Epub 2007 Sep 15.
  http://www.ncbi.nlm.nih.gov/pubmed/17896803

Behcet’s syndrome: 

• Expression of TNFα, APRIL and BCMA in Behcet’s disease – Shaker OG et al., J Immunol Res. 2014;2014:380405. doi: 10.1155/2014/380405. Epub 2014 Nov 5.
  http://www.ncbi.nlm.nih.gov/pubmed/25759827
• Serum BAFF levels and skin mRNA expression in patients with Behçet’s disease. – Hamzaoui K et al., Clin Exp Rheumatol. 2008 Jul-Aug;26(4 Suppl 50):S64-71. http://www.ncbi.nlm.nih.gov/pubmed/19026118

Alopecia Aerata:

• B cell activating factor and Thelper 17 cells: possible synergistic culprits in the pathogenesis of Alopecia Areata – Elela MA et al., Arch Dermatol Res. 2016 Mar;308(2):11521. doi: 10.1007/s004030161617z. Epub 2016 Jan 21,
  http://www.ncbi.nlm.nih.gov/pubmed/26796544

Eczema:

• The Expression of BAFF, APRIL and TWEAK Is Altered in Eczema Skin but Not in the Circulation of Atopic and Seborrheic Eczema Patients. – Chen et al., PLoS One 2011; 6(7): e22202 http://www.ncbi.nlm.nih.gov/pubmed/21765951

Atopic Dermatitis

• Increased serum B cell-activating factor level in children with atopic dermatitis. – Jee HM et al., Clin Exp Dermatol. 2010 Aug;35(6):593-8. doi: 10.1111/j.1365-2230.2009.03635.x Epub 2009 Oct 23 http://www.ncbi.nlm.nih.gov/pubmed/19874366
• Oral tolerance inhibits atopic dermatitis-like type 2 inflammation in mice by modulating immune microenvironments –Baek JO et al, Allergy. 2017 Mar;72(3):397-406. doi: 10.1111/all.12960. Epub 2016 Jul 22 https://www.ncbi.nlm.nih.gov/pubmed/27325577

Rosacea:

•  Inflammatory bowel disease is associated with an increased risk of inflammatory skin diseases: A population-based cross-sectional study. – Miri Kim et al Journal of the American Academy of Dermatology, 2017 Jan; 76, Issue 1, Pages 40–48 https://www.ncbi.nlm.nih.gov/labs/articles/27793451/ doi: 10.1016/j.jaad.2016.08.022
• Risk of inflammatory bowel disease in patients with rosacea: Results from a nationwide cohort study in Taiwan http://www.jaad.org/article/S0190-9622(16)31182-3/fulltext Wu et. al JAAD. 2017 May; 76 (5): 911-917

BAFF and TNF-alfa are very similar (They both belong to the TNF superfamily) and share a lot of actions. The experimental evidence of a good action of TNF-alfa inhibitors in the treatment of ocular rosacea allows us to use the nutritional approach in order to reduce BAFF, PAF and other cytokines in order to treat, with a personalized approach, the ocular complications of rosacea

•  Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients. https://www.ncbi.nlm.nih.gov/pubmed/25731720 Sanf FL et al, Dermatol Ther. 2015 May-Jun;28(3):158-65. doi: 10.1111/dth.12222. Epub 2015 Mar 3,

Ophtalmology:

Here is described the phenotypic profile of BAFF activation in lacrimal problems:

• Potentially pathogenic immune cells and networks in apparently healthy lacrimal glands – Mircheff AK et al., Ocul Surf. 2015 Jan;13(1):4781. doi: 10.1016/j.jtos.2014.06.003. Epub 2014 Nov 6. http://www.ncbi.nlm.nih.gov/pubmed/25557346

Here the connection of BAFF activation in all allergic conjunctivitis and in conjunctival epithelial cells:

• Evaluation of dectin and BAFF expression in conjunctival epithelial cells – Yoshida K et al, Nippon Ganka Gakkai Zasshi. 2014 Apr;118(4):36877 http://www.ncbi.nlm.nih.gov/pubmed/24864436

BAFF is also involved in many immune and inflammatory chronic diseases (like sarcoidosis):

• Elevated serum BAFF levels in patients with sarcoidosis: association with disease activity – Ueda-Hayakawa I et al, Rheumatology (Oxford). 2013 Sep;52(9):165866. doi: 10.1093/rheumatology/ket186. Epub 2013 May 17 http://www.ncbi.nlm.nih.gov/pubmed/23685362

Anti-inflammatory drugs (like chloroquine) have an effect on dry eye because they reduce the levels of BAFF:

• Hydroxychloroquine improves dry eye symptoms of patients with primary Sjogren’s syndrome – Yavuz S. et al., Rheumatol Int. 2011 Aug;31(8):10459. doi: 10.1007/s0029601014154. Epub 2010 Mar 23. http://www.ncbi.nlm.nih.gov/pubmed/20309693
• Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome.Thompson N . et al. Rheumatology (Oxford). 2016 Sep;55(9):1548-55. doi: 10.1093/rheumatology/kev420. Epub 2016 Jan 20. https://www.ncbi.nlm.nih.gov/pubmed/26790457
• Association of BAFF and IL-17A with subphenotypes of primary Sjögren’s syndrome. Deng F et al. Int J Rheum Dis. 2016 Jul;19(7):715-20. doi: 10.1111/1756-185X.12569. Epub 2015 May 4. http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.12569/abstract
• Neuropathic ocular pain: an important yet underevaluated feature of dry eye.Galor A. et al, Eye (Lond). 2015 Mar; 29(3): 301–312. Published online 2014 Nov 7. doi:  10.1038/eye.2014.263 https://www.ncbi.nlm.nih.gov/pubmed/25376119
• Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Lindenlaub T et al, Brain Res. 2000 Jun 2;866(1-2):15-22 https://www.ncbi.nlm.nih.gov/pubmed/10825476
• Neutralization of Ocular Surface TNF-α Reduces Ocular Surface and Lacrimal Gland Inflammation Induced by In Vivo Dry Eye. Ji VW et. al. Investigative Ophthalmology & Visual Science November 2013, Vol.54, 7557-7566. doi:10.1167/iovs.12-11515 https://www.ncbi.nlm.nih.gov/pubmed/24052636
• The Effect of TNF-α Blocker HL036337 and Its Best Concentration to Inhibit Dry Eye Inflammation. Choi W et al, Korean J Ophthalmol. 2016 Aug;30(4):302-8. doi: 10.3341/kjo. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965606/
• Early BAFF receptor blockade mitigates murine Sjögren’s syndrome: Concomitant targeting of CXCL13 and the BAFF receptor prevents salivary hypofunction. Sharma A et al, Clin Immunol. 2016 Mar;164:85-94. doi: 10.1016/j.clim.2016.01.015. Epub 2016 Jan 28. https://www.ncbi.nlm.nih.gov/pubmed/26826598

Dry eye and TNF-alfa

• Pro-inflammatory cytokines associated with clinical severity of dry eye disease of patients with depression. Mrugacz M et al, Adv Med Sci. 2017 May 13;62(2):338-344. doi: 10.1016/j.advms.2017.03.003. https://www.ncbi.nlm.nih.gov/pubmed/28511072
• Determination of immune response and inflammation mediators in tears: Changes in dry eye and glaucoma as compared to healthy controls.  Benitez-Del-Castillo Sanchez J et al, Arch Soc Esp Oftalmol. 2017 May;92(5):210-217. doi: 10.1016/j.oftal.2016.12.009. Epub 2017 Feb 4. https://www.ncbi.nlm.nih.gov/pubmed/28169068
• Interleukin-1β and tumour necrosis factor-α levels in conjunctiava of diabetic patients with symptomatic moderate dry eye:case-control study. Zhang C et al, BMJ Open.2016 Aug 3;6(8): e010979. doi:10.1136/bmjopen-2015-010979 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985792/

We also know that PAF is directly involved in inflammatory and allergic reactions:

• Direct action of platelet activating factor (PAF) induces eosinophil accumulation and
  enhances expression of PAF receptors in conjunctivitis – Zinchuk O et al., Mol Vis. 2005 Feb 9;11:11423
  http://www.ncbi.nlm.nih.gov/pubmed/15735601

We know that PAF is activating also eosinophils and other cytokines:

• Human conjunctival epithelial cell responses to platelet activating factor (PAF): signal transduction and release of proinflammatory cytokines – Sharif NA et al., Mol Vis. 2009 Jun 6;15:115361.
  http://www.ncbi.nlm.nih.gov/pubmed/19513187

Various form of arthritis and osteoarthritis:

The following articles show the strong relationship between  nutritional habit and the induction and maintenance of arthritis:

• BAFF and its receptors involved in the inflammation progress in adjuvant-induced arthritis rats – Wei F et al., Int Immunopharmacol. 2016 Feb;31:18. doi: 10.1016/j.intimp.2015.12.007. Epub 2015 Dec 11, http://www.ncbi.nlm.nih.gov/pubmed/26688104
• The role of BAFF in the progression of rheumatoid arthritis – Wei F et al., Cytokine.
  2015 Dec;76(2):53744. doi: 10.1016/j.cyto.2015.07.014. Epub 2015 Jul 18,
  http://www.ncbi.nlm.nih.gov/pubmed/26198030
• General or personal diet: the individualized model for diet challenges in patients with rheumatoid arthritis. Karatay S. et al.  Rheumatol Int. 2006 Apr;26(6):556-60. Epub 2005 Jul 16 http://www.ncbi.nlm.nih.gov/pubmed/16025333
• Adipokines: novel players in rheumatic diseases. Conde J et al., Discov Med. 2013 Feb;15(81):7383 http://www.ncbi.nlm.nih.gov/pubmed/23449109
• Adipokines as emerging mediators of immune response and inflammation. Lago F et al., Nat Clin Pract Rheumatol. 2007 Dec 3(12):716-24 http://www.ncbi.nlm.nih.gov/pubmed/18037931
• Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies. Krystufkovà O et al., Ann Rheum Dis. 2009 Jun;68(6):836-43 http://ard.bmj.com/content/68/6/836.abstract
• A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Bombardieri M et al., Ann Rheum Dis. 2011 Oct;70(10):1857-65. Epub 2011 Jul 27 http://www.ncbi.nlm.nih.gov/pubmed/21798884